The Reactivity of Enantiopure (S)-6-Oxopipecolic Acid and Corresponding Pyridoisoquinolines Under Acidic Conditions

Article abstract of DOI:10.1002/ejoc.201800908

Enantiopure N-benzyl 6-oxopipecolic acid, obtained from (S)-2-aminoadipic acid, was evaluated under π-cationic cyclization conditions. If the combination of SOCl₂/AlCl₃ seems to be superior in terms of the reaction yields, use of PPA

Full text of DOI:10.1002/ejoc.201800908

A Journal of
Accepted Article
Title: Study on the reactivity of enantiopure (S)-6-oxopipecolic acid and
corresponding pyridoisoquinolines under acid conditions
Authors: Peter Šafář, Štefan Marchalín, Barbora Balónová, Michal
Šoral, Ján Moncol, Alina Ghinet, Benoît Rigo, and Adam
Daïch
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.201800908
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800908
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201800908
FULL PAPER
Study on the reactivity of enantiopure (S)-6-oxopipecolic acid and
corresponding pyridoisoquinolines under acid conditions
[
a]
[a,b]
[c]
[d]
[e]
Peter Šafář, Štefan Marchalín,*
Barbora Balónová, Michal Šoral, Ján Moncol, Alina
[f,g,h]
[f,g]
,‡[b]
Ghinet,
Benoît Rigo,
and Adam Daïch*
Dedication ((optional))
Abstract: Enantiopure N-benzyl 6-oxopipecolic acid, obtained from
S)-2-aminoadipic acid, was evaluated under -cationic cyclization
conditions. If the combination of SOCl /AlCl seems to be superior in
terms of the reaction yields, use of PPA, (CF CO) O/BF .Et O, and
antitumor, immunomodulator agents as well as glycosidase
[2]
(
inhibitors.
Of particular interest are indolizidines and
2
3
quinolizidines fused to -aromatic nucleus, represented by the
popular plant metabolites, belonging to the phenanthro-
indolizidine and phenanthroquinolizidine, classes of alkaloids
(Figure 1). More importantly, phenanthroquinolizidines despite
their lower natural occurrence compared to corresponding
phenanthroindolizidines exhibit very interesting biological
properties. Thus, in addition to their strong activities as anti-
inflammatory, antitumor and cytotoxic agents at low, i.e.
submicromolar concentrations against different cancer cell lines,
some of them including particularly both enantiomers of the
same product (7-methoxycryptopleurine for example), have
shown important antiviral activity against tobacco mosaic virus
3
2
3
2
Eaton’s reagent is also very interesting since in addition to the
expected keto-lactam, reduced- and oxidized keto-lactam, enamides
3
and enamidones containing CF CO- residue are isolated.
Mechanisms leading to these products as well as the ones resulting
from their acidic treatment were proposed and discussed with the
help, in some cases, of univocal transformations and X-ray analysis.
Introduction
[
3]
(
TMV). Again a difference between R- and S-stereomers on
Heterocyclic systems constitute probably the largest and most
varied family of organic compounds. They occupy a privileged
position as pivotal sources for novel scaffolds with synthetic,
the activity was observed outlining the pivotal role of the
stereochemistry of the pyramidal nitrogen atom at the ring
junction as postulated before in many reports. Since
phenanthroquinolizidines are generally more potent compared to
phenanthroindolizidines, allied to their unique mode of action
unlike those of the marketed anticancer drugs, phenanthro-
quinolizidines have received recently intensive attention not only
[
1]
therapeutic and industrial ramifications. Octahydro-indolizine
and octahydro-quinolizine alkaloids commonly known as
indolizidines and quinolizidines, respectively, constitute a family
of 5,6- and 6,6-nitrogen-fused bicycloalkanes. The latter have
received considerable attention by virtue of their varied and
pharmaceutically useful biological actions as potential antiviral,
[4]
due to medicinal chemistry issues but also from the synthetic
[5]
point of view.
[
[
a] Dr. P. Šafář, Prof. Dr. Š. Marchalín
Department of Organic Chemistry, Faculty of Chemical and Food
Technology, Slovak University of Technology, SK-81237 Bratislava,
Slovakia; E-mail: stefan.marchalin@stuba.sk
b] Prof. Dr. Š. Marchalín, Prof. Dr. A. Daïch
Normandie Univ., UNILEHAVRE, FR 3038 CNRS, URCOM, 76600
Le Havre, France. EA 3221, INC3M CNRS-FR 3038, UFR ST, BP:
1
123, 25 rue Philipe Lebon, F-76063 Le Havre Cedex, France
‡
E-mail: adam.daich@univ-lehavre.fr; orcid.org/0000-0002-6942-0519
c] Dipl.-Ing. B. Balónová
[
[
[
University of Kent School of Physical Sciences, Ingram 307,
Canterbury, Kent, CT2 7NH, UK
d] Dr. M. Šoral
Central Laboratories, Faculty of Chemical and Food Technology,
Slovak University of Technology, SK-81237 Bratislava, Slovakia
e] Assoc. Prof. J. Moncol
Department of Inorganic Chemistry, Faculty of Chemical and Food
Technology, Slovak University of Technology, SK-81237 Bratislava,
Slovakia
[
[
[
f] Dr. A. Ghinet, Prof. Dr. B. Rigo
HEI, Yncréa Hauts-de-France, Laboratoire de Pharmacochimie, 13
rue de Toul, F-59046 Lille, France
g] Dr. A. Ghinet, Prof. Dr. B. Rigo
INSERM, U995-LIRIC, CHRU de Lille, Faculté de Médecine-Pôle
Recherche Université Lille, 2 Place Verdun, F-59045 Lille, France
h] Dr. A. Ghinet
Alexandru Ioan Cuza’ University of Iasi, Faculty of Chemistry,
Bd. Carol I nr. 11, 700506 Iasi, Romania
Supporting information for this article is given via a link at the end of
the document. See DOI: 10.1039/x0xx00000x
Figure 1. Representative phenanthroindolizidine and phenanthroquinolizidine
alkaloids and their synthetic analogues 1-3.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800908
FULL PAPER
The simple aromatic analogues of these phenanthro-
quinolizidines were however very scarce and only few examples
of advanced intermediates for the synthesis of chiral aromatic -
hydride transfer during acid treatment. The chemistry of δ-
lactam containing acid has been, for its part, much less studied
since only the results of the behavior of N-arylmethyl piperidone-
[
6]
[24]
amino-acids and a natural potent antitumor Saframycin-A were
6-carboxylic acid under acid conditions in benzene series and
[
7]
[25]
reported. On our part, we have been strongly involved for
thiophene
series were reported, however with different
decades in the elaboration of novel indolizidines 4 (n=1) and
quinolizidines 5 (n=2) fused to aromatic or heteroaromatic
reactivity profile. Because the importance of the exposed
[
8]
[9]
[26]
scaffolds, γ-lactams and δ-lactams containing heterocycle for
[27]
nuclei and the study of their reactivity to obtain divers
compounds with biological profiles as farnesyltransferase
pharmaceutical and agrochemical industry,
we describe
herein our finding on the reactivity of enantiopure (S)-1-benzyl-6-
oxopipecolic acid (8) and corresponding tricyclic ketone 9. This
fits perfectly in our previous work on γ-lactams starting from (S)-
[
10]
[11]
[12]
(
FTase),
tubulin and glycosidase inhibitors. During these
investigations, enantiopure, abundant and cost-effective
glutamic acid (or pyroglutamic acid; PGA) and 2-aminoadipic
acid were used as starting materials both as a nitrogen atom
source and a chiral pool (Figure 2).
[
8]
1-benzyl pyroglutamic acid (6) and ketone 7 (Figure 2). Some
aspects of the reactivity of these δ-lactams containing an acid or
ketone function will be taken in consideration, relying both on
chemical and spectroscopic investigations, including X-ray
crystallographic analysis, and when possible, on the most
plausible reaction mechanism
Results and Discussion
Our work was initiated by considering first the behavior of N-
benzyl piperidone-6-carboxylic acid (8). Although this compound
[
28]
has already been described in a patent, we have described it
recently through an easy three-step synthesis in very good
yields as highlighted in Scheme 1. This comprises reductive
amination of benzaldehyde by mixing commercially available
(
S)-2-aminoadipic acid and benzaldehyde in aqueous alkaline
media (2M NaOH), followed by borohydride reduction of the
imine A, intramolecular peptide coupling of the resulting (S)-N-
[24c]
benzyl aminoadipic acid (10)
followed finally by the reflux of
the dicarboxylic acid 10 in ethanol and water. We then turned
our attention to intramolecular Friedel-Crafts acylation of the
acid 8. We have found that, contrary to the (S)-N-thienylmethyl
Figure 2. Retrosynthetic scheme leading to phenanthroindolizidine and
phenanthroquinolizidine aromatic analogues 7 and 9 starting from natural
carboxylic acids such as (S)-glutamic acid and (S)-2-aminoadipic acid.
[25]
pipecolic acids, with (S)-N-benzyl 6-oxopipecolic acid (8), the
best results were obtained with SOCl and AlCl (Method A),
giving the expected ketone 9 in good yield (71%). Under these
conditions, the AlCl -catalyzed cyclization reaction of the non-
isolated acid chloride B needs only fifteen minutes of time. The
2
3
Elsewhere, the influence of the ring size of saturated
compounds on their reactivity and properties is of prime
3
[13]
1
1
1
13
importance to synthetic chemists. In the lactam series too, this
obtained ketone 9 was properly characterized by H- H, H- C,
[
14]
[15]
1
15
13
13
was observed for alkylation,
hydrolysis
and silylation
H- N and even
C- C NMR correlation methods, thus
[16]
[17]
reactions,
polymerization ability.
reactions with Bredereck’s reagent
or
explicitly proving its structure.
[
18]
Moreover, it was postulated that exo-
cyclic double bonds stabilize 5-membered rings but destabilize
[
19]
[20]
6
-membered ones.
This impact of the ring size of lactams
[
21]
could be associated with the relative order of basicity
and
electron donor capacity; the 6-membered ring being the
strongest electron donor while 5- and 7-membered ring shown
[
22]
very similar properties.
However, in some three component
reactions involving stabilization of exocyclic N-acyliminium salts,
pyrrolidinone leads to good results while lactams possessing 6-,
[23]
7- and 12-carbons in the nucleus do not react.
We are strongly implicated in γ- and δ-lactams reactivity and in
that context we have found that an important part of the
chemistry of N-benzyl pyroglutamic acid (γ-lactams), and
corresponding ketone obtained after Friedel-Crafts cyclization, is
governed by the formation of N-acyliminium salts followed by a
Scheme 1. Synthesis of enantiopure tricyclic ketone 9 from (S)-2-aminoadipic
acid under Friedel-Crafts reaction using SOCl /AlCl .
2 3
[
24c]
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800908
FULL PAPER
It is worth mentioning that these cyclization conditions are
effective in producing thieno-(or furo) indolizidindiones,
corresponding ketones are not susceptible for transformations to
[
9a,d,e]
thieno analogues of dienone 11, owing to their higher stability in
[
9f,g]
[25]
benzothienoindolizidindiones
quinolizidindiones.
as well as phenanthro-
In addition, the best yields of the
cyclization were obtained when the reaction time was very short
15 minutes), its prolongation leading to drastic decreases of
acidic reaction conditions.
