Redox Condensations of o-Nitrobenzaldehydes with Amines under Mild Conditions: Total Synthesis of the Vasicinone Family

Article abstract of DOI:10.1021/acs.joc.0c00794

A total synthesis of the vasicinone family of natural products from bulk chemicals was developed. Reductive condensation of o-nitrobenzaldehydes with amines utilizing iron pentacarbonyl as a reducing agent followed by subsequent oxidation leads to a great variety of polycyclic nitrogen-containing heterocycles under mild conditions. Enantiomerically pure vasicinone, rutaecarpine, isaindigotone, and luotonin were synthesized from readily available starting materials like hydroxyproline, nitrobenzaldehyde, pyrrolidine, and piperidine in two to four operational steps without chromatography. The antifungal activity of all products was tested.

Full text of DOI:10.1021/acs.joc.0c00794

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Note
Redox condensations of o-nitrobenzaldehydes with amines
under mild conditions – total synthesis of the Vasicinone family
Oleg Ilych Afanasyev, Evgeniya Podyacheva, Alexander Rudenko,
Alexey A. Tsygankov, Maria Makarova, and Denis Chusov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00794 • Publication Date (Web): 09 Jun 2020
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The Journal of Organic Chemistry
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Redox condensations of o-nitrobenzaldehydes with amines
under mild conditions – total synthesis of the Vasicinone
family
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Oleg I. Afanasyev,† Evgeniya Podyacheva,† Alexander Rudenko,‡ Alexey A. Tsygankov,† Maria
Makarova,†,‡ and Denis Chusov*†,
§
† A.N.Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences, Vavilova St. 28, Moscow
119991, Russian Federation
‡ Higher Chemical College, Dmitry Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, Moscow
125047, Russian Federation
§ G.V. Plekhanov Russian University of Economics, 36 Stremyanny Per., Moscow 117997, Russia
Supporting Information Placeholder
R2
O
HN
R
gram scale
R
R2
R1
N
R1
Fe(CO)5
N
H
NO2
O
N
N
O
O
O
N
N
N
N
OMe
N
N
N
OH
HN
OH
>99% ee
Vasicinone
OMe
Isaindigotone
Luotonine
Rutaecarpine
ABSTRACT: A total synthesis of the Vasicinone family of natural products from bulk chemicals was developed. Reductive
condensation of o-nitrobenzaldehydes with amines utilizing iron pentacarbonyl as a reducing agent followed by subsequent oxidation
leads to a great variety of polycyclic nitrogen-containing heterocycles under mild conditions. Enantiomerically pure Vasicinone,
Rutaecarpine, Isaindigotone, and Luotonine were synthesized from readily available starting materials like hydroxyproline,
nitrobenzaldehyde, pyrrolidine, and piperidine in two-four operational steps without chromatography. The anti-fungal activity of all
products was tested.
Vasicinone is a natural compound (quinazoline alkaloid family)
with bronchodilatory activity, which was initially isolated from
Adhatoda Vasica Nees.1 A substantial number of structurally
related quinazolinones were isolated from natural sources or
prepared synthetically.2 These compounds possess a broad
range of bioactivity, e.g. anti-tumor, anti-endotoxic, anti-
fungal, etc. Some state-of-the-art approaches toward
quinazolinones include transformations of complex molecules
using aza-Wittig or aza-Nazarov reactions, photoredox
cyclizations, reductive cyclizations of different anthranilic acid
derivatives, and so on.3 In most cases, these approaches involve
multistep synthesis from complex molecules. Therefore, a
direct approach that allows the synthesis of quinazolines or
quinazolinones directly from readily available and inexpensive
starting materials would represent a development of high
synthetic value.
hydroxyproline as bulk and cheap precursors. We started with
the development of reductive condensation procedures for the
coupling of these molecules. The same transformation would be
useful for the preparation of other members of Vasicinone
family, e.g. Rutaecarpine and Isaindigotone.
O
O
H
N
N
H
HOOC
N
OH
NO2
N
Luotonine A
O
O
NH2
H
N
N
H
N
NO2
HN
Rutaecarpine
The initial idea of this project was to develop a total syntheses
of Luotonine A and Rutaecarpine. The structure of Luotonine
(Figure 1) inspired retrosynthetic breakdown into two
molecules of o-nitrobenzaldehyde and one molecule of
Figure 1. Retrosynthetic analysis of Luotonine
Rutaecarpine
A
and
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Analysis of the literature has shown that a great contribution to product 4aa and fully reduced aniline 3aa. Quinazolines 4 can
this field was made by Seidel et al.4 They reported the synthesis
of quinazolinones via oxidation of the corresponding
quinazolines, which can be prepared from o-
aminobenzaldehydes and pyrrolidines. However, the need to
use o-aminobenzaldehydes as starting molecules decreased the
synthetic merit of this approach. o-Aminobenzaldehydes are
unstable compounds with very limited commercial availability
(especially in bulk quantities), and Seidel’s group prepared
them from the corresponding o-aminobenzonitriles by
reduction with DIBAL-H. We, therefore, designed the synthetic
sequence towards quinazolines and quinazolinones to start with
o-nitrobenzaldehyde, which is an inexpensive, stable, and
readily available reagent. (Scheme 1).
serve as convenient precursors to various alkaloids, so we
focused our research on their synthesis. Table 1 summarizes the
influence of different parameters on the reaction outcome
(detailed data on the reaction optimization, side products, and
possible mechanisms are provided in SI). Temperature
demonstrated the strongest effect on the reaction outcome.
Lower reaction temperatures led to increased amounts of
quinazoline 4aa in the reaction mixture, whereas higher
temperatures favored the formation of aniline 3aa. The inert
atmosphere was also an important factor as the presence of air
led to substantially inferior yields.
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With the optimized conditions in hand, we proceeded to
investigation of the substrate scope and started with the
synthesis of the two products of tricyclic family 4 (4aa and 4ad,
scheme 2). Notably, quinazolines 4 appeared to be very
Scheme 1. Approaches to quinazoline synthesis.
Seidel et al.
This work
O
O
sensitive to reduction: as mild of
a
reductant as
triacetoxyborohydride9 easily converts them into anilines 3
(scheme 3). We carried out reductive amination between
quinazoline 4aa and m-nitrobenzaldehyde and no other
products besides compound 6 were detected.
H
H
NH2
NO2
Pyrrolidine,
EtOH, reflux or
MW, 200°C
Pyrrolidine,
Fe(CO)5, RT
N
Scheme 2. Formation of quinazoline products 4
-H2O
-CO2
N
O
H
(CH2)n
N
THF, Fe(CO)5
H
+
Reductive addition without
an external hydrogen source
(CH2)n
N
Redox neutral
N
-30°C, 16 h
25°C, 20 h
H
H
NO2
1a
2
4
Metal carbonyls are selective and powerful agents for reductive
organic transformations.5 We have previously shown that iron
pentacarbonyl can be used in direct reductive amination6 and
reductive condensation between CH-acids and aldehydes.7a
Moreover, iron pentacarbonyl is inexpensive and widely
available, and besides that, it is a useful compound for cancer
treatment.7b At the same time, iron compounds are known as
catalysts for CH-amination reactions, for example, conversion
of o-substituted aryl azides to indoles.8
4aa
4ad
: n = 1, 73% (70%) (scaled up to 3 g)
: n = 2, 70% (62%) isolated yields are in parentheses
Scheme 3 Reductive amination of quinazoline 4aa
N
NaBH(OAc)3
N
N
H
4aa
DCM, 25°C, 24 h
NH2
3aa
, 70%
Table 1 Initial optimization experiments
O
N
O
H
N
Fe(CO)5
N
N
NH
H
+
+
N
H
THF, temperature,
16 h, Ar
NH2
NO2
NO2
1a
2a
3aa
4aa
NaBH(OAc)3, DCM, 25°C, 24 h
NO2
57% (45%)
Entry
1b
2c
3c,d
4e
5e
Temperature
3aaa
4aaa
6,
4°C
25°C
25°C
40°C
60°C
90°C
120°C
17%
25%
10%
27%
39%
59%
81%
75%
69%
34%
67%
60%
22%
traces
One can see from the data shown above that a greater reducing
potential of the system leads to higher yields of anilines 3. The
preparation of anilines 3 was then investigated in greater detail.
Various combinations of primary and secondary amines with o-
nitrobenzaldehydes were tested and good reaction outcomes
were observed regardless of the electronic properties of the
substituent in the aromatic ring (Scheme 4).
6e
7e
Since the goal of this project was to develop a concise total
synthesis of natural compounds, e.g. Luotonine A, a
quinazolinone core was of greater synthetic interest versus a
quinazoline one. Thus, we developed an in situ modification
that allows obtaining molecules containing scaffold 5. Various
approaches to oxidation of quinazolines have been reported by
Seidel et al.4b,4c Potassium permanganate appeared to be a
convenient reagent to convert quinazolines into quinazolinones
(stable and easy-to-handle alkaloids). We used this approach to
a NMR yield. b The reaction was carried out overnight. 1.3 mmol
of 1a, 3.9 mmol of 2a, and 2.6 mmol of Fe(CO)5 were used. See the
general procedure. c 3.9 mmol of Fe(CO)5 were used. d Under air. e
3.9 mmol of Fe(CO)5 were used. 3 hours heating at indicated
temperature, then overnight at room temperature.
We found that o-nitrobenzaldehyde can react with pyrrolidine
and iron pentacarbonyl, resulting in a mixture of quinazoline
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The Journal of Organic Chemistry
work up the reaction mixtures containing quinazolines 4. As a
molecules using the developed protocol with iron
pentacarbonyl. The particular reaction between
1
2
3
4
5
6
7
8
result, different alkaloids were prepared in a single operational
step from commercially available and stable o-
nitrobenzaldehydes and secondary amines with convenient
isolation of target products. This protocol is easily scalable
since it does not require any rare reagents or special conditions
(Scheme 5). Moreover, chromatography can be avoided in most
cases since the purity of the crude products exceeded 90% even
without purification. The reaction outcome was not strongly
dependent on the electronic properties of substituents in the
aromatic ring. Notably, the protocol tolerates bromo-substituted
aromatics, which is interesting in the context of high inhibitory
activities of certain bromo-substituted quinazolinone alkaloids
against topoisomerases I and II.10 Moreover, the ability to use
bromo-substituted aromatics in this method opens the pathway
for further modifications of the products via cross-coupling
reactions. Unfortunately, oxidation with potassium
permanganate could not be applied to the synthesis of
quinazolinones 5 from amines 3. In such cases, tert-butyl
hydroperoxide could be used as an oxidant, which was
demonstrated by preparation of compound 5ag.
hydroxypyrrolidine and nitrobenzaldehyde cannot be set up in
tetrahydrofuran due to the low solubility of the amine. Thus, we
were unable to obtain the reaction mixture enriched with
quinazoline for the oxidative treatment with potassium
permanganate. We, therefore, prepared anilines 3ab and 3ac in
high yields using DMF as a solvent and oxidized them using
tert-butyl hydroperoxide. Hydroxypyrrolidine (required for the
synthesis of 3ab) can be prepared from natural L-
hydroxyproline via one-step decarboxylation (Scheme 6).11
Organic byproducts of the reductive condensation between o-
nitrobenzaldehyde and hydroxypyrrolidine do not interfere with
the oxidation of 3ab to R-Vasicinone. The resulting R-
Vasicinone was crystallized from the reaction mixture and
therefore no chromatography was required for the entire
synthetic sequence starting from o-nitrobenzaldehyde and L-
hydroxyproline. Together with very low costs associated with
starting materials and reagents, this fact can compensate for the
low yield on the last step. All isomers of Vasicinone were
prepared and isolated likewise (5ab, 5ac, 5ab’, 5ac’). Detailed
procedures and characterization are described in the
experimental section.
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Scheme 4. Substrate scope for the synthesis of anilines 3.
Scheme 5. Substrate scope for the one-pot synthesis of
quinazolinones 5.