[
24a,b]
(
reaction yields (e.g., 20% after 2 hours) due to the rapid
decomposition of materials. However, this is reminiscent of the
formation of many by-products observed during the cyclization of
N-arylmethyl pyroglutamic acids of type 6, studies that led to
new interesting enantiopure fused indolizidindiones analogues of
[
8a,e,f, 29-33]
7
(Scheme 1).
In the light of these observations, we were interested to
enlarge the scope of the -cationic cyclization of (S)-N-benzyl
aminoadipic acid (8). Here we consider other conditions we
[
8f,29]
explored before in pyrrolidinone series
and unique
Among them,
.Et O (Method
2
[
25]
piperidinone containing a thiophene nucleus.
we envisioned to use PPA (Method B), TFAA/BF
3
C) and Eaton’s reagent (Method D). This in order to compare the
results with those obtained in fused γ-lactam series starting from
N-substituted (S)-pyroglutamic acids hoping to gain some
insights in this cyclization process.
Thus, in neat PPA at 100-105 °C under conditions of the
Method B, carboxylic acid 8 provides the expected pyrido-
isoquinolindione 9, oxidized pyridoisoquinolone 11 and piperidin-
yldihydropyridinone 12, respectively, in 57%, 30% and 5.6%
yields (Scheme 2).
Scheme 3. Plausible mechanism of the formation of pyridoisoquinolinone 11
from ketone 9 (Part A) and diene 14 from 7 (Part B) in PPA.
The structure of pyridoisoquinoline 11 was confirmed by its
catalytic hydrogenation yielding in good yield (72%) the known
[
34]
rac-13 lactam,
which was identified without ambiguity by
[35]
single-crystal X-ray diffraction analysis (Figure 3).
Scheme 2. Reaction of carboxylic acid 8 under Friedel-Crafts conditions using
neat PPA (Method B).
The formation of oxidized pyridoisoquinolone 11 can be
explained by the transformation of the initially formed tricyclic
ketone
9 in the reaction medium (PPA). Our proposed
Figure 3. Stick drawing of (±)-2,3,11,11a-tetrahydro-1H-pyrido[1,2-b]isoquino-
lin-4(6H)-one (13).
mechanism (Scheme 3, Part A) is similar to the one proposed
by Rigo’s group
[31]
for the conversion of pyrroloisoquinolindione
7
to the corresponding pyrroloisoquinolinone 14 (Scheme 3,
Part B). However, in our case evidently the diene M is not the
ultimate product as observed in the N-benzylpyroglutamic series
As shown in Scheme 4, the formation of the bis-lactam 12 can
be explained by the formation of the acylium cation P under acid
conditions, followed by elimination of carbon monoxide CO and
deprotonation of the stable cyclic N-acyliminium intermediate Q.
Electrophilic substitution of the being formed enamide 15 with
the cyclic electrophile species Q afforded ultimately, via the N-
acyliminium species R, the product 12 as a racemate (Scheme
4). The structure of racemic 12 has been confirmed by an
(
product 14), due to its isomerization to the thermodynamically
more stable conjugated tricyclic dienone 11. Alternatively, when
the starting compound was ketone 9, we have obtained after
heating with PPA lactam 11 as the sole reaction product in good
yield (72% after crystallization). Previously, we have found that
in the case of N-thienylmethyl-6-oxopipecolic acids, the
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800908
FULL PAPER
1
15
expanded series of 2D NMR measurements (including H- N
As we can see, in this reaction the most favourable process
under these conditions starts with the decarbonylation of the
acylium cation P leading to the N-acyliminium species Q, which
provide similarly the enamide 15 and the bis-lactam derivative
1
3
13
HMBC and C- C INADEQUATE) and ultimately by single-
[36]
crystal X-ray diffraction (Figure 4).
12. The product 16 was formed by acylation of the enamide 15
with TFAA. Similarly, the course of this reaction was also
[25]
observed with the N-thienylmethyl-6-oxopipecolic acid.
Scheme 4. Proposed mechanism for the formation of bis-lactam product 12.
Scheme 5. The reaction of (S)-N-benzyl 6-oxopipecolic acid (8) with TFAA
and BF .Et O (Method C).
As planned above, another Method C consisting of the use of
3
2
the combination of TFAA and BF
3 2
.Et O to promote the Friedel-
[
29b]
Crafts cyclization of carboxylic acid
8
was attempted.
Interestingly, under these cyclization conditions, bis-lactam 12
and two piperidin-2-ones 15 and 16, respectively, in yields of
As we expected, all these pyridinone systems 12, 15 and 16
could be independently prepared univocally from easily available
-benzyl-6-hydroxypiperidin-2-one (18) as the precursor of N-
17% (12), 13% (15) and 5.6% (16), were obtained in addition to
1
the expected ketone 9 as the major product (Scheme 5).
acyliminium intermediate Q (Schemes 4 and 6). Along this line,
[
37]
the requisite 1-benzyl-6-hydroxypiperidin-2-one (18)
was
prepared in three steps starting from glutaric anhydride, by
chemoselective DIBAL-H reduction of N-benzyl glutarimide (17)
[
38]
as the key and earliest step of the sequence.
Next we tested
the reaction under acidic conditions with different reagents
enabling selective transformation of starting hydroxyl lactam 18
to lactams 12, 15 and 16. After careful checking of the reaction
conditions, we have found that depending on the temperature,
the use of TFA and TFAA, respectively, it afforded in good yields
lactam 15 as well as trifluoroacetyl derivative 16 as was reported.
The latter was generated by acylation of enamidone 15 acting as
nucleophile followed by deprotonation of the N-acyliminium
intermediate. For the preparation of bis-lactam 12, the reagent of
choice is PPA or Eaton´s reagent under heating (Scheme 6).
Figure 4. Stick drawing of (±)-1-benzyl-5-(1-benzyl-6-oxopiperidin-2-yl)-3,4-
dihydropyridin-2(1H)-one (12).
The elucidation of the structure of the trifluoroacetyl derivative
1
9
13
1
6 was hampered by intriguing F- C couplings observed in its
1
3
C
NMR spectrum. According to the signal assignments
4
obtained from basic 2D NMR methods two
J
CF coupling were
CF coupling constant between the CF
group’s fluorines and the carbon bearing the trifluoroacetyl group
3
observable whilst the
J
3
-
1
3
was of a far lower value than the C peak linewidth (0.4 Hz full
width at half maximum without apodization). The assignment
was supported by the correlations observed in H- N HMBC. To
unambiguously prove the connectivity within the structure, a C-
C INADEQUATE spectrum was acquired, proving the original
1
15
1
3
1
3
assumption about the signal assignment and securing the
Scheme 6. Preparation of lactams 12, 15 and 16 starting from hydroxyl lactam
18 via N-acyliminium chemistry.
expected structure of 16. It should be noted that the complete
1
3
13
C- C correlation appeared in the INADEQUATE spectrum,
1
9
13
despite the F- C interactions present within the molecule.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800908
FULL PAPER
In the ultimate attempt, we have tested Eaton’s reagent
For the sake of comparison, the results obtained for the -
cationic cyclization of (S)-N-benzyl 6-oxopipecolic acid (8) under
different acidic conditions have been summarized in Table 1.
(
P
2
O
5
3
/MeSO H: 1/10 w/w) at 90 °C according to the Method D
we had earlier used for -cationic cyclization of N-substituted
[
29b]
pyroglutamic acids.
Under these conditions, (S)-N-benzyl-6-
oxopipecolic acid (8) afforded, after 2 hours, a complex mixture
from which we were able to extract three products. The latter
were identified as the tricyclic lactams 9, 11 and 19, isolated in
yields of 17%, 9% and 49%, respectively (Scheme 7).
Table 1. Products from catalyzed cyclization of acid 8 (δ-lactams) compared
to the ones obtained from N-arylmethyl glutamic acid of type 6 (γ-lactams).
[
a]
[
b]
Acid
Lactam
Lactam Bis-lactam Enamide Enamidone Lactam
9
11
12
15
16
19
[
f]
Method A
71
no
no
no
15
no
12
no
no
no
no
no
no
nep
nep
nep
nep
6
no
no
no
no
no
no
17
no
[
c]
[e]
‘
’
65-78
no
21
no
no
no
9
Method B
26
no
57
[
c]
[g]
‘
’
-
Method C
13
17-33
no
[
c]
[e]
[e]
‘
’
30-70
no
Method D
49
nep
nep
[
c]
[g]
‘
’
no
no
-
[
a] The ratio of isolated products in %. [b] Method used: SOCl
2
/AlCl
3
(Method
A), PPA (Method B), TFFA/BF .Et O (Method C) and P /MeSO H (Method
D). [c] Results from (S)-N-arylmethyl glutamic acid (6). [d] Not expected
product: nep. [e] Many other by-products were isolated. [f] Not obtained: no.
3
2
2
O
5
3
Scheme 7. The reaction of (S)-N-benzyl 6-oxopipecolic acid (8) with Eaton’s
reagent (Method D).
[g] Only products of N-acyliminium cations trapping with aryl were obtained.
The formation of 19 takes place after protonation of ketone 9
and interfacial hydride transfer in acidic environment provided by
Eaton’s reagent. This compares well with results obtained both
in the pyrroloisoquinolinone 14 and in pyridoisoquinolinone 11
series when PPA was used as an activator (Scheme 3, Parts A
and B). Thus, it starts with ketone 9 protonation into the cation I
followed by hydride migration leading to the N-acyliminium salt S
and the alcohol 20 (Scheme 8). Alcohol 20 furnished the starting
ketone 9 by oxidation or enamide 21 by dehydration. The latter
intermediate afforded ultimately the tricyclic pyridone 11, after an
From the results summarized in Table 1, it appeared that the
treatment of N-substituted pyroglutamic acids of type
(pyrrolidinone series) with PPA (Method B) or TFAA/BF .Et
6
O
3
2
(Method C) often induced a decarbonylation process to generate
stable N-acyliminium salts. The latter in the absence of
nucleophiles, produces N-substituted 1H-pyrrol-2(5H)-ones
similar to the enamide 15 and/or their ancillary -hydroxy
lactams after hydrolysis in the reaction media. However, the
case of N-benzyl oxopiperidine carboxylic acid (8) is more
complex; depending on the exact conditions up to six different
products could be formed. Among those the expected ketone 9
can be isolated in 26 to 71% yields. To the best of our
knowledge, dimers comparable to 12 in pyrrolidinone series
were never reported neither from N-acyliminium salt generated
in situ nor from corresponding enamide obtained by its
[
31]
allylic oxidation and isomerization.
The keto-lactam 19 is
finally obtained by considering the unstable N-acyliminium
species S generated in the second step after its deprotonation
followed by a thermodynamically favorable oxidation via the
enamido-ketone T never isolated in the reaction media.
[
39]
dehydration.
Enaminocarbonyl lactam analogous to 16 were
[40]
for their part obtained only when starting from amino acrylates
[
41]
or from oxidation of N-benzyl azepinones. On the other hand,
the reaction of the nucleophilic enamide 15 with TFAA leads to
the trifluoroacetyl ketone 16 (Method C). Related reactions were
already observed when chlorosulfonyl isocyanate was opposed
to dihydropyridone 15 as partner
methyl tetrahydropyridone series.
[
42]
as well as in the N-thienyl-
[
25]
Importantly, these results confirm again the high impact of the
ring size of saturated aza-compounds on the course of the -
cationic cyclization and the relative stability of the tricyclic
systems towards the reaction conditions.
Having evoked constantly the hydride transfer and oxidation
processes in the various proposed mechanisms (Schemes 3
and 8), we next decided to examine the truthfulness of these
suggestions. Thus for the confirmation of the essential
participation of oxidation process (by air oxygen) in the last step
of transformation of carboxylic acid 8 and corresponding ketone
9
into tricyclic keto-pyridone 19 in a domino process, we have
Scheme 8. Plausible mechanism of the formation of pyridoisoquinolinone 11
from ketone 9 when treated with Eaton’s reagent.
carried out these reactions in the presence of oxygen (see
Scheme 9).
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800908
FULL PAPER
Scheme 9. Transformation of N-benzyl 6-oxopipecolic acid (8) and ketone 9
into pyridoisoquinoline 19 under oxidative conditions.
Figure 6. Stick drawing of racemic methyl 4-(4-oxo-1,2,3,4-tetrahydroiso-
quinolin-3-yl)butanoate (23A).
We were delighted to see that these reactions conditions
modified Method D) in both cases were clean and provided the
(
expected 4H-pyrido[1,2-b]isoquinoline-4,11(6H)-dione (19) as
the sole domino product in good yields of 76% and 72%,
respectively, when starting from 8 and 9. Alternatively, we
noticed that all attempts to aromatize ketone 9 into keto-
pyridone 19 by heating with freshly crystallized DDQ in boiling
As shown in Scheme 10, the hydrolysis of the tricyclic lactam 9
in acidic media leads to the formation of two compounds
identified to be the tricyclic pyridone 11 and the novel and
racemic amino-acid 22 in different ratios depending on the HCl
solution concentration. Because the acid 22 could not be
sufficiently purified, for better characterization it was converted
to the corresponding methyl ester 23 (e.g., AcCl, MeOH, r.t., 14
h; 74%), which was purified by crystallization from dry methanol.
The structure of 23 was ultimately established by X-ray
[
37]
benzene or toluene were unsuccessful.
Finally, the structure
of product 19 was confirmed by single-crystal X-ray diffraction
[
43]
analysis (Figure 5).
[
44]
crystallographic analysis (Figure 6)
confirming that both
isoquinolines 22 and 23 are racemic. This owes to the easy
racemization of the initially formed aminoketo-acid (S)-4-(4-oxo-
1,2,3,4-tetrahydroisoquinolin-3-yl)butanoic acid (23A) in acidic
medium via the enol form 23B (Scheme 10).
The physicochemical and spectral data of the product 11
obtained here by a domino process, consisting on reduction
→
dehydration→oxidation→isomerization, are in full agreement
Figure 5. Stick drawing of 4H-pyrido[1,2-b]isoquinoline-4,11(6H)-dione (19).
with the derivative, prepared by reaction of ketone 4 with PPA
(
Method B, Scheme 2). In addition its structure was established
[45]
by an X-ray crystallographic analysis (Figure 7).
[31]
Based on our previous reports
outlining an intermolecular
shift in the transformation of pyrrolo[1,2-b]isoquinoline-3,10-
dione (7) into 3-(4-hydroxy-3-isoquinolinyl)propanoic acid with
concentrated hydrochloric acid solutions, treatment of tricyclic
ketone 9 with different HCl solutions was intended (Scheme 10).
Figure 7. Stick drawing of 6,11-dihydro-4H-pyrido[1,2-b]isoquinolin-4-one (11).
We then continued to explore mechanistic considerations in
connection with the reaction mechanisms proposed in Schemes
3
and 8 because of the wish to enhance our knowledge about
these transformations. In this perspective, the synthesis and
reactivity of alcohol 20 and enamide 21 as advanced
intermediates for the production of tricyclic systems 11 and 19
as ultimate products in certain acid-catalyzed Friedel-Crafts
cyclization was envisioned.
Scheme 10. Hydrolysis of ketone 9 in hydrochloric acid conditions.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800908
FULL PAPER
All independent reactions given are in perfect agreement with
the mechanism proposed for the formation of the tricyclic system
1
1 in Scheme 8 as reproduced in Scheme 12. Thus, alcohol 20
was generated in situ by a hydride migration followed by proton
displacement accompanied by the N-acyliminium salt
Scheme 8). Protonation of 20, the dehydration of the formed
S
(
intermediate V and the following deprotonation of W provides
the enamide 21. In the latter, the hydrogen in allylic position is
acidic enough to enable its isomerization into enamide Y (never
isolated from the reaction media) by protonation/deprotonation
of the N-acyliminium species X. The tricyclic system 11
stabilized by the semi-aromatic pyridinium form Z was obtained
2
ultimately by oxidation (air, O ).
These results demonstrate the efficacy of the treatment of
tricyclic enamide 21 with a hydrochloric acid solution (12M)
leading to the formation of tricyclic pyridone 11 via a domino
allylic oxidation/ isomerization (Eq. (b), Schemes 12, 13). In this
context the behavior of alcohol 20 under same acid conditions
was considered. Thus, the reaction of 20 at 100 °C for 16 h
Scheme 11. Short pathways leading to tricyclic pyridone 11.
As highlighted in Scheme 11 three reactions were realized.
The reaction of an equimolar mixture of ketone 9 and the
corresponding pure trans-diastereomer of alcohol 20, obtained
(
Scheme 13) provided interestingly a separable mixture of the
acid hydrochloride 22 and the tetrahydrophenanthridin-1(2H)-
one (24) in yields of 9% and 87%, respectively.
by diastereoselective reduction of 9 (e.g., NaBH
4
, MeOH, 0–
[
35a]
5
°C; 73.5%)
with 12.2M HCl resulted in the formation of
tricyclic pyridone 11 in quantitative yield (Eq. (a)). This clearly
implies the generation of alcohol 20 from the ketone in the
reaction media by the protonation of ketone 9 followed by
intermolecular hydride transfer evoked in the beginning of the
proposed reaction mechanism (Schemes 3 and 8). In the same
line, the treatment of tricyclic enamide 21 with hydrochloric acid
(
12M) or hydrobromic acid (8.9M) solution resulted in the
formation of the expected tricyclic pyridone 11 in 82% and 72%
yields, respectively (Eq. (b)). This reaction indicates that allylic
oxidation of enamide 21 followed by dienic isomerization
occurred along with the formation of pyridone 11 from carboxylic
acid 8 or ketone 9. We then anticipated that the treatment of
alcohol 20 with Eaton’s reagent (e.g., Eaton’s reagent, 80 °C, 1
h) would allow the formation of the expected tricyclic system 11.
Again the product 11 was obtained in 100% then 56% yield (Eq.
(
c)) demonstrating the pivotal role of alcohol 20 as proposed in
the reaction mechanisms above.
Scheme 13. Treatment of enantiopure alcohol 20 with 12M hydrochloric acid
solution under same conditions as for the tricyclic ketone 9.
Further post oxidation of tetrahydrophenanthridin-1(2H)-one
(
24) under two different conditions were realized and lead to the
formation, in exactly the same yield of 87%, of the known 3,4-
dihydrophenanthridin-1(2H)-one (25). The latter was previously
obtained in a domino process consisting in a CuI-catalyzed
coupling (2-bromophenyl)methanamine (27) and cyclohexane-
[
46]
1,3-dione (28) followed by spontaneous oxidation.
Since the
characterization of 25 in its first report was not complete, the
structure of this product was then established by X-ray
[
47]
crystallographic analysis among others (Figure 8).
Similarly,
Scheme 12. Plausible mechanism of the formation of 21 and 11 starting from
the tricyclic ketone 9 in hydrochloric acid conditions via the alcohol 20.
the oxidation of the minor product, acid hydrochloride 22, by
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800908
FULL PAPER
using oxygen as oxidant (Scheme 13) resulted in the formation
of 4-(4-hydroxyisoquinol-in-3-yl)-butanoic acid (26B) as the
thermodynamically stable product via the imine-one 26A (71%
yield).
As for the formation of 3,4-dihydrophenanthridin-1(2H)-one
(25), it can be explained by the possible mechanism highlighted
in Scheme 14. Thus, starting alcohol 20, under acid conditions
(HCl 12M), undergoes the tricyclic enone 21 formation via the
intermediacy of protonated species V (Schemes 3, 8). Product
21 after protonation with HCl furnish the stable N-acyliminium
cation X which would cleave into the acylium intermediate AA.
The latter imine in equilibrium with enamine AB by isomerization
can lead to the cyclized product 25 after -cationic cyclization
into AC, its deprotonation into enamino-ketone 24 followed
ultimately by air oxidation. In our case, we were able to isolate
the fused enaminone 24 as the major reaction product in 87%
yield (Scheme 13).
Figure 8. Stick plot of 3,4-dihydro-phenanthridin-1(2H)-one (24).
Conclusions
In summary, we reported here the treatment of (S)-N-benzyl 6-
oxopiperidine carboxylic acid (δ-lactam) (8) under various
Friedel-Crafts conditions - a process richer and more complex
than reported for the corresponding (S)-N-substituted
pyroglutamic acids (γ-lactams) earlier. In short, we have shown
that the standard protocol using Method A (SOCl /AlCl ) is
2 3
superior in terms of yields of the expected tricyclic keto-lactam.
On the other hand, approaches using PPA (Method B),
Mechanistically speaking (Scheme 14), the co-formation of the
acid hydrochloride 22 (isolated in only 9% yield) supposes the
transformation of the alcohol 20 into the corresponding ketone 9.
This is made possible by the presence air oxygen in the reaction
medium. The oxidation is then followed by the lactam cleavage
activated by hydrochloride acid via the intermediate D as
mentioned in aromatic and heteroaromatic fused indolizine
[
8a,9h,31b,33a,48]
series.
This fact is also confirmed by the obtained
(
3 2 3 2
CF CO) O/BF .Et O (Method C) and Eaton’s reagent (Method
result when the ketone 9 is directly treated with an hydrochloric
acid solution. Under these conditions the reaction provides to
same product 22 with 86% yield in the best case (Scheme 10).
D) are also very interesting since parallel to the expected keto-
lactam (26-71% yields), other keto-lactams, uncyclized enamide
monomers and dimers as well as enamidones containing a
3
CF CO fragment in certain cases are isolated generally in good
overall yields.
From these results, it appears that the use of Methods B and
C often induces a decarbonylation process to generate stable N-
acyliminium salts in addition to the acylium cation. The Method
A provides only the ketone 9 (the Friedel-Crafts product) in
contrary to carboxylic acids in γ-lactams which furnished in
addition to the -cationic cyclization compounds many other by
products. To the best of our knowledge, dimers in γ-lactams
series were never reported either from N-acyliminium salt
generated in situ or from corresponding enamide obtained by its
dehydration, contrary to the results reported in this paper dealing
with δ-lactams derivatives (Methods B, C). On the other side,
reaction of the nucleophilic uncyclised enamide with TFAA leads
to the trifluoroacetyl ketone (Method C). If similar behaviour was
never observed in δ-lactams series, a related reaction has
already been observed in the N-thienylmethyl tetrahydro-
pyridone series reported by our group.