O
THF, 120°C, 3-6 h
then r.t., 16 h
R3
H
N
N
R1
H
+
R1
O
R2
R2 R3
O
1. Fe(CO)5, -30°C, 16 h,
then 25°C, 20 h
2. KMnO4, acetone,
reflux 1 h
Fe(CO)5
R1
R
R
R1
R2
NH2
NO2
HN
H +
N
1
2
3
R2
NO2
N
N
N
N
1
2
5
NH2
NH2
OH
89% (86%)
NH2
O
O
N
N
Cl
O
N
OH
a
a,b
3aa,
81% (73%)
3ab,
3ac
, 75% (69%)
N
N
(scaled up to 13 g)
N
5aa,
5ad,
5ea
54%
46%
, 38%
N
OH
OH
(scaled up to 10 g)
N
H
NH2
N
H
NH2
NH2
O
O
N
N
O
Cl
3ad
3ae
3ca
3af
, 88% (70%)
85% (66%)
, 73% (60%)
N
N
Cl
N
Cl
N
N
N
N
a
5da
5ca
, 39%
, 43%
5ag,
15%
Cl
NH2
Br
3ba
NH2
NH2
c
c
c
89% (80%)
3da
, 97% (83%)
, 84% (74%)
O
N
O
N
MeO
MeO
Cl
N
N
MeO
N
N
N
Br
NH2
MeO
3fa
NH2
5fa
5ba
, 43%
, 52%
NH2
80% (77%)
d
c
c
3ag,
86% (77%)
3ea
, 95% (93%)
1.3 mmol of 1, 3.9 mmol of 2, and 3.9 mmol of Fe(CO)5 were used.
a
3 hours heating at 120°C, then overnight at room temperature. 1.3
Isolated yields. Prepared from 3ag using oxidation by tBuOOH,
mmol of 1, 3.9 mmol of 2, and 3.9 mmol of Fe(CO)5 were used.
see experimental section.
NMR yields. Isolated yields are in parentheses. a DMF was used as
Quinazolinones 5 open a simple synthetic pathway to other
alkaloids via one or two-step protocols. This was demonstrated
by the preparation of Luotonine A 7, Rutaecarpine 8, and
Isaindigotone 9.
b
a solvent.
An amine was generated from corresponding
hydrochloride in the reaction mixture. c 1.3 mmol of 1, 6.5 mmol of
2, and 3.9 mmol of Fe(CO)5 were used. 6 hours at 120°C. d Initial
mixing of starting molecules at -70°C, then gradual warming up to
r.t. and stirring overnight at r.t. 1.3 mmol of 1, 6.5 mmol of 2, and
3.9 mmol of Fe(CO)5 were used.
The developed protocol was applied to the preparation of some
natural alkaloids and their analogs. First, natural Vasicinone
and its isomers were prepared. We started from R-3-
hydroxypyrrolidines and prepared Vasicinone and related
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Scheme 6. Preparation of Vasicinone and its isomers
Anti-fungal activity of all compounds, prepared during this
1
2
3
4
5
6
7
8
work, was tested: the effect against some widespread
agriculturally-relevant fungi was investigated (10 species).
Compounds 6, 5ag, 3da, Rutaecarpine 8, and Isaindigotone 9
showed inhibitory activity, comparable to or even higher than
commercially available fungicide Triadimefon. All details are
provided in SI.
H
H
HOOC
N
N
cat. cyclohexenone
EtOH, 160°C, 48 h
OH
OH
2b
L-hydroxyproline
1.1 Fe(CO)5, DMF
1a
1.2 tBuOOH, KI
25°C, 16 h
In conclusion, the unique reducing ability of iron pentacarbonyl
allows tandem reduction of the aromatic nitro group with CH-
activation of aliphatic CH-bond, leading to the formation of
quinazolines or o-substituted anilines. Quinazolines can be
oxidized in situ to the corresponding Vasicinone analogs thus
opening a convenient and scalable way to different molecules
of interesting biomedical potential. This was demonstrated by
the preparation of 15 natural or synthetic alkaloids.
, 60°C, 16 h
O
O
N
N
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N
OH
+
N
OH
5ab
5ab'
R-Isovasicinone (10%)
R-Vasicinone (16%)
ee > 99%
EXPERIMENTAL SECTION
General information
Without chromatography - 2.0 g of R-Vasicinone
We developed a novel synthetic route towards Luotonine A
starting from o-nitrobenzaldehyde and Vasicinone by using iron
pentacarbonyl as a reducing agent. To the best of our
knowledge, no direct condensations of this type were disclosed
earlier. Thus, Luotonine was prepared from 2 molecules of o-
nitrobenzaldehyde and one molecule of hydroxyproline in 3
operational steps (Scheme 7). Even though yields in Luotonine
synthesis were lower than we expected, two new reactions were
found during this work.
Unless otherwise stated, all reagents were purchased from
commercial suppliers and were used without further
purification, THF was distilled over sodium/benzophenone.
1
DMF was distilled over CaH2. H and 13C NMR spectra were
recorded on Bruker AV-300, AV-400, AV-600, and Varian
Inova-400 spectrometers at ambient temperature. Chemical
shifts δ are reported in ppm using the solvent resonance signal
as an internal standard. NMR yields were calculated with
mesitylene, p-dinitrobenzene, or DMF as internal standards
(unless otherwise noted). The following abbreviations were
used to designate chemical shift multiplicities: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad, p =
pentet (quintet); coupling constants are given in Hertz (Hz).
Chemical shifts are reported in parts per million relative to
Scheme 7. Preparation of Luotonine A, Rutaecarpine,
Bromorutaecarpine and Isaindigotone
1. 3-Pyrrolidinole, DMF,
Fe(CO)5, 60°C, 16 h
2. tBuOOH, KI, H2O
25°C, 16 h
O
1
N
CHCl3 (7.26 and 77.16 ppm for H and 13C respectively),
1a
3. , Fe(CO)5,
DMSO (2.50 ppm for 1H, 39.52 for 13C). All 13C NMR spectra
were recorded with proton decoupling.
160°C, 16 h
N
N
1. Piperidine, THF,
Fe(CO)5, -20°C (149 h)
then 25°C (1 h)
2. KMnO4, acetone,
reflux 1 h
3. Aniline, NaNO2, HCl
5°C, 3 h
4. PPA, 160-180°C, 1 h
Luotonine A
High-resolution mass spectra (HRMS) were registered on a
Bruker Daltonics microTOF-Q II hybrid quadrupole time-of-
flight mass spectrometer using electrospray ionization (ESI);
measurements were done in positive ion mode. The voltage on
the capillary was 4500 V; range of scanned masses, m/z 50-
3000; external calibration (Electrospray Calibrant Solution;
Fluka, Germany); nebulizer pressure: 0.4 bar; flow rate: 3
μl/min; nitrogen as dry gas (6 l/min); interface temperature: 180
°C.
7
, 2% from nitrobenzaldehyde
(15% for the last step)
O
O
N
N
HN
NO2
Rutaecarpine
1a
8
, 29% from nitrobenzaldehyde
(83% for the last step)
1. Pyrrolidine,
Enantiomeric excesses were measured using Shimadzu HPLC
equipped with Daicel Chiralpak IA-3 column (4.6 × 150 mm)
and diode array detector. Hexane/isopropanol mixtures were
used as eluent with a flow rate 1 mL/min.
Fe(CO)5, -30°C (16 h)
then 25°C (2 h)
2. KMnO4, acetone,
reflux 1 h
O
N
OMe
N
3. 3,5-dimethoxy-4-
hydroxybenzaldehyde,
AcONa, AcOH,
reflux 15 h,
Analytical gas chromatography (GC) was performed using a
Chromatec Crystal 5000.2 Gas Chromatograph fitted with a
flame ionization detector (He was used as the carrier gas, 37
mL/min) and MS detector. Injections were made on a
Chromatec CR-5 and Chromatec CR-5MS (30 meters) capillary
column. The injector temperature was 250 °C, the FID
temperature was 250 °C, with a split ratio of 50:1. Column
compartment temperature program: 60°C for 4 min, 60°C →
250°C at 30°C/min, 250°C for 10 min. MSD parameters: ion
source temperature 200°C, transfer line temperature 230°C.
Retention times (tR) and integrated ratios were obtained using
Chromatec Analytic Software.
OH
Isaindigotone
OMe
then 25°C, 48 h
9
, 43% from nitrobenzaldehyde
(81% for the last step)
9.5 gram without chromatography
Quinazolinones 5aa and 5ad were used as starting molecules
for the preparation of Isaindigotone and Rutaecarpine
respectively. Isaindigotone was prepared on a gram scale (9.5
g) from o-nitrobenzaldehyde without the need for
chromatography.
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In most cases, chromatographic isolation was done using flash mixture with accurate temperature control is required. Schlenk
1
2
3
4
5
6
7
8
chromatograph InterChim PuriFlash in DCM – MeOH binary
system with UV detection. Details about particular gradient
parameters for chromatography are provided for each
substance.
[α]D20 was measured using PerkinElmer polarimeter Model341
in 10 cm cell (5 mL) at 589 nm.
tube was disconnected from the Schlenk line and put into an
acetone-liquid nitrogen bath. The bath with a Schlenk tube was
allowed to warm up to -30°C. After that, it was allowed to stir
at this temperature overnight. It is very important to warm up
the reaction mixture gradually. If the reaction mixture is
warmed up to about 0°C in 30 minutes after the addition of iron
pentacarbonyl, a very vigorous exothermic reaction initiates,
which leads to self-heating of the reaction mixture.
Concentrated reaction mixture solution (approx. 5 mmol/mL),
being allowed to warm up too fast, emits as much heat as it is
needed to boil the DMF, used as a solvent. This leads to the
preferential formation of anilines 3 with only traces of
quinazolines 4. Products 4 are unstable at elevated temperatures
in the presence of iron pentacarbonyl and transforms into
products 3 under these conditions. After stirring at -30°C
overnight the reaction vessel was allowed to warm up to room
temperature and then stirring was continued for 20 hrs.
Unless otherwise stated, all procedures were carried out under
argon atmosphere using the standard Schleck technique. When
freezing of reaction mixtures below -30 ° C was needed, an
acetone-liquid nitrogen bath was used. Reactions at -30°C were
carried out inside a freezer. Heating was carried out using an oil
bath with a controlled temperature.
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A detailed description of biotests is provided in SI.
General procedure A: Preparation of anilines 3
Appropriate screw-cap Schlenk tube was prepared according to
the standard Schlenk technique and charged with the indicated
amounts of o-nitrobenzaldehyde, amine, and a solvent. The
reaction mixture was frozen in liquid nitrogen to the solid state.
After that, the indicated amount of iron pentacarbonyl was
added. It is also possible to combine the reactants at -70°C or
even at higher temperatures (up to -10°C), but in this case
temperature control should be applied to avoid rapid warming
up of the reaction. At -10°C slow addition of iron carbonyl to
the reaction mixture with accurate temperature control is
required. Schlenk tube was disconnected from the Sсhlenk line
and put into an acetone-liquid nitrogen bath. The bath with the
Schlenk tube was allowed to warm up to room temperature
slowly. The reaction usually initiates at approx. 0°C. It is also
possible to add iron pentacarbonyl to a solution of aldehyde,
then freeze the solution and add amine to the frozen reaction
mixture.
After that, the reaction mixture was quenched with 10% HCl
solution to achieve pH≈1 in the water phase. Then the resulting
mixture was extracted with DCM three times (or until the
organic layer became colorless). The water phase was basified
with NaOH solution to pH 12 and extracted with DCM three
times. In case of reactions for more than 1 mmol scale
intermediate filtration from iron hydroxides may be required.
The combined organic phase after the second extraction
(extraction of basified solution) was dried over sodium sulfate
and concentrated under reduced pressure. GC and NMR
analyses of the resulting mixture show that it contains mostly
quinazoline 4 with 20-50% of aniline 3 and 10-15% of
deoxyvasicine.