The use of Method D demonstrates the formation of keto-
lactam via the acylium species accompanied by interesting
events, namely the protonation of ketone 9, followed by an
interfacial hydride transfer and oxidation. These events were
observed also with other methodologies used herein and in the
case of the γ-lactams series. These phenomena were proved by
independent reactions driven from tricyclic ketone alone or
mixed with corresponding alcohol in the presence of air/oxygen
or not. In this context, treatment of tricyclic alcohol with HCl
resulted not only in the cleaved amino-keto-acid product which
Scheme 14. Plausible mechanism of the formation of carboxylic acid 22,
ketones 24 and 25 starting from the tricyclic alcohol 20 under hydrochloric acid
conditions.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800908
FULL PAPER
re-aromatize spontaneously to functioned isoquinoline but also
to original tetrahydrophenanthridin-1(2H)-one (24) and
corresponding 3,4-dihydrophenanthridin-1(2H)-one (25).
Finally, these results confirm once again the high impact of the
ring size of saturated aza-compounds on the course of the -
cationic cyclization. They confirm also the relative stability of the
tricyclic systems in δ-lactams series compared to the ones in γ-
lactams towards the acidic reaction conditions.
(39.52 ppm) and CD
Depending on the possibilities and amount of information needed to
3
OD (49.00 ppm) were used as references.
1
13
provide the best possible structural proof H, standard C, quantitative
1
3
13
15
1
C, C-attached proton test, N with inverse gated H decoupling, and
19
1
1
F NMR measurements were underdone, supported by H- H COSY
(
with gradient coherence selection and with/without zero quantum
1
13
filtering), H- C HSQC (with varied use of gradient coherence selection,
13
adiabatic 180 ° pulses on the C channel and non-uniform sampling),
1
13
H- C HMBC (with gradient coherence selection and varied use of
1
3
13
adiabatic 180 ° pulses on the C channel and semi-selective
excitation with WURST2i
C
[
52]
13
13
pulses), C- C INADEQUATE (with an
adiabatic 180 ° pulse for compound 12 and with a universal 180 ° rotation
Experimental Section
[
53]
[54]
pulse
and H-
for compounds 9 and 16 ), f2-coupled Perfect CLIP-HSQC
N HMBC (with gradient coherence selection) spectra.
1
15
Crystallography: Data collection and cell refinement for 11, 12, 13, 19,
Experimental and processing parameters, together with raw NMR data
are available on demand from the authors. For the precise extraction of
chemical shift and J-coupling values manual spin simulation was
performed if needed in the spin simulation package built in the
MestReNova software (version 11.0.2-18153). The elemental analyses
were carried out by the microanalysis laboratory of IRCOF, F-76130 Mt.
St. Aignan, France or carbon, nitrogen, hydrogen and sulfur content was
determined by elemental analysis, using an analyser Vario Macro Cube.
High-resolution spectrometry was performed on Micromass Q-Tof Micro
2
3A and 24 were carried out using diffractometer Stoe StadiVari using
Pilatus3 R 300K detector at 100 K, and using CuKα radiation (λ =
.54186 Å, microfocus source Xenocs Genix3D Cu HF) The structures
1
[
49]
[50]
were solved using program SHELXT or SuperFlip, and refined by a
full-matrix least-squares procedure with the SHELXL (ver. 2018/3),
and drawn with the OLEX2 package.
been deposited with the Cambridge Crystallographic Data Centre (CCDC
nos° 1839259–1839264) for the products. Copies of the data can be
obtained free of charge at the following address: http://www.ccdc.cam
[
49]
[
51]
Full crystallographic data have
+
+
MS system with ESI ionization (measured mass represents M+Na ) and
LC-MS chromatographic separation was performed on Agilent 1260B LC-
MS system using HALO C18 column (2,1 × 50 mm, 5.0 μm particle size).
A 10 min gradient elution was performed at 1,5 mL/min flow rate as
General Remarks. Melting points were obtained using
a Boetius
apparatus and are corrected. Commercial reagents were used without
further purification. All solvents were distilled before use. Flash column
liquid chromatography (FLC) was performed on silica gel Kieselgel pore
size 60 Å (40–63 μm particle size, 230–400 mesh particle size) and
analytical thin-layer chromatography (TLC) was performed on aluminium
plates pre-coated with either 0.2 mm (DC-Alufolien, Merck) or 0.25 mm
silica gel 60 F254 (ALUGRAM-SIL G/UV254, Macherey-Nagel). The
compounds were visualized by UV fluorescence and by dipping the
following: maintain H O/MeOH with 0,1% formic acid from 5% to 100%.
2
MS detector used combined ionization (ESI + APCI) in positive mode,
50% scan and 50% SIM. All samples for analysis and NMR spectroscopy
were dried for 48 hours at Laboratory Freeze Dryer Alpha 2-4 LDplus
Lyophilizer.
(
S)-1,2,3,11a-Tetrahydro-4H-pyrido[1,2-b]isoquinoline-4,11(6H)-
dione (9). Method A: To a solution of a freshly crystallized carboxylic
acid 8 (23.33 g, 0.1 moL) in dry CH Cl (750 mL) was added thionyl
chloride (10.9 mL, 0.15 moL) at 0 °C. The mixture was stirred under
reflux for 4 h, and then cooled to -5 °C. Under vigorous stirring, dry AlCl
33.3 g, 0.25 moL) was added in small portions. The mixture was stirred
2 4
plates in an aqueous H SO solution of cerium sulphate/ammonium
molybdate followed by charring with a heat gun. HPLC analyses were
performed on Varian system 9012 with diode array Varian 9065
polychrom UV detector: column CC 250/3 Nucleosil 120-5 C18, 250x3
2
2
3
mm
(Macherey
Nagel).
Mobile
phase:
solvent
A:
(
water/acetonitrile/methanesulfonic acid (1000/25/1), solvent B:
water/acetonitrile/methanesulfonic acid (25/1000/1), elution mode:
gradient with 5-50% solvent B, flow rate: 0.65 ml/min, UV detection: 210
nm (DAD), 35 C, 20 min. GC-MS analyses were performed on GC MS
Varian Saturn 2100 T, ion trap MS detector, 70 eV. Column: Varian,
FactorFour capillary column VF -5ms 30mx0.25 mm ID, DF=0.25. Optical
for 15 min. at 0 °C, cold water (220 mL) was added carefully. The two
pure layers were separated and the aqueous layer was extracted twice
with CH
dried with MgSO
by flash column chromatography (400 g SiO
CH Cl /MeOH 50:1) to yield a light yellow solid. Recrystallization from
toluene/n-heptane (3:2) gave 9 (9.25 g, 71%) as light yellow crystals; mp:
05.4-109.4 °C. See the Supporting Information part for complete NMR
2
Cl
2
(50 mL). After washing with brine, the CH
and concentrated. The resulting product was purified
, 4 cm x 125 cm, CH Cl
2 2
Cl phase was
o
4
2
2
2
,
2
2
rotations were measured with
a POLAR L-lP polarimeter (IBZ
Messtechnik) with a water-jacketed 10.000 cm cell at the wavelength of
1
-
the sodium line D (λ = 589 nm). Specific rotations are given in units of 10
signal assignment.
1
2
-1
deg.cm .g and concentrations are given in g/100 mL. Infrared spectra
were recorded on a Nicolet 5700 FT-IR spectrometer as ATR discs
ATR) or as thin films on ATR plates (film). NMR spectra were recorded
on a VNMRS 600 NMR spectrometer (Varian) with operating frequencies
Method B: A mixture of freshly crystallized carboxylic acid 8 (1.75 g, 7.5
mmol) and freshly prepared PPA (45 g) was heated at 100 °C for 1 h.
(
The reaction mixture was cooled, neutralized with a saturated Na
solution and the aqueous layer was extracted with CH Cl (3 x 45 mL).
The combined extracts were washed with H O (3 x 30 mL), brine (30 mL)
and dried (Na SO ). Evaporation of the solvent afforded a dark-yellow oil
1.37 g) as a mixture of products 9, 11 and 12, which was separated and
purified by chromatography (30 mm x 120 cm, 100 g SiO , CH Cl
CH Cl /MeOH 250:1, CH Cl /MeOH 50:1) on a silica gel column. After
2 3
CO
1
19
13
5
99.76 MHz for H, 564.28 MHz for F, 150.82 MHz for C and 60.78
15
2
2
MHz for N nuclei. The spectrometer was equipped by an inverse triple
resonance probe and a standard double channel X/H tunable probe with
the possibility to tune the high frequency channel to the resonance
2
2
4
(
19
frequency of F. NMR spectra from all samples were measured in CDCl
-DMSO or CD OD at 25 °C. Chemical shifts (δ) are quoted in ppm; the
chemical shift axes were calculated using the reference signals of TMS
3
,
2
2
2
,
d
6
3
2
2
2
2
chromatography we isolated (S)-1,2,3,11a-tetrahydro-4H-pyrido[1,2-b]-
isoquinoline-4,11(6H)-dione (9) as a light yellow solid in 26% yield (421
mg), 6,11-dihydro-4H-pyrido[1,2-b]isoquinolin-4-one (11) as light yellow
crystals in 21% yield (305 mg) and finally 1-benzyl-5-(1-benzyl-6-
oxopiperidin-2-yl)-3,4-dihydropyridin-2(1H)-one (12) as light yellow
crystals in 15% yield (210 mg).
1
13
19
15
(
3 3 2
for H and C NMR), CFCl (for F NMR) and CH NO (for N NMR).
These axes were shifted using an automatic re-calculation system
2
exploiting the H signal of the used solvent; for the precise correction of
1
13
the chemical shift axes, the H and C signals of TMS (present in
1
spectra obtained in CDCl
3
; 0.000 ppm), H signals of residual d
5
-DMSO
-DMSO
13
(
2.50 ppm) and CD HOD (3.31 ppm), and the C signals of d
2
6
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800908
FULL PAPER
Method C: A stirred mixture of freshly crystallized acid 8 (1.17 g, 5
mmol) and trifluoroacetic anhydride (TFAA, 1.26 mL, 10 mmol) in dry 1,2-
dichloroethane (50 mL) was heated at 45 °C for 45 min., then cooled with
dried. Evaporation afforded
chromatography (20 mm x 70 cm, 55 g SiO , CH Cl , CH Cl /methanol
2 2 2 2 2
100:1) on a silica gel column – the procedure afforded dimer 12 (532 mg,
a
yellow oil, which was purified by
an ice bath and boron trifluoride etherate (BF
was added. After stirring at 60 °C for 18 h under nitrogen atmosphere
solvents were evaporated, then a saturated solution of K CO in water
150 mL) was added and the mixture was stirred at room temperature for
min. The aqueous phase was extracted with CH Cl (3 x 50 mL); the
organic phase was washed with water and dried (Na SO ). Evaporation
of the solution afforded a yellow oil (1.02 g) as a mixture of 9, 12, 15 and
6, which was purified by slow chromatography (30 mm x 120 cm, 100 g
SiO , CH Cl , CH Cl /MeOH 600:1, CH Cl /MeOH 400:1, CH Cl /MeOH
00:1, CH Cl /MeOH 30:1) on a silica gel column. After chromatography
the products were identified to be (S)-1,2,3,11a-tetrahydro-4H-pyrido
1,2-b]isoquinoline-4,11 (6H) dione (9) as yellow crystals in 57% yield
615 mg), 1-benzyl-5-(1-benzyl-6-oxopiperidin-2-yl)-3,4-dihydropyridin-
(1H)-one (12) as yellow crystals in 17% yield (154 mg), 1-benzyl-3,4-
3
.Et
2
O, 5.7 mL, 46 mmol)
71% yield) as a light yellow oil which slowly solidifies. Crystallization from
f
dry n-heptane provide pure 12 (480 mg, 64 %), mp 108.1-109.8 °C. R =
-
1
2
3
2 2
0.47 (CH Cl /i-PrOH; 10:1), IR ( ,ꢀ cm , ATR): 3028, 2945, 1668, 1634,
(
5
1495, 1438, 1400, 1379, 1358, 1325, 1298, 1270, 1182, 1146, 1072,
2
2
1027, 989, 944, 862, 850, 728, 696, 655, 607, 496, 459. HRMS: (ESI)
+
2
4
Calculated for C24H N O
26 2 2
(374.48) [M+Na] : 397.1886, found 397.1882.