Then the organic residue was dissolved in acetone and 10
equivalents of KMnO4, which was grinded to a thin powder
beforehand, were added. The reaction mixture was refluxed for
the indicated time under air. GCMS analysis was used to check
the completeness of reaction. Usually, 1 hour is enough to
achieve complete oxidation to quinazolinone 5. Three hours of
reflux was enough in all cases. It is not recommended to leave
this reaction mixture overnight as deoxyvasicine,
deoxyvasicione and other amines present in this reaction
mixture are more or less strong bases. For example,
deoxyvasicine 4’ is structurally similar to DBU. They can
catalyze acetone self-aldol reaction, leading to 4-hydroxy-4-
methylpentan-2-one formation, which was detected in all
reactions of this type. After the reaction was complete, KMnO4
and MnO2 residues were filtered off, and acetone was removed
under reduced pressure.
After warming up to room temperature, the reaction vessel was
transferred to a preheated oil bath and kept at elevated
temperature for the indicated time (in most cases 120°C for 3
hours). The reaction time at elevated temperatures is important.
Usually, 120°C for 3-6 hours is enough. If the reaction mixture
is left at this temperature overnight, products start to degrade.
After cooling the reaction mixture to room temperature it was
allowed to stir overnight. However, this step is not necessary,
and it is possible to work up the reaction right after cooling it
down. After that, the reaction mixture was quenched with a 10%
HCl solution to achieve pH≈1 in the water phase. Then the
resulting mixture was extracted with DCM three times (or until
the organic layer became colorless). The water phase was
basified with NaOH solution to pH 12 and extracted with DCM
three times. In case of reactions for more than 1 mmol scale
intermediate filtration from iron hydroxides may be required.
The combined organic phase after the second extraction
(extraction of basified solution) was dried over anhydrous
sodium sulfate and concentrated under reduced pressure.
In some cases, the solution has a violet color after filtration as
it contains small amounts of dissolved KMnO4. In this case,
isopropyl alcohol can be added to reduce the soluble KMnO4 to
insoluble MnO2. After that, removal of the solvents in a
vacuum, dissolving of the organic residue in DCM and the
second filtration of the resulting solution is needed.
General procedure B: Preparation of quinazolinones 5
4-hydroxy-4-methylpentan-2-one can be removed under a high
vacuum with heating (its boiling point is 166°C at normal
pressure) or separated chromatographically. Quinazolinones 5
can be purified by standard laboratory techniques or used as-is
for further modifications since their purity after described
workup is about 80-90%.
Appropriate screw-cap Schlenk tube was prepared according to
the standard Schlenk technique and charged with the indicated
amounts of o-nitrobenzaldehyde, amine, and a solvent. The
reaction mixture was frozen in liquid nitrogen to the solid state,
and the indicated amount of iron pentacarbonyl was added. It is
also possible to combine the reactants at -70°C or even at higher
temperatures (up to -10°C), but in this case temperature control
should be applied to avoid rapid warming up of the reaction. At
-10°C very slow addition of iron carbonyl to the reaction
Synthesis of quinazolines 4
1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazoline (4aa)
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Page 6 of 17
25 mL Schlenk tube was prepared according to the standard g (70%) of 4aa as a yellowish solid (eluent: hexane:ethyl
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Schlenk technique and charged with o-nitrobenzaldehyde
(128.6 mg, 100 mol%, 0.85 mmol), pyrrolidine (349 µL, 300
mol%, 4.25 mmol) and 5 mL of THF. The reaction mixture was
frozen in liquid nitrogen to the solid state, and iron
pentacarbonyl (344 µL, 300 mol%, 2.6 mmol) was added.
Schlenk tube was disconnected from the Shlenk line and put
into an acetone-liquid nitrogen bath. The bath with a Schlenk
tube was allowed to warm up to -30°C and the mixture was
stirred at this temperature overnight. After overnight stirring at
-30°C reaction vessel was allowed to warm to room temperature
and stirring was continued for an additional 20 hrs. Some
additional experimental details and considerations are provided
in General procedure B.
acetate:triethylamine = 1:2:0.3, Rf 0.4). Characterization is
provided above with the milligram scale synthesis.
5a,6,7,8,9,11-hexahydro-5H-pyrido[2,1-b]quinazoline (4ad)
Schlenk tube was prepared according to the standard Schlenk
technique and charged with o-nitrobenzaldehyde (2.0 g, 100
mol%, 13.23 mmol), piperidine (3.92 mL, 300 mol%, 39.70
mmol) and 50 mL of THF. The reaction mixture was frozen in
acetone-liquid nitrogen bath to the solid state, and iron
pentacarbonyl (5.33 mL, 300 mol%, 39.70 mmol) was added.
Reaction mixture was slowly warmed up (-110oC → -20oC for
8 h) and stirred (149 h (-20oC) → 2h (0oC) → 1h (r.t)) until dark
brown color developed.
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The reaction mixture was quenched with 10% HCl solution to
achieve pH of water phase around 1, resulting mixture was
extracted with DCM three times (or until colorless organic
layer), the water phase was basified with NaOH solution to pH
12 and extracted with DCM three times. The combined organic
phase after the second extraction (extraction of basified
solution) was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. 70% yield by NMR. 20%
of 4aa was also detected in the reaction mixture. The obtained
dark yellow oil was purified by column chromatography
(eluent: hexane:ethyl acetate:triethylamine = 1:2:0.1 Rf 0.3) to
afford 1.52 g (62%) of the product as a slightly yellow solid.
Melting point 71-73°C (lit. melting point 71-72°C).13
1H NMR (600 MHz, Chloroform-d) δ 7.01 (t, J = 7.7 Hz, 1H),
6.91 (d, J = 7.3 Hz, 1H), 6.68 (t, J = 7.4 Hz, 1H), 6.55 (d, J =
7.9 Hz, 1H), 3.84 – 3.79 (br s, 1H), 3.79 – 3.70 (m, 3H), 3.10 –
3.03 (m, 1H), 2.29 – 2.22 (m, 1H), 1.97 – 1.90 (m, 1H), 1.83 –
1.76 (m, 1H), 1.76 – 1.71 (m, 2H), 1.62 – 1.54 (m, 1H), 1.52 –
1.43 (m, 1H).
The reaction mixture was quenched with 10% HCl solution to
achieve pH of water phase around 1, resulting mixture was
extracted with DCM three times (or until colorless organic
layer), water phase was basified with NaOH solution to pH 12
and extracted with DCM three times. Combined organic phase
after the second extraction (extraction of basified solution) was
dried over anhydrous sodium sulfate and concentrated under
reduced pressure. 74% yield by NMR. 15% of 3aa was also
detected in the reaction mixture. Pure product was isolated by
column chromatography to yield 94 mg (63%) of 4aa as a
yellowish solid (eluent: hexane:ethyl acetate:triethylamine =
1:2:0.3, Rf 0.4). Melting point 63-64°C. (lit. melting point 63-
64°C) 12
1H NMR (400 MHz, Chloroform-d) δ 7.02 (t, J = 7.6 Hz, 1H),
6.95 (d, J = 7.4 Hz, 1H), 6.70 (t, J = 7.7 Hz, 1H), 6.53 (d, J =
7.9 Hz, 1H), 4.18 – 4.11 (m, 1H), 4.04 (d, J = 15.6 Hz, 1H),
3.90 (d, J = 15.6 Hz, 1H), 3.85 – 3.67 (br s, 1H), 3.03 (td, J =
8.8, 5.5 Hz, 1H), 2.68 (dt, J = 8.8, 5.5 Hz, 1H), 2.19 – 2.07 (m,
1H), 2.05 – 1.84 (m, 2H), 1.66 (ddt, J = 12.2, 10.2, 4.4 Hz, 1H).
13C{1H} NMR (151 MHz, Chloroform-d) δ 141.9, 127.6, 126.9,
119.3, 118.3, 114.7, 70.4, 56.1, 52.1, 31.8, 25.3, 21.6.
NMR spectra are in accordance with literature data.13
13C{1H} NMR (101 MHz, Chloroform-d) δ 143.1, 127.4, 127.2,
119.6, 118.2, 115.1, 71.4, 50.7, 50.4, 32.0, 21.3.
NMR spectra are in accordance with literature data. 4a
Reduction
of
1,2,3,3a,4,9-hexahydropyrrolo[2,1-
Gram scale synthesis of 4aa
b]quinazoline with sodium triacetoxyborohydride
250 mL Schlenk tube was prepared according to the standard
Schlenk technique and charged with o-nitrobenzaldehyde (3 g,
100 mol%, 19.85 mmol), pyrrolidine (4.89 mL, 300 mol%,
59.55 mmol) and 50 mL of THF. The reaction mixture was
frozen in liquid nitrogen to the solid state, and iron
pentacarbonyl (8.05 mL, 300 mol%, 59.55 mmol) was added.
Schlenk tube was disconnected from the Shlenk line and put
into an acetone-liquid nitrogen bath. The bath with a Schlenk
tube was allowed to warm up to -30°C and the mixture was
stirred at this temperature overnight. After overnight stirring at
-30°C reaction vessel was allowed to warm to room temperature
and stirring was continued for an additional 20 hrs. Some
additional experimental details and considerations are provided
in General procedure B.
N
NaBH(OAc)3
CH2Cl2
N
N
+
N
H
NH2
NHAc
4aa
3aa
Ac-3aa
A 10 mL vial was charged with sodium triacetoxyborohydride
(182.5 mg, 300 mol%, 0.861 mmol) and a solution of
1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazoline 4aa (50 mg,
100 mol%, 0.287 mmol) in DCM (1 mL) under air. The reaction
mixture was stirred at room temperature for 24 h, then quenched
by adding an aqueous saturated solution of NaHCO3 (3 mL) and
the product was extracted with EtOAc (3x5 mL), dried with
anhydrous Na2SO4, and the solvent was evaporated to give an
yellow oil. 70% NMR yield of aniline 3aa and 15% of acylated
byproduct Ac-3aa.
The reaction mixture was quenched with 10% HCl solution to
achieve pH of water phase around 1, resulting mixture was
extracted with DCM three times (or until colorless organic
layer), the water phase was basified with NaOH solution to pH
12 and extracted with DCM three times. The combined organic
phase after the second extraction (extraction of basified
solution) was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. 73% yield by NMR. 14%
of 3aa was also detected in the reaction mixture. The pure
product was isolated by column chromatography to yield 2.42
NMR spectra (full characterization is provided in
corresponding section):
1
3aa: H NMR (300 MHz, Chloroform-d) δ 7.13 – 7.04 (m, 1H),
7.03 – 6.97 (m, 1H), 6.70 – 6.58 (m, 2H), 4.94 – 4.52 (br s, 2H),
3.62 (s, 2H), 2.50 – 2.43 (m, 4H), 1.80 – 1.72 (m, 4H).
1
Ac-3aa: H NMR (300 MHz, Chloroform-d) δ 11.13 – 10.90
(br s, 1H), 8.26 (d, J = 8.1 Hz, 1H), 7.33 – 7.24 (m, 1H), 7.13 –
7.04 (m, 1H), 7.02 – 6.94 (m, 1H), 3.70 (s, 2H), 2.57 – 2.51 (m,
4H), 2.13 (s, 3H), 1.88 – 1.80 (m, 4H).
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The Journal of Organic Chemistry
N-(3-nitrobenzyl)-2-(pyrrolidin-1-ylmethyl)aniline (6)
NMR spectra are in accordance with literature data. 15
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A 10 mL vial was charged with sodium triacetoxyborohydride
(182.5 mg, 300 mol%, 0.861 mmol), a solution of 1,2,3,3a,4,9-
hexahydropyrrolo[2,1-b]quinazoline 4aa (50 mg, 100 mol%,
0.287 mmol) and 3-nitrobenzaldedhyde (52 mg, 150 mol%,
0.344 mmol) in DCM (1 mL). The reaction mixture was stirred
at the room temperature for 24h, then quenched by adding an
aqueous saturated solution of NaHCO3 (3 mL) and the product
was extracted with EtOAc (3x5mL), dried with anhydrous
Na2SO4, and the solvent was evaporated to give an orange oil.
57% yield by NMR. Product was purified by column
chromatography (eluent: hexane:ethyl acetate:triethylamine =
3:1:0.01, Rf 0.3) to afford 40 mg (45%) of the product as yellow
oil.
1H NMR (400 MHz, Chloroform-d) δ 8.20 (s, 1H), 8.10 (d, J =
8.2 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.49 (dd appears as t, J =
7.9 Hz, 1H), 7.20 – 7.08 (br s, 1H), 7.08 (dd appears as t, J =
8.0 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 6.63 (dd appears as t, J =
7.3 Hz, 1H), 6.43 (d, J = 8.0 Hz, 1H), 4.49 (s, 2H), 3.69 (s, 2H),
2.57 – 2.43 (m, 4H), 1.84 – 1.73 (m, 4H).
(R)-1-(2-aminobenzyl)pyrrolidin-3-ol (3ab)
Some important general details are described in general
procedure A. A dry 100 mL screw-cap Schlenk tube with a
magnetic stirring bar was flushed with argon three times. 2-
Nitrobenzaldehyde (1.0 g, 100 mol%, 6.62 mmol), (R)-
pyrrolidinol (1.73 g, 300 mol%, 19.85 mmol, >99%
enantiomeric purity) (may be prepared by decarboxylation of
chiral hydroxyproline or pursued; procedure for
decarboxylation is provided in the section about Vasicinone
preparation) and 40 mL of DMF were added. The reaction
mixture was frozen with liquid nitrogen up to solid state. Iron
pentacarbonyl (2.68 mL, 300 mol%, 19.85 mmol) was added
under argon atmosphere to a frozen mixture. It was slowly
warmed up to room temperature. Schlenk tube with the reaction
mixture was placed into an oil bath preheated to 60°C and
stirred at this temperature overnight. The reaction mixture was
quenched with conc. HCl (10 mL) and distilled water (100 mL)
(to pH 1-2). This mixture was extracted with dichloromethane
(3×50 mL). The water layer was separated. NaOH was added to
the water layer up to pH 12. It was extracted with
dichloromethane (4×50 mL). Filtration from iron hydroxides
may be required. The organic layer was dried using anhydrous
Na2SO4, and solvent was evaporated. NMR yield 89%. The
residue was purified using preparative flash chromatograph
InterChim PuriFlash in DCM – MeOH binary system (gradient
100% DCM to 10% MeOH in DCM for 30 min, Rf 0.4 in 10:1
DCM:MeOH) to afford 1.030 g (86%) as a white solid. Melting
point 72-73°C. ([α]D20 = +6.5°, 10.3 mg/mL in CHCl3).
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13C{1H} NMR (101 MHz, Chloroform-d) δ 148.7, 147.4, 142.9,
133.2, 129.6, 129.5, 128.4, 123.9, 122.1, 121.8, 116.8, 110.1,
60.0, 53.8, 46.7, 23.8.
+
HRMS: Calculated for C18H22N3O2 ([M+H]+): 312.1707;
Found: 312.1703
Synthesis of anilines 3
2-(pyrrolidin-1-ylmethyl)aniline (3aa)
Some important general details are described in general
procedure A. A dry 25 mL screw-cap Schlenk tube with a
magnetic stirring bar was flushed with argon three times. 2-
Nitrobenzaldehyde (200 mg, 100 mol%, 1.32 mmol) and
pyrrolidine (326 µL, 300 mol%, 3.97 mmol) in 4 mL of THF
were added. The reaction mixture was frozen with liquid
nitrogen up to solid state. Iron pentacarbonyl (536 µL, 300
mol%, 3.97 mmol) was added under argon atmosphere to the
frozen mixture. It was slowly warmed up to room temperature.
Schlenk tube with the reaction mixture was placed into an oil
bath preheated to 120 °C. After 4 h of heating, the reaction
mixture was cooled to room temperature and stirred during 16
h (overnight). The reaction mixture was transferred to a round-
bottom flask and quenched with conc. HCl (2 mL) and distilled
water (30 mL) (to pH 1-2). This mixture was extracted with
dichloromethane (3×30 mL). The water layer was separated.
NaOH was added to the water layer up to pH 12. It was
extracted with dichloromethane (4×30 mL). The organic layer
was dried using anhydrous Na2SO4, and solvent was
evaporated. 81% yield by NMR. The residue was purified using
preparative flash chromatograph InterChim PuriFlash in DCM
– MeOH binary system (gradient 100% DCM to 10% MeOH in
DCM for 30 min, Rf 0.6 in 10:1 DCM:MeOH) to afford 172 mg
(73%) of the product 3aa as a slightly yellow solid. Melting
point 32-34°C (lit. melting point 31-32°C).14 Alternatively this
product can be purified by preparative thin-layer
chromatography (eluent = ethyl acetate:hexane:triethylamine =
13.3:6.6:1; Rf 0.52).
1H NMR (400 MHz, Chloroform-d) δ 7.09 (t, J = 7.6 Hz, 1H),
7.00 (d, J = 7.3 Hz, 1H), 6.71 – 6.60 (m, 2H), 4.35 (s, 1H), 4.14
– 3.76 (br s, 2H), 3.66 (d, J = 12.9 Hz, 1H), 3.61 (d, J = 12.9
Hz, 1H), 2.83 (q, J = 7.5, 6.7 Hz, 1H), 2.66 – 2.52 (m, 2H), 2.34
(q, J = 8.1 Hz, 1H), 2.23 – 2.10 (m, 1H), 1.73 (dt, J = 14.1, 7.2
Hz, 1H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 146.7, 129.9, 128.4,
123.5, 117.8, 115.6, 71.5, 62.8, 59.2, 52.4, 35.1.
Chiral HPLC: Cellucoat
3
column;
1
mL/min
heptane/isopropanol: 95/5; detection at 240 nm. tR (R) = 17.8
min, tR (S) = 20.9 min, ee > 99%.
NMR spectra are in accordance with the literature data.16
(S)-1-(2-aminobenzyl)pyrrolidin-3-ol (3aс)
Some important general details are described in general
procedure A. A dry 100 mL screw-cap Schlenk tube with a
magnetic stirring bar was flushed with argon three times. (S)-
pyrrolidinol hydrochloride (4.91 g, 300 mol%, 39.70 mmol,
>99% enantiomeric purity), potassium tert-butoxide (4.46 g,
300 mol%, 39.70 mmol) and 50 mL of DMF were added.
Resulting suspension was stirred for 30 min. 2-
Nitrobenzaldehyde (2.0 g, 100 mol%, 13.23 mmol) was added.
The reaction mixture was frozen with liquid nitrogen up to solid
state. Iron pentacarbonyl (5.36 mL, 300 mol%, 39.70 mmol)
was added under argon atmosphere to the frozen mixture. It was
slowly warmed up to room temperature. Schlenk tube with the
reaction mixture was placed into an oil bath preheated to 60°C
and stirred at this temperature overnight. The reaction mixture
was quenched with conc. HCl (10 mL) and distilled water (100
mL) (to pH 1-2). This mixture was extracted with
dichloromethane (3×50 mL). The water layer was separated.
NaOH was added to the water layer up to pH 12. It was
extracted with dichloromethane (4×50 mL). Filtration from iron
1H NMR (400 MHz, Chloroform-d) δ 7.08 (t, J = 7.71 Hz, 1H),
7.01 (d, J = 7.33, 1H), 6.68-6.63 (m, 2H), 4.80-4.62 (br s, 2H),
3.62 (s, 2H), 2.49-2.46 (m, 4H), 1.78-1.73 (m, 4H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 147.0, 129.8, 128.2,
123.9, 117.6, 115.4, 59.4, 53.8, 23.7.
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The Journal of Organic Chemistry
Page 8 of 17
hydroxides may be required. The organic layer was dried using 300 mol%, 3 mmol) was added under argon atmosphere to the
1
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4
5
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7
8
anhydrous Na2SO4, and solvent was evaporated. NMR yield
75%. The residue was purified using preparative flash
chromatograph InterChim PuriFlash in DCM – MeOH binary
system (gradient 100% DCM to 10% MeOH in DCM for 30
min, Rf 0.4 in 10:1 DCM:MeOH) to afford 1.75 g (69%) as a
white solid. Melting point 73-74°C. ([α]D20 = -3.7°, 4.3 mg/mL
in CHCl3).
1H NMR (300 MHz, Chloroform-d) δ 7.08 (td, J = 7.4, 1.6 Hz,
1H), 7.00 (dd, J = 7.4, 1.6 Hz, 1H), 6.71 – 6.60 (m, 2H), 4.31
(ddt, J = 7.7, 5.3, 2.7 Hz, 1H), 4.90 – 3.01 (br s, 2H), 3.62 (d, J
= 12.9 Hz, 1H), 3.57 (d, J = 12.9 Hz, 1H), 2.82 – 2.73 (m, 1H),
2.60 – 2.44 (m, 2H), 2.28 (td, J = 8.8, 6.4 Hz, 1H), 2.20 – 2.07
(m, 1H), 1.74 – 1.61 (m, 1H).
frozen mixture. It was slowly warmed up to room temperature.
Schlenk tube with the reaction mixture was placed into an oil
bath preheated to 120 °C. After 3 h of heating, the reaction
mixture was cooled up to room temperature and stirred during
16 h. The reaction mixture was transferred to a round-bottom
flask and quenched with conc. HCl (1 mL) and distilled water
(10 mL) (pH 1-2). This mixture was extracted with
dichloromethane (2×5 mL). The water layer was separated.
NaOH was added to the water layer up to pH 12. It was
extracted with dichloromethane (4×10 mL). The organic layer
was dried using anhydrous Na2SO4, and solvent was
evaporated. NMR yield 73% (with mesitylene as internal
standard). The residue was purified by preparative thin-layer
chromatography (eluent = ethyl acetate:hexane:triethylamine =
33.3:6.6:1, Rf = 0.48) to afford 108 mg (60%) of the product as
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13C{1H} NMR (75 MHz, Chloroform-d) δ 146.5, 129.8, 128.4,
123.5, 117.9, 115.6, 71.2, 62.7, 59.1, 52.4, 34.9.
a white solid. ([α]D = +4.9o, 4.5 mg/mL in CHCl3). Melting
20
Chiral HPLC: Cellucoat
3
column;
1
mL/min
point 81-82°C.
heptane/isopropanol: 95/5; detection at 240 nm. tR (R) = 17.8
min, tR (S) = 20.9 min, ee > 99%
NMR spectra are in accordance with literature data. 17
1H NMR (400 MHz, Chloroform-d) δ 7.09 (t, J = 7.6 Hz, 1H),
7.05 (d, J = 7.3 Hz, 1H), 6.72-6.66 (m, 2H), 3.91 (d, J = 12.5
Hz, 1H), 3.74 (d, J = 12.5 Hz, 1H), 3.61 (dd, J = 10.8, 4.0 Hz,
1H), 3.35 (dd, J = 10.7, 7.1 Hz, 1H), 3.45 – 3.02 (br s, 3H),
2.87-2.79 (m, 1H), 1.11 (d, J = 6.4 Hz, 3H).
2-(piperidin-1-ylmethyl)aniline (3ad)
13C{1H} NMR (101 MHz, Chloroform-d) δ 146.3, 130.1, 128.7,
Some important general details are described in general
procedure A. A dry 25 mL screw-cap Schlenk tube with a
magnetic stirring bar was flushed with argon three times. 2-
Nitrobenzaldehyde (150 mg, 100 mol%, 1 mmol), iron
pentacarbonyl (400 µL, 300 mol%, 3 mmol) and THF (2 mL)
were added. The reaction mixture was frozen with liquid
nitrogen up to solid state. Piperidine (293 µl, 300 mol%, 3
mmol) was added under argon atmosphere to the frozen
mixture. It was slowly warmed up to room temperature. Schlenk
tube with the reaction mixture was placed into an oil bath
preheated to 120 °C. After 3 h of heating, the reaction mixture
was cooled up to room temperature and stirred during 16 h. The
reaction mixture was transferred to a round-bottom flask and
quenched with conc. HCl (2 mL) and distilled water (10 mL)
(pH 1-2). This mixture was extracted with dichloromethane
(2×5 mL). The water layer was separated. NaOH was added to
the water layer up to pH 12. It was extracted with
dichloromethane (4×10 mL). The organic layer was dried using
anhydrous Na2SO4, and solvent was evaporated. NMR yield
85%. The residue was purified by preparative gradient column
chromatography (eluent = EtOAc:hexane (1/100) → (100/1), Rf
0.5) to afford 124 mg (66%) of the product as a slightly yellow
oil.