See the Supporting Information part for complete NMR signal assignment.
1
2
2
2
2
2
2
2
2
2
(
(
R,S)-1,2,3,6,11,11a-Hexahydro-4H-pyrido[1,2-b]isoquinolin-4-one
rac-13). 10% Pd-C (60 mg) was added to a solution of freshly
1
2
2
crystalized 6,11-dihydro-4H-pyrido[1,2-b]isoquinolin-4-one (11) (394.0
mg, 2.0 mmol) in dry methanol (25 mL). The solution was stirred for 6 h
under a pressure of hydrogen at 203 kPa (TLC monitoring). After
completion, the solution was filtered through a Celite pad to remove the
catalyst and concentrated in vacuo. The crude product (390 mg) was
[
(
2
dihydropyridin-2(1H)-one (15) as colorless crystals in 13% yield (121 mg)
and finally 1-benzyl-5-(2,2,2-trifluoroacetyl)-3,4-dihydropyridin-2(1H)-one
chromatographed on silica gel (20 mm x 75 cm, 80 g SiO
2
, eluent:
(
16) as a colorless oil in 5.6% yield (79 mg).
CH Cl /methanol 50:1) to afford pure rac-13 (338 mg, 84% yield) as a
2
2
colorless oil, which quickly crystallized on standing. After crystallization
Method D: A mixture of freshly prepared carboxylic acid 8 (2.33 g, 10
mmol) and Eaton’s reagent (P /CH SO H/1/10 w/w) (25 mL) was
heated at 90 °C for 1 h. The reaction mixture was cooled and ice (20 g)
and water (80 mL) were added carefully. The aqueous phase was
from i-hexane, the product rac-13 was obtained as colorless crystals (298
O
2 5
3
3
mg, 74% yield); m.p. 80.6-81.3 °C. R
HRMS: (ESI) Calculated for C13 15NO (201.27) [M+Na] : 224.1046,
found 224.1043. Spectral data of 13 was consistent with data reported in
f
= 0.19 (AcOEt/i-hexane 3:1).
+
H
[
34b]
extracted with CH
diluted with AcOEt (200 mL), washed with saturated Na
O (30 mL), brine (20 mL), dried (Na SO ) and evaporated under
reduced pressure to give crude yellow semi-crystalline solid (2.88 g)
which was purified by chromatography (30 mm x 120 cm, 120 g SiO
CH Cl , CH Cl /MeOH 200:1, CH Cl /MeOH 100:1, CH Cl /MeOH 30:1
2
Cl
2
(3 x 20 mL). The combined organic extracts were
the literature.
2
CO (50 mL),
3
[
37]
H
2
2
4
1
-Benzyl-3,4-dihydropyridin-2(1H)-one (15). Hydroxy-amide 18 (411
mg, 2 mmol) was added to trifluoroacetic acid (TFA, 10 mL) at room
temperature. The solution was stirred at room temperature for 6 h,
2
,
2
2
2
2
2
2
2
2
solvent was evaporated and the residue was dissolved in CH
solution was extracted with aqueous sodium bicarbonate, aqueous
phases were washed with CH Cl again. CH Cl and the organic phases
were dried (sodium sulfate) then evaporated giving a yellow oil which
was purified by chromatography (20 mm x 70 cm, 80 g SiO , CH Cl
CH Cl /methanol 250:1) on a silica gel column – the procedure afforded
2 2
Cl . The
as eluent) on a silica gel column. The chromatography purification
provided 358 mg (17% yield) of (S)-1,2,3,11a-tetrahydro-4H-pyrido
2
2
2
2
[
1,2-b]isoquinoline-4,11(6H)-dione (9), 177 mg (9% yield) of 6,11-
dihydro-4H-pyrido[1,2-b]isoquinolin-4-one (11) and ultimately 1.01
g
2
2
2
,
(
49% yield) of 4H-pyrido[1,2-b]isoquinoline-4,11(6H)-dione (19).
2
2
olefin 15 (318 mg, 85%) as a colorless oil, which slowly crystallized on
standing. Recrystallization from n-pentane gave olefin 15 (266 mg, 71%
6
9
,11-Dihydro-4H-pyrido[1,2-b]isoquinolin-4-one (11). The keto-amide
(1.08 g, 5 mmol) was added to PPA (15 g) at 80 °C and the mixture
[
38]
yield) as colorless crystals; mp 41.6-42.3 °C (reported as colorless oil)
.
was then heated at 110 °C for 2 h in an argon atmosphere (TLC
monitoring). After cooling to room temperature, 20 ml of cold water was
added and the mixture was neutralized slowly with a saturated solution of
R
f
= 0.68 (CH Cl /i-PrOH; 10:1). HRMS: (ESI) Calculated for C12H13NO
2
2
+
(187.24) [M+Na] : 210.0889, found 210.0886. See the Supporting
Information for NMR signal assignment. Spectral data of 15 were
consistent with data reported in the literature.
[
38]
Na
combined organic layers were dried, concentrated and the resulting dark-
red oil (1.0 g) was purified by column chromatography (80 g SiO , 25 mm
x 75 cm, CH Cl , CH Cl /MeOH, 50:1) to give diene-lactam 11 (889 mg,
0% yield) as a light yellow oil, which crystallizes when standing on air
2
CO
3
. The aqueous layer was extracted with AcOEt (3 x 60 mL), the
2
1-Benzyl-5-(2,2,2-trifluoroacetyl)-3,4-dihydropyridin-2(1H)-one (16).
2
2
2
2
N-Benzyldihydropyridine-2(1H)-one (15) (187 mg, 1 mmol) was added
slowly to trifluoroacetic anhydride (TFAA, 10 mL) and the mixture was
then heated at 80 °C for 2 hours in an ace round-bottom pressure flask
with a magnetic stir bar. After cooling to room temperature, TFAA was
evaporated, then a saturated solution of sodium carbonate in water (20
mL) was added and the mixture was stirred at room temperature for 5
min. The aqueous phase was extracted with dichloromethane (3 x 50
mL); the organic phase was washed with water and dried. Evaporation
afforded a pink oil, which was purified by chromatography (20 mm x 70
9
slowly. Recrystallization from a mixture of cyclohexane/n-heptane (5:1)
gave pure diene (489 mg, 72% yield) as light yellow crystals; mp 99.1-
-
1
9
1
1
7
f 2 2
9.8 °C; R = 0,45 (CH Cl /i-PrOH; 10:1), IR ( ,ꢀ cm , ATR): 3033, 2968,
650, 1590, 1573, 1544, 1490, 1459, 1433, 1423, 1414, 1340, 1315,
269, 1223, 1186, 1153, 1142, 1113, 1054, 958, 945, 885, 840, 794, 774,
54, 719, 707, 656, 617, 564, 541, 508, 429. HRMS: (ESI) Calculated for
+
C
13
H
11NO (197.24) [M+Na] : 220.0733, found 220.0732. See the
Supporting Information part for complete NMR signal assignment.
cm, 55 g SiO
2
, CH
2
Cl
2 2
, CH Cl
2
/methanol 500:1) on silica gel column gave
= 0.78
2 2
(CH Cl /i-PrOH; 10:1), IR ( ,ꢀ cm , ATR): 3033, 1707, 1677, 1619, 1496,
trifluoroacetyl 16 (224 mg, 79 % yield) as a colorless oil. R
f
-
1
1-Benzyl-5-(1-benzyl-6-oxopiperidin-2-yl)-3,4-dihydropyridin-2(1H)-
one (12). Hydroxy-amide 18 (411 mg, mmol) was added to
2
1454, 1367, 1331, 1265, 1195, 1163, 1132, 1082, 1029, 972, 908, 884,
trifluoroacetic acid (TFA, 10 mL) at r.t. and the mixture was then heated
at 100 °C for 5 h in an argon atmosphere (TLC monitoring). After cooling
to room temperature, TFA was evaporated, then a saturated solution of
sodium carbonate in water (20 mL) was added and the mixture was
stirred at room temperature for 5 min. The aqueous phase was extracted
745, 721, 698, 664, 598, 532, 498, 426. HRMS: (ESI) Calculated for
+
14 12 3
C H F NO
2
(283.25) [M+Na] : 306.0712, found 306.0708. See the
Supporting Information part for complete NMR signal assignment.
4H-Pyrido[1,2-b]isoquinoline-4,11(6H)-dione (19). A flask containing
2 2
with CH Cl (3 x 50 mL); the organic phase was washed with water and
freshly crystallized carboxylic acid 8 (467 mg, 2 mmol) or freshly
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800908
FULL PAPER
crystallized dione 9 (431 mg, 2 mmol) was dried in vacuo for 0.5 h before
it was charged with oxygen. To this flask was added Eaton´s reagent (8
mL). The mixture was stirred at 85 °C for 12 h in an oxygen atmosphere.
After cooling to room temperature, 10 mL of cold water was added and
agreement with the derivative prepared by reaction of ketone 9 with PPA
as described above.
Preparation of 11 from ketone 9 and alcohol 20. Using the procedure
as described for the synthesis of acid 22 from an equimolar mixture of
ketone 9 (215 mg, 1 mmol) and alcohol 20 (217 mg, 1 mmol) in 37% HCl
the mixture was neutralized slowly with a saturated solution of Na
The aqueous layer was extracted with 3 x 25 mL of CH Cl
2
CO
, the
3
.
2
2
combined organic layers were dried, concentrated and the resulting dark-
yellow oil (428 mg from 8 and 402 mg from 9) was purified by column
(
10 mL) at 110 °C for 24 h. The yellow oil obtained after evaporation of
dichloromethane was purified by silica gel column chromatography (10 x
50 mm, 60 g SiO , eluent: CH Cl /MeOH, 50:1) to afford pale yellow
2 2 2 2 2
chromatography (80 g SiO , 25 mm x 85 cm, CH Cl , CH Cl /MeOH,
4
2
2
2
5
0:1) to give keto-diene 19 (320 mg, 76% yield from 3 and 303 mg, 72%
crystals of diene 11 (144 mg, 73% yield). The physicochemical and
spectral data of the compound obtained are in full agreement with the
derivative 11 prepared above by reaction of ketone 9 with PPA.
yield from 9) as light yellow crystals. Recrystallization from a mixture of
acetone/n-pentane (5:1) gave pure keto-diene 19 (257 mg, 61% yield
calculated when starting from 8 and 249 mg, 59% yield calculated when
starting from 9) as light yellow crystals; mp 178.8-181.4 °C; R
f
= 0,49
cm , ATR): 3309, 3066, 2962, 2449, 1643,
603, 1580, 1454, 1398, 1350, 1297, 1255, 1208, 1179, 1162, 1143,
107, 1058, 999, 971, 951, 905, 867, 734, 723, 686, 634, 614, 554, 484,
3
,4,5,6-Tetrahydrophenanthridin-1(2H)-one (24). Using the procedure
-
1
2 2
(CH Cl /i-PrOH; 10:1), IR ( ,ꢀ
as described for the synthesis of acid 22 from alcohol 20 (869 mg, 4
mmol) in a 37% HCl (20 mL) at 110 °C for 18 h. Acid hydrochloride 22
1
1
4
(
97 mg, 9% yield) was obtained after filtration. Then concentration of
dichloromethane gave yellow semi-crystalline mass which after
purification by silica gel column chromatography (25 x 600 mm, 100 g
SiO , eluent: AcOEt/MeOH 30:1) gave the crude enaminone 24 (694 mg,
7% yield). Crystallization from a mixture of AcOEt/n-heptane provided
pure 24 (540 mg, 68% yield) as light yellow crystals, mp 181.2-184.7 °C.
+
9 2
36. HRMS: (ESI) Calculated for C13H NO (211.22) [M+Na] : 234.0525,
a
found 234.0521. See the Supporting Information par for complete NMR
signal assignment.
2
8
3-(3-Carboxypropyl)-4-oxo-1,2,3,4-tetrahydroisoquinolinium chloride
(
22). Ketone 9 (2.17 g, 10 mmol) was stirred at 55 °C for 16 h in a
-1
TLC (Silica gel): R
f
= 0.53 (AcOEt: MeOH, 10:1). IR ( ,
242, 3099, 2945, 1608, 1574, 1530, 1483, 1445, 1422, 1397, 1369,
328, 1285, 1271, 1204, 1175, 1143, 1114, 1082, 1053, 1034, 1010, 837,
10, 727, 652, 581, 536, 504, 443, 433. H NMR (600 MHz, CD OD) δ
3
.41 (dd, J = 8.0, 1.3 Hz, 1H), 7.12 (dddd, J = 8.0, 7.3, 1.4, 0.7 Hz, 1H),
.03 (ddd, J = 7.5, 7.3, 1.3 Hz, 1H), 6.93 (ddq, J = 7.5, 1.4, 0.8 Hz, 1H),
.47 (app s, 2H), 2.50 (app t, J = 6.3 Hz, 2H), 2.42 (app t, J = 6.4 Hz, 2H),
3
.92 – 1.81 (m, 2H). C NMR (151 MHz, CD OD) δ 195.18, 166.85,
32.36, 128.02, 127.75, 126.37, 126.01, 125.89, 105.59, 46.12, 38.96,
0.20, 21.77. HRMS: (ESI) Calculated for C13
ꢀ cm , ATR) =
mixture of 37% HCl (12 mL) and water (10 mL) in an ace round-bottom
pressure flask with a magnetic stir bar. After cooling, the reaction mixture
was concentrated to dryness and the obtained oil was vigorously stirred
3
1
8
8
7
4
1
1
3
2
1
2 2
overnight with dry CH Cl (150 ml). Acid 22 precipitated upon stirring at
room temperature. The solid (2.32 g, 86% yield) was filtered off, [TLC
1
(
d
Silica gel): R
) δ 7.94 (dd, J = 8.1, 1.3 Hz, 1H), 7.73 (td, J = 7.5, 1.3 Hz, 1H), 7.53 (t,
J = 7.1 Hz, 2H), 4.58 (d, J = 16.1 Hz, 1H), 4.53 (d, J = 16.0 Hz, 1H), 4.31
t, J = 6.0 Hz, 1H), 2.37 (ddd, J = 19.8, 11.7, 5.2 Hz, 2H), 2.15 – 2.05 (m,
H), 1.89 – 1.75 (m, 3H)] and the organic phase was washed with water,
dried (Na SO ), and evaporated. The yellow oil obtained was purified by
silica gel column chromatography (10 x 400 mm, 40 g SiO , eluent:
CH Cl /MeOH, 50:1) to afford pale yellow crystals of diene 11 (158 mg,
% yield). Because the acid could not be sufficiently purified, for better
characterization it was converted to the corresponding methyl ester.
f
= 0.19 (AcOEt: MeOH, 10:1), H NMR (600 MHz, DMSO-
13
6
(
1
+
H13NO (199.25) [M+Na] :
22.0889, found 222.0892.
2
4
2
3,4-Dihydrophenanthridin-1(2H)-one (25). Method A: Solution of i-
2
2
PrOH (5 mL) and water (1 mL) was bubbled with O
2
for 10 min. The
8
tetrahydrophenanthridinone 24 (200 mg, 1 mmol) was added and then
stirred at 50 °C in an oxygen atmosphere for 18 h to give 100% of
isoquinoline 25 with a total yield of 78% after crystallization from n-
heptane.
3-(4-Methoxy-4-oxobutyl)-4-oxo-1,2,3,4-tetrahydroisoquinolinium
chloride (23). Acetyl chloride (0.64 mL, 9 mmol, 3 eq.) was added to a
stirred mixture of acid hydrochloride 22 (HCl, 810 mg, 3 mmol) in
anhydrous MeOH (5 mL) at 0 °C. The mixture was stirred for 14 h at
room temperature. The solid ester hydrochloride (600 mg, 71% yield)
was filtered off and the filtrate was evaporated to dryness, the resulting
oil was dissolved in a minimum amount of water, neutralized with
Method B: The tetrahydrophenanthridinone 24 (200 mg, 1 mmol) was
dissolved in DCM (25 mL) and stirred 5 days on air give 100% of
isoquinoline 25 with total yield of 76% after crystallization from n-heptane,
mp 102.1-104.3°C (light yellow crystals). TLC (Silica gel): R
f
= 0.62
cm , ATR) = 2954, 2480, 1742, 1626, 1581,
497, 1435, 1373, 1350, 1319, 1297, 1244, 1173, 1136, 1103, 1045, 991,
-1
(
1
9
AcOEt: MeOH, 10:1). IR ( ,ꢀ
saturated Na
organic phase was washed with saturated NaCl solution, dried (Na
concentrated and purified by silica gel column chromatography (15 mm x
5 cm, 60 g SiO , eluent: AcOEt-MeOH, 25:1) to afford pale crystals (165
2
CO
3
and extracted 3 times with DCM (total, 60 mL). The
2
SO ),
4
1
3
35, 866, 754, 741, 681, 590, 548, 488, 409. H NMR (600 MHz, CDCl )
δ 9.39 (dd, J = 8.7, 0.8 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.84 (ddd, J =
.6, 6.9, 1.4 Hz, 1H), 7.62 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 3.35 (t, J = 6.2
7
2
8
mg, 19% yield). Crystallization of the combined esters from methanol
13
Hz, 2H), 2.81 (dd, J = 7.4, 6.0 Hz, 2H), 2.25 (dq, J = 7.7, 6.5 Hz, 2H).
NMR (151 MHz, CDCl ) δ 200.73, 160.82, 156.77, 133.89, 133.47,
28.42, 127.81, 127.23, 125.94, 120.85, 40.53, 33.60, 21.84. HRMS:
C
provided pure 23 (630 mg, 74% yield) as white crystals, mp 179.1-
3
-
1
1
80.5 °C. TLC (Silica gel): R
f
= 0.58 (AcOEt: MeOH, 10:1). IR ( ,ꢀ cm ,
1
ATR) = 2942, 2736, 2688, 2624, 2577, 2474, 2349, 1729, 1704, 1604,
+
13
(ESI) Calculated for C H11NO (197.23) [M+Na] : 220.0733, found
1
1
4
562, 1455, 1437, 1371, 1315, 1274, 1259, 1215, 1190, 1159, 1119,
220.0736
087, 1057, 995, 982, 951, 923, 889, 820, 758, 736, 672, 640, 579, 525,
+
80, 432. LC-MS, Calculated for C14
H18ClNO
3
(283.75) [M] : m/z 283
4-(4-hydroxyisoquinolin-3-yl)butanoic acid (26B). Solution of i-PrOH
(
100%). See the Supporting Information part for NMR signal assignment.
(5 mL) and water (0.5 mL) was bubbled with O
2
for 5 min. The tetrahydro-
isoquinole 22 (270 mg, 1 mmol) was added and then stirred at 65 °C in
an oxygen atmosphere for 48 h to give 100% of isoquinolinecarboxylic
acid 26b with a total yield of 71% after crystallization from water. This
product melted at mp 102.1-104.3 °C (white crystals, the substance gets
6
,11-Dihydro-4H-pyrido[1,2-b]isoquinolin-4-one (11). Using the
procedure as described for the synthesis of acid 22 from ketone 9 (1.09 g,
5
4
mmol) in a 37% HCl (25 mL) at 115 °C for 16 h. The acid 22 (54 mg,
% yield) and diene 11 (860 mg, 87% yield) were obtained. The
a pale pink color after a few weeks). TLC (Silica gel): R
f
= 0.49 (AcOEt:
physicochemical and spectral data of the compound obtained are in full
-1
MeOH, 10:1). IR ( ,ꢀ cm , ATR) = 3185, 2638, 2260, 2042, 1695, 1651,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800908
FULL PAPER
1
616, 1587, 1429, 1421, 1394, 1273, 1235, 1199, 1154, 1092, 966, 883,
c) X. Yang, Q. Shi, C.-Y. Lai, C.-Y. Chen, E. Ohkoshi, S.-C. Yang, C.-Y.
Wang, K. F. Bastow, T.-S. Wu, S.-L. Pan, C.-M. Teng, P.-C. Yang, K.-
H. Lee, J. Med. Chem. 2012, 55, 6751–6761; d) M. S. Christodoulou, F.
Calogero, M. Baumann, A. N. García-Argáez, S. Pieraccini, M. Sironi,
F. Dapiaggi, R. Bucci, G. Broggini, S. Gazzola, S. Liekens, A. Silvani,
M. Lahtela-Kakkonen, N. Martinet, A. Nonell-Canals, E. Santamaría-
Navarro, I. R. Baxendale, L. Dalla Via, D. Passarella, Eur. J. Med.
Chem. 2015, 92, 766−775; e) F. Liéby-Muller, F. Marion, P. Schmitt, J.-
P. Annereau, A. Kruczynski, N. Guilbaud, C. Bailly, Bioorg. Med. Chem.
Lett. 2015, 25, 184–187; f) Y. Kwon, J. Song, H. Lee, E.-Y. Kim, K. Lee,
S. K. Lee, S. Kim, J. Med. Chem. 2015, 58, 7749−7762; g) Y. Liu, L.
Qing, C. Meng, J. Shi, Y. Yang, Z. Wang, G. Han, Y. Wang, J. Ding, L.-
H Meng, Q. Wang, J. Med. Chem. 2017, 60, 2764−2779.