124.0, 118.2, 116.1, 66.2, 54.3, 49.9, 16.9.
NMR spectra are in accordance with literature data. 19
2-((2-aminobenzyl)amino)-3-methylbutan-1-ol (3af)
Some important general details are described in general
procedure A. A dry 25 mL screw-cap Schlenk tube with a
magnetic stirring bar was flushed with argon three times. 2-
Nitrobenzaldehyde (150 mg, 100 mol%, 1 mmol), iron
pentacarbonyl (400 µL, 300 mol%, 3 mmol) and THF (2 mL)
were added. The reaction mixture was frozen with liquid
nitrogen up to solid state. (S)-(+)-2-Amino-3-methyl-1-butanol
(328 µl, 300 mol%, 3 mmol) was added under argon atmosphere
to the frozen mixture. It was slowly warmed up to room
temperature. Schlenk tube with the reaction mixture was placed
into an oil bath preheated to 120°C. After 3 h of heating, the
reaction mixture was cooled up to room temperature and stirred
during 16 h. The reaction mixture was transferred to a round-
bottom flask and quenched with conc. HCl (1 mL) and distilled
water (10 mL) (pH 1-2). This mixture was extracted with
dichloromethane (2×5 mL). The water layer was separated.
NaOH was added to the water layer up to pH 12. It was
extracted with dichloromethane (4×10 mL). The organic layer
was dried using anhydrous Na2SO4, and solvent was
evaporated. NMR yield 88%. (with mesitylene as internal
standard, average of two experiments). The residue was purified
by preparative thin-layer chromatography (eluent = ethyl
acetate:hexane:triethylamine = 13.3:6.6:1, Rf = 0.5) to afford
1H NMR (400 MHz, Chloroform-d) δ 7.09 (t, J = 7.6 Hz, 1H),
6.97 (d, J = 7.3 Hz, 1H), 6.68-6.63 (m, 2H), 5.02 – 4.93 (br s,
2H), 3.50 (s, 2H), 2.44-2.34 (m, 4H), 1.59-1.53 (m, 4H), 1.48-
1.42 (m, 2H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 147.2, 130.6, 128.4,
122.4, 117.5, 115.6, 62.6, 54.1, 26.1, 24.5.
143 mg (70%) of the product as a beige solid. ([α]D = +19°,
4.8 mg/mL in CHCl3). Melting point 54-56°C.
20
1H NMR (400 MHz, Chloroform-d) δ 7.10 (t, J = 7.6 Hz, 1H),
7.04 (d, J = 7.2 Hz, 1H), 6.72-6.76 (m, 2H), 3.84 (d, J = 12.5
Hz, 1H), 3.78 (d, J = 12.5 Hz, 1H), 3.65 (dd, J = 10.8, 4.0 Hz,
1H), 3.46 (dd, J = 10.9, 6.8 Hz, 1H), 3.52 – 3.14 (br s, 3H),
2.46-2.42 (m, 1H), 1.90 (dq, J = 13.2, 6.7 Hz, 1H), 0.95 (d, J =
6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H).
NMR spectra are in accordance with literature data. 18
2-((2-aminobenzyl)amino)propan-1-ol (3ae)
Some important general details are described in general
procedure A. A dry 25 mL screw-cap Schlenk tube with a
magnetic stirring bar was flushed with argon three times. 2-
Nitrobenzaldehyde (150 mg, 100 mol%, 1 mmol), iron
pentacarbonyl (400 µL, 300 mol%, 3 mmol) and THF (2 mL)
were added. The reaction mixture was frozen with liquid
nitrogen up to solid state. (S)-(+)-2-amino-1-propanol (232 µl,
13C{1H} NMR (101 MHz, Chloroform-d) δ 146.3, 130.1, 128.6,
124.3, 118.2, 116.1, 64.1, 61.3, 50.5, 28.7, 19.3, 18.7.
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The Journal of Organic Chemistry
HRMS: Calculated for C12H21N2O+ ([M+H]+): 209.1648;
Found: 209.1648.
DCM:MeOH) to afford 136 mg (80%) as a beige solid. Melting
point 41-43°C.
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4
5
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7
8
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5-bromo-2-(pyrrolidin-1-ylmethyl)aniline (3ba)
1H NMR (400 MHz, Chloroform-d) δ 6.92 (d, J = 8.4 Hz, 1H),
6.63-6.62 (m, 2H), 5.06-4.74 (br s, 2H), 3.59 (s, 2H), 2.46 (m,
4H), 1.77 (m, 4H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 148.3, 133.5, 130.6,
122.5, 117.3, 115.0, 59.1, 53.8, 23.8.
Some important general details are described in general
procedure A. A dry 25 mL screw-cap Schlenk tube with a
magnetic stirring bar was flushed with argon three times. 4-
bromo-2-nitrobenzaldehyde (150 mg, 100 mol%, 0.65 mmol),
iron pentacarbonyl (263 µL, 300 mol%, 1.97 mmol) and THF
(2 mL) were added. The reaction mixture was frozen with liquid
nitrogen up to solid state. Pyrrolidine (268 µl, 500 mol%, 3.26
mmol) was added under argon atmosphere to the frozen
mixture. It was slowly warmed up to room temperature. Schlenk
tube with the reaction mixture was placed into an oil bath
preheated to 120 °C. After 6 h of heating, the reaction mixture
was cooled up to room temperature and stirred overnight. The
reaction mixture was transferred to a round-bottom flask and
quenched with conc. HCl (3 mL) and distilled water (20 mL)
(pH 1-2). This mixture was extracted with dichloromethane
(2×20 mL). The water layer was separated. NaOH was added to
the water layer up to pH 12. It was extracted with
dichloromethane (3×20 mL). The organic layer was dried using
anhydrous Na2SO4, and solvent was evaporated. NMR yield
97% (with 1,4-dinitrobenzene as internal standard). The residue
was purified using preparative flash chromatograph InterChim
PuriFlash in DCM – MeOH binary system (gradient 100%
DCM to 10% MeOH in DCM for 30 min, Rf 0.3 in 10:1
DCM:MeOH). Isolation using preparative TLC is also possible
(for TLC: Rf = 0.58 in hexane:ethyl acetate:triethylamine =
5:1:0.3) to afford 138 mg (83%) as a beige solid. Melting point
38-39°C.
+
HRMS: Calculated for C11H16ClN2 ([M+H]+): 211.0997;
Found: 211.0997.
4-chloro-2-(pyrrolidin-1-ylmethyl)aniline (3da)
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Some important general details are described in general
procedure A. A dry 25 mL screw-cap Schlenk tube with a
magnetic stirring bar was flushed with argon three times. 5-
chloro-2-nitrobenzaldehyde (150 mg, 100 mol%, 0.81 mmol),
iron pentacarbonyl (326 µL, 300 mol%, 2.43 mmol) and THF
(2 mL) were added. The reaction mixture was frozen with liquid
nitrogen up to solid state. Pyrrolidine (332 µl, 500 mol%, 4.04
mmol) was added under argon atmosphere to the frozen
mixture. It was slowly warmed up to room temperature. Schlenk
tube with the reaction mixture was placed into an oil bath
preheated to 120°C. After 6 h of heating, the reaction mixture
was cooled up to room temperature and stirred overnight. The
reaction mixture was transferred to a round-bottom flask and
quenched with conc. HCl (3 mL) and distilled water (20 mL)
(pH 1-2). This mixture was extracted with dichloromethane
(2×20 mL). The water layer was separated. NaOH was added to
the water layer up to pH 12. It was extracted with
dichloromethane (3×20 mL). The organic layer was dried using
anhydrous Na2SO4, and solvent was evaporated. NMR yield
84% (with 1,4-dinitrobenzene as internal standard). The residue
was purified using preparative flash chromatograph InterChim
PuriFlash in DCM – MeOH binary system (gradient 100%
DCM to 10% MeOH in DCM for 30 min, Rf 0.6 in 10:1
DCM:MeOH) to afford 125 mg (74%) as a beige solid. Melting
point 65-66°C.
1H NMR (400 MHz, Chloroform-d) δ 6.85 (d, J = 7.6 Hz, 1H),
6.76-6.74 (m, 2H), 4.99-4.80 (br s, 2H), 3.55 (s, 2H), 2.44 (m,
4H), 1.75 (m, 4H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 148.5, 130.9, 122.9,
121.6, 120.2, 117.8, 59.1, 53.7, 23.8.
+
HRMS: Calculated for C11H16BrN2 ([M+H]+): 255.0491;
1H NMR (400 MHz, Chloroform-d) δ 7.03-6.98 (m, 2H), 6.54
(d, J = 9.8 Hz, 1H), 4.99-4.56 (br s, 2H), 3.55 (s, 2H), 2.45 (m,
4H), 1.76 (m, 4H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 145.6, 129.3, 127.8,
125.6, 121.9, 116.3, 59.1, 53.8, 23.8.
Found: 255.0494
5-chloro-2-(pyrrolidin-1-ylmethyl)aniline (3ca)
Some important general details are described in general
procedure A. A dry 25 mL screw-cap Schlenk tube with a
magnetic stirring bar was flushed with argon three times. 4-
chloro-2-nitrobenzaldehyde (150 mg, 100 mol%, 0.81 mmol),
iron pentacarbonyl (326 µL, 300 mol%, 2.43 mmol) and THF
(2 mL) were added. The reaction mixture was frozen with liquid
nitrogen up to solid state. Pyrrolidine (332 µl, 500 mol%, 4.04
mmol) was added under argon atmosphere to the frozen
mixture. It was slowly warmed up to room temperature. Schlenk
tube with the reaction mixture was placed into an oil bath
preheated to 120 °C. After 6 h of heating, the reaction mixture
was cooled up to room temperature and stirred overnight. The
reaction mixture was transferred to a round-bottom flask and
quenched with conc. HCl (3 mL) and distilled water (20 mL)
(pH 1-2). This mixture was extracted with dichloromethane
(2×20 mL). The water layer was separated. NaOH was added to
the water layer up to pH 12. It was extracted with
dichloromethane (3×20 mL). The organic layer was dried using
anhydrous Na2SO4, and solvent was evaporated. NMR yield
89% (with 1,4-dinitrobenzene as internal standard). The residue
was purified using preparative flash chromatograph InterChim
PuriFlash in DCM – MeOH binary system (gradient 100%
DCM to 10% MeOH in DCM for 30 min, Rf 0.3 in 10:1
+
HRMS: Calculated for C11H16ClN2 ([M+H]+): 211.0997;
Found: 211.0994
4,5-dimethoxy-2-(pyrrolidin-1-ylmethyl)aniline (3fa)
Some important general details are described in general
procedure A. A dry 25 mL screw-cap Schlenk tube with a
magnetic stirring bar was flushed with argon three times. 4,5-
dimethoxy-2-nitrobenzaldehyde (150 mg, 100 mol%, 0.71
mmol), iron pentacarbonyl (287 µL, 300 mol%, 2.13 mmol) and
THF (2 mL) were added. The reaction mixture was frozen with
liquid nitrogen up to solid state. Pyrrolidine (175 µl, 300 mol%,
2.13 mmol) was added under argon atmosphere to the frozen
mixture. It was slowly warmed up to room temperature. Schlenk
tube with the reaction mixture was placed into an oil bath
preheated to 120 °C. After 6 h of heating, the reaction mixture
was cooled up to room temperature and stirred overnight. The
reaction mixture was transferred to a round-bottom flask and
quenched with conc. HCl (3 mL) and distilled water (20 mL)
(pH 1-2). This mixture was extracted with dichloromethane
(2×20 mL). The water layer was separated. NaOH was added to
the water layer up to pH 12. It was extracted with
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dichloromethane (3×20 mL). The organic layer was dried using reaction mixture gradually. Details are provided in general
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anhydrous Na2SO4, and solvent was evaporated. NMR yield
95% (with 1,4-dinitrobenzene as internal standard). The residue
was purified using preparative flash chromatograph InterChim
PuriFlash in DCM – MeOH binary system (gradient 100%
DCM to 10% MeOH in DCM for 30 min, Rf 0.6 in 10:1
DCM:MeOH) to afford 164 mg (93%) as a beige solid. Melting
point 81-82°C.
1H NMR (400 MHz, Chloroform-d) δ 6.58 (s, 1H), 6.25 (s, 1H),
4.81-4.03 (br s, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.53 (s, 2H),
2.45 (m, 4H), 1.74 (m, 4H).
procedure B. After overnight stirring at -30°C reaction vessel
was allowed to warm to room temperature and stirring was
continued for 20 hrs. The reaction mixture was transferred to a
round-bottom flask and quenched with conc. HCl (2 mL) and
distilled water (30 mL) (to pH 1-2). This mixture was extracted
with dichloromethane (3×30 mL). The water layer was
separated. NaOH was added to the water layer up to pH 12. It
was extracted with dichloromethane (4×30 mL). The organic
layer was dried using anhydrous Na2SO4, and solvent was
evaporated. 86% yield by NMR The residue was purified using
preparative flash chromatograph InterChim PuriFlash in DCM
– MeOH binary system (gradient 100% DCM to 10% MeOH in
DCM for 30 min, Rf 0.7 in 10:1 DCM:MeOH) to afford 153 mg
(77%) of the product 3ag as a slightly yellow oil.
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13C{1H} NMR (101 MHz, Chloroform-d) δ 149.1, 141.0, 140.8,
115.4, 114.9, 100.8, 59.0, 57.0, 55.9, 53.8, 23.7.
+
HRMS: Calculated for C13H21N2O2 ([M+H]+): 237.1598;
Found: 237.1597
1H NMR (400 MHz, Chloroform-d) δ 7.09 (td, J = 7.6, 1.6 Hz,
1H), 6.98 (dd, J = 7.3, 1.5 Hz, 1H), 6.69 – 6.62 (m, 2H), 4.82 –
4.61 (br s, 2H), 3.41 (s, 2H), 2.19 (s, 6H).
3-chloro-2-(pyrrolidin-1-ylmethyl)aniline (3ea)
Some important general details are described in general
procedure A. A dry 25 mL screw-cap Schlenk tube with a
magnetic stirring bar was flushed with argon three times. 2-
chloro-6-nitrobenzaldehyde (150 mg, 100 mol%, 0.81 mmol),
iron pentacarbonyl (326 µL, 300 mol%, 2.43 mmol) and THF
(2 mL) were added. The reaction mixture was frozen with liquid
nitrogen up to solid state. Pyrrolidine (332 µl, 500 mol%, 4.04
mmol) was added under argon atmosphere to the frozen
mixture. It was slowly warmed up to room temperature. Schlenk
tube with the reaction mixture was placed into an oil bath
preheated to 120 °C. After 6 h of heating, the reaction mixture
was cooled up to room temperature and stirred overnight. The
reaction mixture was transferred to a round-bottom flask and
quenched with conc. HCl (3 mL) and distilled water (20 mL)
(pH 1-2). This mixture was extracted with dichloromethane
(2×20 mL). The water layer was separated. NaOH was added to
the water layer up to pH 12. It was extracted with
dichloromethane (3×20 mL). The organic layer was dried using
anhydrous Na2SO4, and solvent was evaporated. NMR yield
80% (with 1,4-dinitrobenzene as internal standard). The residue
was purified using preparative flash chromatograph InterChim
PuriFlash in DCM – MeOH binary system (gradient 100%
DCM to 10% MeOH in DCM for 30 min, Rf 0.7 in 10:1
DCM:MeOH) to afford 130 mg (77%) as a beige oil.
13C{1H} NMR (101 MHz, Chloroform-d) δ 147.2, 130.3, 128.4,
123.4, 117.6, 115.5, 63.5, 45.1.
NMR spectra are in accordance with the literature data. 20
Synthesis of quinazolinones 5
2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (5aa)
6 mmol (0.5 g) scale synthesis is provided here. 10 g scale
synthesis is provided in the section about Isaindigotone
preparation. 50 mL Schlenk tube with a magnetic stirring bar
was prepared according to the standard Schlenk technique and
charged with o-nitrobenzaldehyde (900 mg, 100 mol%, 6
mmol), pyrrolidine (1.48 mL, 300 mol%, 18 mmol) and 12 mL
of THF. The reaction mixture was frozen with liquid nitrogen
up to solid state. Iron pentacarbonyl (2.42 mL, 300 mol%, 18
mmol) was added under argon atmosphere to a frozen mixture.
Schlenk tube was disconnected from the Schlenk line, and put
into the acetone-liquid nitrogen bath. The bath with a Schlenk
tube was allowed to warm up to -30°C and stirred at this
temperature overnight. It is very important to warm up reaction
mixture gradually. Details are provided in general procedure B.
After overnight stirring at -30°C reaction vessel was allowed to
warm to room temperature and stirring was continued for 20
hrs.
1H NMR (400 MHz, Chloroform-d) δ 6.96 (t, J = 8.0 Hz, 1H),
6.73 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 7.9 Hz, 1H), 5.13-4.85 (br
s, 2H), 3.85 (s, 2H), 2.52 (m, 4H), 1.76 (m, 4H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 149.0, 134.3, 128.4,
121.1, 118.7, 114.0, 53.9, 53.5, 23.8.
The reaction mixture was transferred to a round-bottom flask
and quenched with conc. HCl (4.5 mL) and distilled water (20
mL) (to pH 1-2). This mixture was extracted with
dichloromethane (2×10 mL). The water layer was separated.
NaOH was added to the water layer up to pH 12. It was
extracted with dichloromethane (4×20 mL). The organic layer
was dried using anhydrous Na2SO4, and solvent was
evaporated. The mixture of 3aa and 4aa was obtained in the
ratio 1/5 (m = 853 mg, 82%) as a yellowish solid. It was used
in the next step without additional purification.
+
HRMS: Calculated for C11H16ClN2 ([M+H]+): 211.0997;
Found: 211.0997
2-((dimethylamino)methyl)aniline (3ag)
Some important general details are described in general
procedures A and B. A dry 25 mL screw-cap Schlenk tube with
a magnetic stirring bar was flushed with argon three times. 200
mg (1.32 mmol) of 2-nitrobenzaldehyde and dimethylamine
solution in THF (3.68 mL of 1.8 M solution, 6.62 mmol, 500
mol%) were added. The reaction mixture was frozen with liquid
nitrogen up to solid state. Iron pentacarbonyl (536 µL, 300
mol%, 3.97 mmol) were added under argon atmosphere to the
frozen mixture. Schlenk tube was disconnected from the Shlenk
line, and put into the acetone-liquid nitrogen bath. The bath with
a Schlenk tube was allowed to warm up to -30°C and stirred at
this temperature overnight. It is very important to warm up
This organic residue was dissolved in 50 mL of acetone, put
into a round-bottom flask (100 mL), and KMnO4 (9.5 g, 1000
mol%, 60 mmol), grinded to thin powder, was added. The
reaction mixture was refluxed for 1 hour. Some additional
details are provided in general procedure B. After the reaction
was complete, KMnO4 and MnO2 residues were filtered off, and
acetone was removed at reduced pressure. The crude product
has a purity around 90%. It was purified using preparative flash
chromatograph InterChim PuriFlash in DCM – MeOH binary
system (gradient 100% DCM to 10% MeOH in DCM for 30
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The Journal of Organic Chemistry
min, Rf 0.6 in 10:1 DCM:MeOH) to get 598 mg (54% from of reaction KMnO4 and MnO2 residues were filtered off, and
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nitrobenzaldehyde) as a white solid. Melting point 110-115°С
acetone was removed under reduced pressure. The crude
product has a purity around 90%. It was purified using
preparative flash chromatograph InterChim PuriFlash in DCM
– MeOH binary system (gradient 100% DCM to 10% MeOH in
DCM for 30 min, Rf 0.5 in 10:1 DCM:MeOH) to get 90 mg
(38% from nitrobenzaldehyde) as an off-white solid. Melting
point 152-153°С.
1H NMR (400 MHz, Chloroform-d) δ 7.57 – 7.48 (m, 2H), 7.40
(dd, J = 7.4, 1.6 Hz, 1H), 4.19 – 4.15 (m, 2H), 3.15 (t, J = 8.0
Hz, 2H), 2.27 (p, J = 7.8 Hz, 2H).
(lit. melting point 105-107°C).4a
1H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J = 8.0 Hz, 1H),
7.72 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.44 (t, J =
7.5 Hz, 1H), 4.21 (t, J = 7.3 Hz, 2H), 3.18 (t, J = 8.0 Hz, 2H),
2.29 (p, J = 7.8 Hz, 2H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 161.1, 159.5, 149.2,
134.2, 126.8, 126.4, 126.3, 120.5, 46.6, 32.6, 19.6.
NMR spectra are in accordance with literature data.4a
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6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-11-one (5ad)
13C{1H} NMR (151 MHz, Chloroform-d) δ 158.2, 157.2, 149.9,
A round-bottom flask (250 mL) was charged with 4ad (1.2 g,
100 mol%, 63.74 mmol) and 100 mL of acetone. KMnO4 (15.11
g, 500 mol%, 95.61 mmol) was grinded to powder and added to
the reaction mixture. It was refluxed for 4 h (the reaction was
monitored by TLC). Then the reaction mixture was filtered to
separate from MnO2. The dark purple solution was evaporated
under reduced pressure. DCM was added to the rest of reaction
mixture and insoluble MnO2 was filtered off through a pad of
silica gel. The orange solution was evaporated under reduced
pressure. The product was obtained as slightly yellow solid (592
mg) in 46% yield. TLC (eluent: hexane:ethyl
acetate:triethylamine = 1:2:0.1, Rf 0.43). Melting point 79-
82°C (lit. melting point 81-83°C).21
1H NMR (600 MHz, Chloroform-d) δ 8.11 (dd, J = 8.0, 1.5 Hz,
1H), 7.58 (td, J = 7.6, 1.5 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H),
7.29 (t, J = 7.5 Hz, 1H), 3.94 (t, J = 6.3 Hz, 2H), 2.87 (t, J = 6.7
Hz, 2H), 1.86 (dq, J = 32.1, 6.3 Hz, 4H).
13C{1H} NMR (151 MHz, Chloroform-d) δ 161.9, 154.8, 147.1,
134.0, 126.4, 126.1, 125.9, 120.2, 42.2, 31.7, 21.9, 19.2.
132.2, 131.6, 127.1, 124.3, 115.9, 45.0, 30.7, 17.4.
HRMS: Calculated for C11H10ClN2O+ ([M+H]+): 221.0476;
Found: 221.0475
Calculated for C11H9ClN2ONa+ ([M+Na]+): 243.0296; Found:
243.0297
7-chloro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one
(5da)
25 mL Schlenk tube with a magnetic stirring bar was prepared
according to the standard Schlenk technique and charged with
5-chloro-2-nitrobenzaldehyde (200 mg, 100 mol%, 1.08 mmol),
pyrrolidine (266 µL, 300 mol%, 3.24 mmol) and 5 mL of THF.
The reaction mixture was frozen with liquid nitrogen up to solid
state. Iron pentacarbonyl (436 µL, 300 mol%, 3.24 mmol) was
added under argon atmosphere to a frozen mixture. Schlenk
tube was disconnected from the Shlenk line, and put into the
acetone-liquid nitrogen bath. The bath with a Schlenk tube was
allowed to warm up to -30°C and stirred at this temperature
overnight. It is very important to warm up reaction mixture
gradually. Details are provided in general procedure B. After
overnight stirring at -30°C reaction vessel was allowed to warm
to room temperature and stirring was continued for 20 hrs.
NMR spectra are in accordance with literature data.21
8-chloro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one
(5ea)
The reaction mixture was transferred to a round-bottom flask
and quenched with conc. HCl (1.5 mL) and distilled water (20
mL) (to pH 1-2). This mixture was extracted with
dichloromethane (3×30 mL). The water layer was separated.
NaOH solution was added to the water layer up to pH 12. It was
extracted with dichloromethane (4×30 mL). The organic layer
was dried using anhydrous Na2SO4, and solvent was
evaporated.