1
846, 769, 714, 661, 636, 552, 545, 519, 475, 435. H NMR (600 MHz,
DMSO-d
6
) δ 9.79 (s, 1H, OH), 8.45 (d, J = 8.2 Hz, 1H), 8.28 (s, 1H), 8.19
(
(
(
d, J = 8.3 Hz, 1H), 8.12 (t, J = 7.5 Hz, 1H), 7.91 (t, J = 7.5 Hz, 1H), 3.09
t, J = 7.5 Hz, 2H), 2.33 (t, J = 7.3 Hz, 2H), 2.08 – 1.99 (m, 2H). C NMR
151 MHz, DMSO-d
13
6
) δ 173.91, 147.63, 146.27, 138.48, 135.84, 129.95,
129.63, 126.87, 125.91, 122.83, 32.71, 31.90, 24.03. HRMS: (ESI)
+
Calculated for C13
H
3
13NO (231.25) [M+Na] : 254.0788, found 254.0791.
Isomerization of 21 to pyridone 11 in hydrochloric acid solution.
Using the procedure as described for the synthesis of 22 from 2,3-
dihydro-1H-pyrido[1,2-b]isoquinolin-4(6H)-one (21) (190 mg, 1 mmol) in a
3
7% HCl (15 mL) at 120 °C for 10 h. The yellow oil obtained after cooling
and concentration of dichloromethane was purified by silica gel column
chromatography (20 x 600 mm, 100 g SiO , eluent: CH Cl /MeOH, 50:1)
the procedure provided pale yellow crystals of dienone 11 in 82% yield
161 mg). The physicochemical and spectral data of both compounds
[
6]
a) T. F. Buckley, H. Rapoport, J. Org. Chem. 1983, 48, 4222−4232; (b)
A. Kubo, T. Nakai, Y. Koizumi, N. Saito, Y. Mikami, K. Yazawa, J. Uno,
Heterocycles 1992, 34, 1201−1211; c) W. Dong, W. Liu, X. Liao, B.
Guan, S. Chen, Z. Liu J. Org. Chem. 2011, 76, 5363–5368.
2
2
2
–
(
[
[
7]
8]
X. Tian, X. Chen, L. Gan, J. C. Hayes, A. G. Switzer, M. G. Solinsky, F.
H. Ebetino, J. A. Wos, B. B. Pinney, J. A. Farmer, D. Crossdoersen, R.
J. Sheldon, Bioorg. Med. Chem. Lett. 2006, 16, 1721−1725.
obtained are in full agreement with the derivative prepared by reaction of
ketone 9 with PPA as described above.
a) B. Rigo and N. Kolocouris, J. Heterocycl. Chem., 1983, 20, 893−898;
b) B. Rigo, P. Gautret, A. Legrand, S. El Ghammarti, D. Couturier,
Synth. Commun. 1994, 24, 2609−2615; c) S. Al Akoum Ebrik, A.
Legrand, B. Rigo, D. Couturier, J. Heterocycl. Chem. 1999, 36,
Acknowledgements
9
97−1000; d) A. Legrand, B. Rigo, P. Gautret, J.–P. Hénichart, D.
This work was supported by the Grant Agency of the Slovak
Republic (No. 1/0371/16). The authors gratefully acknowledge
the Research Centre for Industrial Synthesis of Drugs, ITMS
Couturier, J. Heterocycl. Chem. 1999, 36, 1263−1270; e) A. Legrand,
B. Rigo, J.–P. Hénichart, B. Norberg, F. Camus, F. Durant, D.
Couturier, J. Heterocycl. Chem. 2000, 37, 215−227; f) R. Akué-Gédu,
S. Al Akoum Ebrik, A. Witczak-Legrand, D. Fasseur, S. El Ghammarti,
D. Couturier, B. Decroix, M. Othman, M. Debacker, B. Rigo,
Tetrahedron 2002, 58, 9239–9247; g) K. Kadlečíková, V. Dalla, Š.
Marchalín, B. Decroix, P. Baran, Tetrahedron 2005, 61, 4743–4754.
a) Š. Marchalín, B. Decroix, J. Morel, Acta Chem. Scand. 1993, 47,
26240220061, supported by the Research & Development
Operational Program funded by the ERDF. This contribution is
also made by technical help of “Fondation de La Catho de Lille”,
the French School of High Studies in Engineering (HEI), and the
University of Le Havre Normandie for technical and financial
aids. The crystal structure determinations were made with the
support of the project "University Science Park of STU
Bratislava", ITMS 26240220084, supported by the Research &
Development Operational Program funded by the ERDF.
[
9]
287–291; b) Š. Marchalin, B. Decroix, J. Heterocycl. Chem. 1994, 31,
495−499; c) A. Daïch, B. Decroix, J. Heterocycl. Chem. 1996, 33,
873−878; d) N. Szemes, Š. Marchalín, F. Bar, B. Decroix, J. Heterocycl.
Chem. 1998, 35, 1371–1375; e) Š. Marchalín, F. Szemes, N. Bar, B.
Decroix, Heterocycles 1999, 50, 445–452; f) P. Šafář, J. Žúžiová, M.
Bobošikova, Š. Marchalín, N. Prónayová, S. Comesse, A. Daïch,
Tetrahedron: Asymmetry 2009, 20, 2137–2144; g) P. Šafář, J. Žúžiová,
Š. Marchalín, E. Tothova, N. Prónayová, Ĺ. Švorc, V. Vrábel, A. Daïch,
Tetrahedron: Asymmetry 2009, 20, 626–634; h) R. Akué-Gédu, D.
Couturier, J.-P. Hénichart, B. Rigo, G. Sanz, L.Van Hijfte, A. Bourry,
Tetrahedron 2012, 68, 1117–1127.
Keywords: Amino acids • (S)-Aminoadipic acid • -Cationic
Cyclization • N-Acyliminium Species • Isoquinolines • Lactams •
Nitrogen heterocycles • Pyridoisoquinolines
[
[
[
1]
2]
3]
P. Clinton, O. Wyman, M. Mozeson, The Pharm. Exec. 50.
Pharmaceutical Executive 2010, pp. 69-80.
[10] For recent example of FTase inhibitors from the group, see: I.-M.
Moise, A. Ghinet, D. Belei, J. Dubois, A. Farce, El. Bîcu, Bioorg. Med.
Chem. Lett. 2016, 26, 3730–3734.
For interesting review on this area, see: J. P. Michael, Nat. Prod. Rep.
2008, 25, 139-165.
[11] For recent example of tubulin polymerization inhibitors, see: a) C.-M.
Abuhaie, E. Bîcu, B. Rigo, P. Gautret, D. Belei, A. Farce, J. Dubois, A.
Ghinet, Bioorg. Med. Chem. Lett. 2013, 23, 147-152; b) A. Ghinet, P.
Gautret, N. Van Hijfte, B. Ledé, J.-P. Hénichart, E.Bîcu, U. Darbost, B.
Rigo, A. Daïch, Chem. Eur. J. 2014, 20, 10117–10130.
a) H. Hamamoto, Y. Shiozaki, H. Nambu, K. Hata, H. Tohma, Y. Kita,
Chem. - Eur. J. 2004, 10, 4977−4982; b) W. Zeng, S. R. Chemler, J.
Org. Chem. 2008, 73, 6045−6047; c) A. McIver, D. D. Young, A.
Deiters, Chem. Commun. 2008, 4750−4752; d) A. Stoye, T. Opatz, Org.
Lett. 2010, 12, 2140−2141; e) T. N. Barrett, D. C. Braddock, A. Monta,
M. R. Webb, A. J. P. White, J. Nat. Prod. 2011, 74, 1980−1984; f) Z.
Wang, A. Feng, M. Cui, Y. Liu, L. Wang, Q. Wang, PLoS One 2012, 7,
e52933-e52933; g) A. A. van Loon, M. K. Holton, C. R. Downey, T. M.
White, C. E. Rolph, S. R. Bruening, G. Li, K. M. Delaney, S. J. Pelkey,
E. T. Pelkey, J. Org. Chem. 2014, 79, 8049−8058.
[12] a) P. Šafář, J. Žúžiová, E. Tothova, Š. Marchalín, N. Prónayová, Ĺ.
Švorc, V. Vrábel, S. Comesse, A. Daïch, Tetrahedron: Asymmetry
2010, 21, 623−630; b) P. Šafář, J. Žúžiová, Š. Marchalín, N. Prónayová,
Ĺ. Švorc, V. Vrábel, S. Šesták, D. Rendić, V. Tognetti, L. Joubert, A.
Daïch, Eur. J. Org. Chem. 2012, 5498−5514.
[13] V. G. Granik, Russ. Chem. Rev. 1982, 51, 119–134.
[14] N. O. Brace, J. Org. Chem. 1995, 60, 2059–2071.
[
[
4]
5]
C. Anton-Torrecillas, I. Bosque, J.C. Gonzalez-Gomez, M. Isabel Loza,
J. Brea, J. Org. Chem. 2015, 80, 1284−1290.
[15] A. K. Bonetskaya, N. F. Erofeeva, S. M. Skuratov, Azv. Vyssh. Uchebn.
Zaved., Khim. Khim. Tekhnol. 1960, 1027–1030; Chem. Abstr. 1961, 55,
87095.
a) For significant biological activities of phenanthroquinolizidines, see:
X. Yang, Q. Shi, S.-C. Yang, C.-Y. Chen, S.-L. Yu, K. F. Bastow, S. L.
Morris-Natschke, P.-C. Wu, C.-Y. Lai, T.-S. Wu, S.-L. Pan, C.-M. Teng,
J.-C. Lin, P.-C. Yang, K.-H. Lee, J. Med. Chem. 2011, 54, 5097-5107;
b) M. W. Leighty, G. I. Georg, ACS Med. Chem. Lett. 2011, 2, 313–315;
[16] T. H. Lane, C. L. Fry, J. Org. Chem. 1978, 43, 4890–4891.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800908
FULL PAPER
[
17] G. Homerin, E. Lipka, B. Rigo, R. Millet, X. Dezitter, C. Furman, A.
Ghinet, Tetrahedron 2017, 73, 5327–5336 and the references cited
therein.
0.0205, Rsigma = 0.0165) which were used in all calculations. The
final R
1 2
was 0.0356 (I > 2σ(I)) and wR was 0.0936 (all data), CCDC no.
1839259.
[
[
[
18] A. A. Strepikheev, Usp. Khim. Tekhnol. Polim. 1957, 3–12; Chem. Abstr.
[37] M. D. Ganton, M. A. Kerr, Org. Lett. 2005, 21, 4777–4779.
[38] I. Suarez del Villars, A. Gradillas, J. Perez-Castells, Eur. J. Org. Chem.
2010, 5850–5862.
1
958, 52, 120039.
19] H. C. Brown, J. H. Brewster, H. Shechter, J. Amer. Chem. Soc. 1954,
6, 467–474.