25 mL Schlenk tube with a magnetic stirring bar was prepared
according to the standard Schlenk technique and charged with
2-chloro-6-nitrobenzaldehyde (200 mg, 100 mol%, 1.08 mmol),
pyrrolidine (266 µL, 300 mol%, 3.24 mmol) and 5 mL of THF.
The reaction mixture was frozen with liquid nitrogen up to solid
state. Iron pentacarbonyl (436 µL, 300 mol%, 3.24 mmol) was
added under argon atmosphere to a frozen mixture. Schlenk
tube was disconnected from the Shlenk line, and put into the
acetone-liquid nitrogen bath. The bath with a Schlenk tube was
allowed to warm up to -30°C and stirred at this temperature
overnight. It is very important to warm up reaction mixture
gradually. Details are provided in general procedure B. After
overnight stirring at -30°C reaction vessel was allowed to warm
to room temperature and stirring was continued for 20 hrs.
This organic residue was dissolved in 50 mL of acetone, put
into a round-bottom flask (100 mL), and KMnO4 (1.7 g, 1000
mol%, 10.8 mmol), grinded to thin powder, was added. The
reaction mixture was refluxed for 1 hour. Some additional
details are provided in general procedure B. After completeness
of reaction KMnO4 and MnO2 residues were filtered off, and
acetone was removed at reduced pressure. The crude product
has a purity around 90%. It was purified using preparative flash
chromatograph InterChim PuriFlash in DCM – MeOH binary
system (gradient 100% DCM to 10% MeOH in DCM for 30
min, Rf 0.7 in 10:1 DCM:MeOH) to get 102.3 mg (43% from
nitrobenzaldehyde) as an off-white solid. Melting point 176-
177°С. (lit. melting point 177°C). 22
1H NMR (400 MHz, Chloroform-d) δ 8.19 (s, 1H), 7.62 (dd, J
= 9.0, 2.1 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H), 4.18 (t, J = 7.3 Hz,
2H), 3.15 (t, J = 7.9 Hz, 2H), 2.28 (p, J = 7.7 Hz, 2H).
13C{1H} NMR (75 MHz, Chloroform-d) δ 160.0, 159.9, 147.7,
134.6, 132.0, 128.5, 125.8, 121.6, 46.7, 32.6, 19.6.
The reaction mixture was transferred to a round-bottom flask
and quenched with conc. HCl (1.5 mL) and distilled water (20
mL) (to pH 1-2). This mixture was extracted with
dichloromethane (3×30 mL). The water layer was separated.
NaOH solution was added to the water layer up to pH 12. It was
extracted with dichloromethane (4×30 mL). The organic layer
was dried using anhydrous Na2SO4, and solvent was
evaporated.
This organic residue was dissolved in 50 mL of acetone, put
into a round-bottom flask (100 mL), and KMnO4 (1.7 g, 1000
mol%, 10.8 mmol), grinded to thin powder, was added. The
reaction mixture was refluxed for 1 hour. Some additional
details are provided in general procedure B. After completeness
23
NMR spectra are in accordance to the literature data
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Page 12 of 17
3-methylquinazolin-4(3H)-one (5ag)
min, Rf 0.7 in 10:1 DCM:MeOH) to get 93 mg (39% from
1
2
3
4
5
6
nitrobenzaldehyde) as an off-white solid. Melting point 187-
100 mL round bottom flask with magnetic stirring bar was
charged with 2-((dimethylamino)methyl)aniline (3ag) (198 mg,
100 mol%, 1.32 mmol), potassium iodide (65.6 mg, 30 mol%,
0.4 mmol), 70% water solution of tert-butyl hydroperoxide was
added (1.8 mL, 1000 mol%, 13.18 mmol) and 1.8 mL of
distilled water. Stirring was continued overnight.
188°С. (lit. melting point 186-188°C).25
1H NMR (300 MHz, Chloroform-d) δ 8.16 (d, J = 8.5 Hz, 1H),
7.59 (s, 1H), 7.36 (d, J = 8.5 Hz, 1H), 4.17 (t, J = 7.3 Hz, 2H),
3.15 (t, J = 8.0 Hz, 2H), 2.28 (p, J = 7.7 Hz, 2H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 160.9, 160.4, 150.2,
7
8
9
The reaction mixture was transferred to a round-bottom flask
and quenched with conc. HCl (1.5 mL) and distilled water (20
mL) (to pH 1-2). This mixture was extracted with
dichloromethane (3×30 mL). The water layer was separated.
NaOH solution was added to the water layer up to pH 12. It was
extracted with dichloromethane (4×30 mL). The organic layer
was dried using anhydrous Na2SO4, and solvent was
evaporated.
140.4, 127.9, 126.9, 126.5, 119.1, 46.7, 32.7, 19.6.
HRMS: Calculated for C11H10ClN2O+ ([M+H]+): 221.0476;
Found: 221.0476
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58
59
60
1H NMR spectrum is in accordance with literature data. 25
6,7-dimethoxy-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-
one (5fa)
25 mL Schlenk tube with a magnetic stirring bar was prepared
according to the standard Schlenk technique and charged with
4,5-dimethoxy-2-nitrobenzaldehyde (200 mg, 100 mol%, 0.947
mmol), pyrrolidine (233 µL, 300 mol%, 2.84 mmol) and 5 mL
of THF. The reaction mixture was frozen with liquid nitrogen
up to solid state. Iron pentacarbonyl (384 µL, 300 mol%, 2.84
mmol) was added under argon atmosphere to a frozen mixture.
Schlenk tube was disconnected from the Sсhlenk line, and put
into the acetone-liquid nitrogen bath. The bath with a Schlenk
tube was allowed to warm up to -30°C and stirred at this
temperature overnight. It is very important to warm up reaction
mixture gradually. Details are provided in general procedure B.
After overnight stirring at -30°C reaction vessel was allowed to
warm to room temperature and stirring was continued for 20
hrs.
The residue was purified using preparative flash chromatograph
InterChim PuriFlash in DCM – MeOH binary system (gradient
100% DCM to 10% MeOH in DCM for 30 min, Rf 0.6 in 10:1
DCM:MeOH) to get 32 mg (15%) as a white solid. Melting
point 110-111°С. (lit. melting point 110-112°C).24
1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J = 8.0 Hz, 1H),
8.05 (s, 1H), 7.79 – 7.67 (m, 2H), 7.50 (t, J = 7.4 Hz, 1H), 3.60
(s, 3H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 161.7, 148.4, 146.9,
134.3, 127.6, 127.4, 126.7, 122.1, 34.2.
NMR spectra are in accordance to the literature data.24
6-chloro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one
(5ca)
The reaction mixture was transferred to a round-bottom flask
and quenched with conc. HCl (1.5 mL) and distilled water (20
mL) (to pH 1-2). This mixture was extracted with
dichloromethane (3×30 mL). The water layer was separated.
NaOH solution was added to the water layer up to pH 12. It was
extracted with dichloromethane (4×30 mL). The organic layer
was dried using anhydrous Na2SO4, and solvent was
evaporated.
25 mL Schlenk tube with a magnetic stirring bar was prepared
according to the standard Schlenk technique and charged with
4-chloro-2-nitrobenzaldehyde (200 mg, 100 mol%, 1.08 mmol),
pyrrolidine (266 µL, 300 mol%, 3.24 mmol) and 5 mL of THF.
The reaction mixture was frozen with liquid nitrogen up to solid
state. Iron pentacarbonyl (436 µL, 300 mol%, 3.24 mmol) was
added under argon atmosphere to a frozen mixture. Schlenk
tube was disconnected from the Shlenk line, and put into the
acetone-liquid nitrogen bath. The bath with a Schlenk tube was
allowed to warm up to -30°C and stirred at this temperature
overnight. It is very important to warm up reaction mixture
gradually. Details are provided in general procedure B. After
overnight stirring at -30°C reaction vessel was allowed to warm
to room temperature and stirring was continued for 20 hrs.
This organic residue was dissolved in 50 mL of acetone, put
into a round-bottom flask (100 mL), and KMnO4 (1.5 g, 1000
mol%, 9,47 mmol), grinded to thin powder, was added. The
reaction mixture was refluxed for 1 hour. Some additional
details are provided in general procedure B. After completeness
of reaction KMnO4 and MnO2 residues were filtered off, and
acetone was removed at reduced pressure. The crude product
has a purity around 80%. It was purified using preparative flash
chromatograph InterChim PuriFlash in DCM – MeOH binary
system (gradient 100% DCM to 10% MeOH in DCM for 30
min, Rf 0.5 in 10:1 DCM:MeOH) to get 121 mg (52% from
nitrobenzaldehyde) as a yellow solid. Melting point 205-206°С.
(lit. melting point 205-207°C).26
1H NMR (600 MHz, Chloroform-d) δ 7.50 (s, 1H), 6.96 (s, 1H),
4.13 (dd, J = 8.0, 6.5 Hz, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.08
(t, J = 7.9 Hz, 2H), 2.22 (p, J = 7.8 Hz, 2H).
13C{1H} NMR (151 MHz, Chloroform-d) δ 160.4, 158.1, 154.7,
148.5, 145.4, 113.7, 107.3, 105.4, 56.3, 56.2, 46.5, 32.4, 19.6.
The reaction mixture was transferred to a round-bottom flask
and quenched with conc. HCl (1.5 mL) and distilled water (20
mL) (to pH 1-2). This mixture was extracted with
dichloromethane (3×30 mL). The water layer was separated.
NaOH solution was added to the water layer up to pH 12. It was
extracted with dichloromethane (4×30 mL). The organic layer
was dried using anhydrous Na2SO4, and solvent was
evaporated.
This organic residue was dissolved in 50 mL of acetone, put
into a round-bottom flask (100 mL), and KMnO4 (1.7 g, 1000
mol%, 10.8 mmol), grinded to thin powder, was added. The
reaction mixture was refluxed for 1 hour. Some additional
details are provided in general procedure B. After completeness
of reaction KMnO4 and MnO2 residues were filtered off, and
acetone was removed at reduced pressure. The crude product
has a purity around 90%. It was purified using preparative flash
chromatograph InterChim PuriFlash in DCM – MeOH binary
system (gradient 100% DCM to 10% MeOH in DCM for 30
6-bromo-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one
(5ba)
25 mL Schlenk tube with a magnetic stirring bar was prepared
according to the standard Schlenk technique and charged with
4-bromo-2-nitrobenzaldehyde (200 mg, 100 mol%, 0.870
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The Journal of Organic Chemistry
mmol), pyrrolidine (214 µL, 300 mol%, 2.61 mmol) and 5 mL The enantiomeric excess was determined by GC using a
1
2
3
4
5
6
7
8
of THF. The reaction mixture was frozen with liquid nitrogen
up to solid state. Iron pentacarbonyl (352 µL, 300 mol%, 2.61
mmol) was added under argon atmosphere to a frozen mixture.
Schlenk tube was disconnected from the Shlenk line, and put
into the acetone-liquid nitrogen bath. The bath with a Schlenk
tube was allowed to warm up to -30°C and stirred at this
temperature overnight. It is very important to warm up the
reaction mixture gradually. Details are provided in general
procedure B. After overnight stirring at -30°C reaction vessel
was allowed to warm to room temperature and stirring was
continued for 20 hrs.
Chromatec Crystal 5000.2 Gas Chromatograph fitted with a
flame ionization detector, on Astec Chiraldex G-TA capillary
column (30m x 250 µm), column temperature = 125 °C
(isothermal), injector temperature
=
250°C, detector
temperature = 250°C, flow rate (He) = 34.26 cm/s, split ratio =
100:1: tR (R) = 24.1 min, tR (S) = 27.1 min, ee > 99%.