7
[39] For some dimers from N-phenyl analogues, see: J. B. P. A. Wijnberg, J.
J. J. De Boer, W. N. Speckamp, Recl. Trav. Chim. Pays-Bas 1978,
97, 227–231.
20] E. A. Zheltonogova, G. I. Oleneva, A. G. Shipov, Y. Baukov, J. Org.
Chem. USSR 1990, 26, 412–418.
[
[
21] C. D. Schmulbach, D. M. Hart, J. Org. Chem. 1964, 29, 3122–3124.
22] a) Rogstad, A.; Augdahl, E. Acta Chem. Scand. 1971, 25, 2889-2893;
b) Rogstad, A.; Augdahl, E. Acta Chem. Scand. 1971, 25, 225-234.
23] V. P. Muralidharan, M. Alagumuthu, S. K. Iyer, Bioorg. Med. Chem. Lett.
[40] H. R. Campello J. Parker, M. Perry, P. Ryberg, T. Gallagher, Org. Lett.
2016, 18, 4124– 4127.
[41] G. G. Dubinina, W. J. Chain, Tetrahedron Lett. 2011, 52, 939–942.
[42] P. Salanski, Y. K. Ko, K.-I. Lee, Mendeleev Commun. 2006, 16, 46–48.
[
[
2017, 27, 2510–2514.
9 2
[43] Crystal Data for C13H NO (M =211.21 g/mol) (19): monoclinic, space
24] a) T. F. Buckley III, H. Rapoport, J. Org. Chem. 1983, 48, 4222−4232;
b) A. Kubo, T. Nakai, Y. Koizumi, N. Saito, Y. Mikami, K. Yazawa, J.
Uno, Heterocycles 1992, 34, 1201−1211; c) J. Sivý, V. Vrábel, Š.
Marchalín, P. Šafář, Asian J. Chem. 2015, 27, 2635−2638
group P2
1
/c (no. 14), a = 13.9334(8) Å, b = 4.9033(3) Å, c =
3
14.6482(7) Å, β = 112.990(4)°, V = 921.27(9) Å , Z = 4, T = 100 K,
-
1
3
μ(CuKα) = 0.849 mm , Dcalc = 1.523 g/cm , 12369 reflections
measured (6.892° 2Θ 155.562°), 1709 unique (Rint = 0.0402,
sigma = 0.0391) which were used in all calculations. The final R was
0.0378 (I > 2σ(I)) and wR was 0.0946 (all data), CCDC no. 1839261.
≤
≤
[
[
25] P. Šafář, Š. Marchalín, N. Prónayová, V. Vrábel, A. M. Lawson, M.
Othman, A. Daïch, Tetrahedron 2016, 72, 3221–3231.
R
1
2
26] a) B. J. Whittle, IDrugs 2002, 5, 590–593; b) J. Perumattam, B. G.
Shearer, W. L. Confer, R. M. Mathew, Tetrahedron Lett. 1991, 32,
[44] Crystal Data for product 23,
orthorhombic, space group P2
C
14
H
18ClNO
3
(M
=
283.74 g/mol):
1
2
1
2
1
(no. 19), a = 5.3473(3) Å, b =
3
7
183–7186; c) T. K. Jones, S. G. Mills, R. A. Reamer, D. Askin, R.
Desmond, R. P. Volante, I. Shinkai, J. Am. Chem. Soc. 1989, 111,
157–1159; d) S. N. Sehgal, H. Baker, C. P. Eng, K. Singh, C. Véezina,
11.6243(6) Å, c = 22.6116(15) Å, V = 1405.51(14) Å , Z = 4, T = 100 K,
-
1
3
μ(CuKα) = 2.446 mm , Dcalc = 1.341 g/cm , 86165 reflections
measured (7.82° ≤ 2Θ ≤ 143.056°), 2737 unique (Rint = 0.0397, Rsigma
0.0118) which were used in all calculations. The final R was 0.0293 (I
> 2σ(I)) and wR was 0.0807 (all data), CCDC no. 1839263.
[45] Crystal Data for product 11, 11NO (M 197.23 g/mol):
1
=
J. Antibiot. 1983, 36, 351–354.
1
[
27] a) R. A. Jones, G. P. Bean, In The Chemistry of Pyrroles, Academic
Press, London, 1977; pp 209–238; b) R. T. Coutts, A. F. Casy, In
Heterocyclic Compounds. Pyridine and Its Derivatives, Vol. 14 (ed: R.
A. Abramovitch), John Wiley Intersciences, New York, 1975, pp 445–
2
C
13
H
=
orthorhombic, space group Pbca (no. 61), a = 7.4420(2) Å, b =
3
22.1357(9) Å, c = 12.0860(4) Å, V = 1990.97(12) Å , Z = 8, T = 100 K,
-
1
3
524.
μ(CuKα) = 0.664 mm , Dcalc = 1.316 g/cm , 17240 reflections
measured (7.988° 2Θ 143.034°), 1911 unique (Rint = 0.0628,
sigma = 0.0336) which were used in all calculations. The final R was
0.0397 (I > 2σ(I)) and wR was 0.1039 (all data), CCDC no. 1839262.
[
[
28] P. J. Beswick, R. J. Gleave, J. Graham, A. Steadman, D. S. Walter,
PCT Int. Appl., 2008, 116845; Chem. Abstr. 2008, 149, 425801.
≤
≤
R
1
29] For decarbonylation, see: a) B. Rigo, D. Fasseur, N. Cherepy, D.
Couturier, Tetrahedron Lett. 1989, 30, 7057–7060; b) A. Ghinet, N. Van
Hijfte, P. Gautret, B. Rigo, H. Oulyadi, J. Rousseau, Tetrahedron 2012,
2
[46] B. Wang, B. Lu, Y. Jiang, Y. Zhang, D. Ma, Org. Lett. 2008, 10,
2761−2763.
68, 1109–1116.
[47] Crystal Data for product 24, C13H13NO (M = 199.24 g/mol): monoclinic,
[
[
30] a) B. Rigo, E. Tullier, D. Barbry, D. Couturier, V. Warin, J. Lamiot, F.
Baert, J. Heterocycl. Chem. 1990, 27, 1383–1386; b) A. Ghinet, S.
Oudir, J.-P. Hénichart, B. Rigo, N. Pommery, P. Gautret, Tetrahedron
space group C2/c (no. 15), a = 15.0509(19) Å, b = 7.1424(6) Å, c =
3
18.789(2) Å, β = 100.184(10)°, V = 1988.0(4) Å , Z = 8, T = 100 K,
-
1
3
μ(CuKα) = 0.666 mm , Dcalc = 1.331 g/cm , 9833 reflections measured
(9.566° ≤ 2Θ ≤ 143.048°), 1894 unique (Rint = 0.0527, Rsigma = 0.0363)
2
010, 66, 215–221.
31] a) B. Rigo, D. Barbry, D. Couturier, Synth. Commun. 1991, 21, 741–
47; b) R. Akué-Gédu, A. Bourry, F. Camus, B. Norberg, F. Durant, D.
which were used in all calculations. The final R
1
was 0.0547 (I > 2σ(I))
7
and wR was 0.1618 (all data), CCDC no. 1839264.
2
Couturier, M. Debacker, B. Rigo, Heterocycles 2004, 63, 1855–1873.
32] A. Bourry, R. Akué-Gédu, J.-P. Hénichart, G. Sanz, B. Rigo,
Tetrahedron Lett. 2004, 45, 2097–2101.
[48] R. Akué-Gédu, D. Couturier, J.-P. Hénichart, B. Rigo, G. Sanz, L. Van
Hijfte, A. Bourry, Tetrahedron 2012, 68, 5644–5654 and the references
cited therein.
[
[
33] A. Bourry, D. Couturier, G. Sanz, L. Van Hijfte, J.-P. Hénichart, B. Rigo,
Tetrahedron 2006, 62, 4400–4407; b) A. Ghinet, A. Farce, S. Oudir, J.
Pommery, J. Vamecq, J.-P. Hénichart, B. Rigo, P. Gautret, Med. Chem.
[49] G. M. Sheldrick, Acta Crystallogr. 2015, A71, 3–8.
[50] L. Palatinus, G. Chapuis, J. Appl. Crystallogr. 2007, 40, 786–790.
[51] G. M. Sheldrick, Acta Crystallogr. 2015, C71, 3–8.
[52] K. Stott, J. Stonehouse, J. Keeler, T.-L. Hwang, A. J. Shaka, J. Am.
Chem. Soc. 1995, 117, 4199-4200.
2
012, 8, 942–946.
34] a) P. Šafář, Š. Marchalín, M. Šoral, J. Moncol, A. Daïch, Org. Lett.
017, 19, 4742−5514; b) X.-J. Li, J.-B. Qiao, J. Sun, X.-Q. Li, P. Gu,
Org. Lett. 2014, 16, 2864−2867.
35] Crystal Data for product 13, C13
[
2
[53] B. Luy, K. Kobzar, T. E. Skinner, N. Khaneja, S. J. Glaser, J. Magn.
Reson. 2005, 176, 179-186.
[
H
15NO (M = 201.26 g/mol): monoclinic,
[54] L. Castañar, E. Sistaré, A. Virgili, R. T. Williamson, T. Parella, Magn.
Reson. Chem. 2015, 53, 115-119.
space group P2
1
/c (no. 14), a = 8.2461(7) Å, b = 14.6728(13) Å, c =
3
9.0290(7) Å, β = 108.738(6)°, V = 1034.55(15) Å , Z = 4, T = 100 K,
-
1
3
μ(CuKα) = 0.640 mm , Dcalc = 1.292 g/cm , 12302 reflections
measured (11.332° ≤ 2Θ ≤ 142.728°), 1983 unique (Rint = 0.0643,
R
sigma = 0.0478) which were used in all calculations. The final R
.0480 (I > 2σ(I)) and wR was 0.1170 (all data), CCDC no. 1839260.
36] Crystal Data for product 12, (M 374.47 g/mol):
monoclinic, space group P2
1
was
0
2
[
C
24
H
26
N
O
2 2
=
1
/n (no. 14), a = 10.6028(3) Å, b =
3
9.5288(2) Å, c = 19.5497(5) Å, β = 95.633(2)°, V = 1965.61(9) Å , Z =
-
1
3
4, T = 100 K, μ(CuKα) = 0.637 mm , Dcalc = 1.265 g/cm , 18384
reflections measured (9.092° ≤ 2Θ ≤ 143.986°), 3748 unique (Rint
=
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800908
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
Fused aza-heterocyclic systems
P. Šafář, Š. Marchalín,* B. Balónová, M.
Šoral, J. Moncol, A. Ghinet, B. Rigo, and
A. Daïch*
Page No. – Page No.
Enantiopure N-benzyl 6-oxopipecolic acid, generated from (S)-2-aminoadipic
acid, was evaluated under different -cationic cyclization conditions. If the
Study on the reactivity of enantiopure
(S)-6-oxopipecolic acid and
combination of SOCl
yields, use of other activators resulted in the change of the reaction profile and
thus, interestingly, in the diversification of the aza-heterocyclic systems.
2
/AlCl
3
seems to be superior in terms of the reaction
corresponding pyridoisoquinolines
under acid conditions
This article is protected by copyright. All rights reserved.