(R)-1-(2-aminobenzyl)pyrrolidin-3-ol
(3ab)
scaled-up
experiment
Some important general details are described in general
procedure A. A small scale procedure is described above. A dry
250 mL Schlenk tube with a magnetic stirring bar was flushed
with argon three times. 2-Nitrobenzaldehyde (10 g, 100 mol%,
66.17 mmol), (R)-pyrrolidinol (17.3 g, 300 mol%, 198.52
mmol) and 100 mL of DMF were added. The reaction mixture
was frozen with liquid nitrogen up to solid state. Iron
pentacarbonyl (26.82 mL, 300 mol%, 198.52 mmol) was added
under argon atmosphere to the frozen mixture. It was slowly
warmed up to room temperature. Schlenk tube with the reaction
mixture was placed into an oil bath preheated to 60°C and
stirred at this temperature overnight. The reaction mixture was
quenched with conc. HCl (20 mL) and distilled water (400 mL)
(to pH 1-2). This mixture was extracted with dichloromethane
(3×100 mL). The water layer was separated. NaOH was added
to the water layer up to pH 12. It was extracted with
dichloromethane (4×100 mL). Filtration from iron hydroxides
may be required. The organic layer was dried using anhydrous
Na2SO4, and solvent was evaporated. NMR yield 86%. DMF
residues were removed in high vacuum, and the residue was
dissolved in 50 mL of DCM. The product was purified by flash
chromatography on silica gel (the cake of silica gel had 6 cm in
diameter and 4 cm in height): DCM solution was applied to
silica gel, the cake was washed with 50 mL of DCM, than
washed with 200 mL of DCM and MeOH mixture (10:1 v/v)
(collected separately). Resulting solution was evaporated on the
rotary evaporator to get 13.7 g of the crude oil with 93% purity
(by NMR), used in the next step without additional purification.
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The reaction mixture was transferred to a round-bottom flask
and quenched with conc. HCl (1.5 mL) and distilled water (20
mL) (to pH 1-2). This mixture was extracted with
dichloromethane (3×30 mL). The water layer was separated.
NaOH solution was added to the water layer up to pH 12. It was
extracted with dichloromethane (4×30 mL). The organic layer
was dried using anhydrous Na2SO4, and solvent was
evaporated.
This organic residue was dissolved in 50 mL of acetone, put
into a round-bottom flask (100 mL), and KMnO4 (686 mg, 500
mol%, 4.35 mmol), grinded to thin powder, was added. The
reaction mixture was refluxed for 1 hour. Some additional
details are provided in general procedure B. After completeness
of reaction KMnO4 and MnO2 residues were filtered off, and
acetone was removed at reduced pressure. The crude product
has a purity around 80%. It was purified using preparative flash
chromatograph InterChim PuriFlash in DCM – MeOH binary
system (gradient 100% DCM to 10% MeOH in DCM for 30
min, Rf 0.3 in 50:1 DCM:MeOH) to get 100 mg (43% from
nitrobenzaldehyde) as a white solid. Melting point 223-225°С.
1H NMR (400 MHz, Chloroform-d) δ 8.09 (d, J = 8.5 Hz, 1H),
7.78 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 4.17 (t, J = 7.3 Hz, 2H),
3.16 (t, J = 7.8 Hz, 2H), 2.28 (p, J = 7.6 Hz, 2H).
13C{1H} NMR (75 MHz, Chloroform-d) δ 160.9, 160.6, 150.3,
129.7, 129.7, 128.9, 127.9, 119.5, 46.7, 32.7, 19.6.
(R)-3-hydroxy-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-
HRMS: Calculated for C11H10BrN2O+ ([M+H]+): 264.9971;
Found: 264.9966.
one
((R)-Vasicione,
5ab)
and
(R)-2-hydroxy-2,3-
((R)-
dihydropyrrolo[2,1-b]quinazolin-9(1H)-one
Vasicinone and its isomers
Isovasicinone, 5ab’)
This section describes preparation of natural S-vasicinone and
its enantio- and regioisomers.
200 mL round bottom flask with magnetic stirring bar was
charged with crude (R)-1-(2-aminobenzyl)pyrrolidin-3-ol (3ab)
from the previous step and potassium iodide (3.3 g, 30 mol%,
19.85 mmol) under air atmosphere. Then 70% water solution of
tert-butyl hydroperoxide (90.6 mL, 1000 mol%, 661.72 mmol)
and 90 mL of distilled water were added. Self-heating to
approx. 50°C was noted. Stirring was continued overnight.
(R)-pyrrolidin-3-ol preparation (2b)
Reaction was carried out by modified procedure of Martens et
al.11 A 100 mL stainless steel autoclave with magnetic stirring
bar was charged with (L)-hydroxyproline (48.5 g, 100 mol%,
0.37 mmol), cyclohexanone (3.58 mL, 10 mol%, 37 mmol) and
30 mL of ethanol. Autoclave was sealed, flushed 3 times with
nitrogen and kept at 160°C for 48 hours. Autoclave was cooled
to the room temperature, opened, and the content was
transferred to the 100 mL round bottom flask. Methanol was
used as a rinsing solvent. Solvents were evaporated and the
product was distilled off in vacuum to get 13 g (40%) as a
colorless viscous liquid. Boiling point 80-82°C at 1 mbar.
1H NMR (400 MHz, d6-DMSO) δ 4.17 – 4.11 (m, 1H), 2.91 –
2.82 (m, 1H), 2.76 – 2.63 (m, 2H), 2.61 – 2.56 (m, 1H), 2.51 –
2.48 (m, 1H), 1.75 – 1.65 (m, 1H), 1.55 – 1.46 (m, 1H).
13C{1H} NMR (101 MHz, d6-DMSO) δ 71.0, 55.3, 44.8, 35.6.
NMR spectra are in accordance with literature data. 11
The reaction mixture was transferred to a round-bottom flask
and quenched with conc. HCl (15 mL) and distilled water (200
mL) (to pH 1-2). This mixture was extracted with
dichloromethane (3×100 mL). The water layer was separated.
NaOH solution was added to the water layer up to pH 12. It was
extracted with dichloromethane (4×100 mL). The organic layer
was dried using anhydrous Na2SO4, and solvent was evaporated
to get 4 g of brown oil.
The residue was dissolved in 5 mL of DCM with 2% MeOH
and left at -30°C overnight. 2.0 g (15%) of (R)-Vasicinone 5ab
was obtained as a white precipitate. The mother liquid was
purified using preparative flash chromatograph InterChim
PuriFlash in DCM – MeOH binary system (isocratic elution 3%
MeOH for 20 min, then gradient to 10% MeOH for 20 min), Rf
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The Journal of Organic Chemistry
Page 14 of 17
of 5ab is 0.50 in 10:1 DCM:MeOH and Rf of 5ab’ 0.45 in 10:1
DCM:MeOH) to get 95 mg of 5ab and 1.3 g (10%) of 5ab’ as
a white solid.
1H NMR (600 MHz, Chloroform-d) δ 8.29 (d, J = 8.3 Hz, 1H),
1
2
3
4
5
6
7
8
7.77 – 7.71 (m, 2H), 7.48 (ddd, J = 8.2, 6.4, 2.0 Hz, 1H), 6.36 –
6.27 (br s, 1H), 5.24 (t, J = 7.5 Hz, 1H), 4.36 (ddd, J = 12.4, 8.8,
3.9 Hz, 1H), 4.00 (dt, J = 12.2, 7.7 Hz, 1H), 2.73 – 2.62 (m,
1H), 2.37 – 2.25 (m, 1H).
13C{1H} NMR (151 MHz, Chloroform-d) δ 160.7, 160.5, 148.7,
134.6, 127.1, 126.8, 126.8, 121.1, 72.0, 43.5, 29.6.
(R)-Vasicinone 5ab: Melting point 210-211°C. (lit. melting
point 200-201°C).25 ([α]D20 = +54°, 3.5 mg/mL in CHCl3).
1H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J = 8.0 Hz, 1H),
7.79 – 7.70 (m, 2H), 7.49 (ddd, J = 8.3, 6.0, 2.1 Hz, 1H), 5.76 –
5.69 (br s, 1H), 5.26 (t, J = 7.6 Hz, 1H), 4.38 (ddd, J = 12.4, 8.7,
3.7 Hz, 1H), 4.01 (dt, J = 12.3, 7.8 Hz, 1H), 2.73 – 2.62 (m,
1H), 2.37 – 2.25 (m, 1H).
NMR spectra are in accordance with literature data. 25
Chiral HPLC: Daicel Chiralpak IA-3 column (4.6 × 150 mm);
1 mL/min heptane/isopropanol: 90/10; detection at 254 nm. tR
(R) = 19.2 min, tR (S) = 21.1 min, ee 99%.
9
13C{1H} NMR (101 MHz, Chloroform-d) δ 160.7, 160.6, 148.6,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
134.6, 127.1, 126.7, 126.7, 121.0, 71.9, 43.5, 29.5.
NMR spectra are in accordance with literature data. 25
(S)-Isovasicinone 5ac’: Melting point 159-160°С. ([α]D
+8°, 3.1 mg/mL in CHCl3).
1H NMR (600 MHz, Chloroform-d) δ 8.13 (d, J = 7.6 Hz, 1H),
7.69 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.40 (t, J =
7.5 Hz, 1H), 4.78 (t, J = 4.9 Hz, 1H), 4.32 (d, J = 13.1 Hz, 1H),
4.16 (dd, J = 13.1, 4.8 Hz, 1H), 4.02 – 3.71 (br s, 1H), 3.37 (dd,
J = 17.6, 5.7 Hz, 1H), 3.18 (d, J = 17.6 Hz, 1H).
=
20
Chiral HPLC: Daicel Chiralpak IA-3 column (4.6 × 150 mm);
1 mL/min heptane/isopropanol: 90/10; detection at 254 nm. tR
(R) = 19.2 min, tR (S) = 21.1 min, ee > 99%
(R)-Isovasicinone 5ab’: Melting point 167-168 °С. (lit.
melting point 168-171°C).4b ([α]D = -16°, 4.8 mg/mL in
20
CHCl3). Enantiomeric purity >99% (chiral HPLC).
13C{1H} NMR (151 MHz, Chloroform-d) δ 161.0, 157.9, 148.8,
134.5, 126.7, 126.6, 126.5, 120.5, 65.9, 55.5, 42.4.
1H NMR (300 MHz, Chloroform-d) δ 8.14 (d, J = 7.6 Hz, 1H),
7.70 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.41 (t, J =
7.6 Hz, 1H), 4.83 – 4.75 (m, 1H), 4.33 (d, J = 13.3 Hz, 1H),
4.17 (dd, J = 13.3, 4.7 Hz, 1H), 3.82 – 3.68 (br s, 1H), 3.38 (dd,
J = 17.8, 5.6 Hz, 1H), 3.18 (d, J = 18.1 Hz, 1H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 161.0, 158.0, 148.7,
134.5, 126.6, 126.5, 126.4, 120.3, 65.7, 55.5, 42.4.
Chiral HPLC: Cellucoat
3
column;
1
mL/min
heptane/isopropanol: 80/20; detection at 227 nm. tR (R) = 7.0
min, tR (S) = 5.6 min, ee = 96%.
Luotonine A (7)
1 mL high pressure vial with a magnetic stirring bar was flushed
with argon two times. (R)-Vasicinone (5ab) (30 mg, 0.149
mmol, 100 mol%) and 2-nitrobenzaldehyde 1a with 100 µL of
THF were added. Both organic precursors were grinded to a thin
powder and thoroughly mixed before addition. Iron
pentacarbonyl (60 µL, 0.447 mmol, 300 mol%) was added, the
vial was sealed and kept at 160°C with stirring overnight. Then
the reaction vial was cooled, opened, and its content was
suspended in 20 mL of DCM using ultrasonic bath. Resulting
suspension was filtered through a layer of silica gel (3 cm in
diameter, 2 cm in height). The silica gel cake was washed with
50 mL of ethyl acetate. Combined solution (DCM and ethyl
acetate) was evaporated, and the residue was purified using
preparative flash chromatograph InterChim PuriFlash in hexane
– ethyl acetate binary system (isocratic elution 30% ethyl
acetate for 10 min, then gradient to 100% of ethyl acetate for 20
min) to afford 6.4 mg (15%) as a white solid, Rf of 6 is 0.3 in
1:1 hexane:ethyl acetate mixture. mp: 267-268 °C (lit. mp: 265-
270 °C). 27
NMR spectra are in accordance with literature data. 4b
Chiral HPLC: Cellucoat
3
column;
1
mL/min
heptane/isopropanol: 80/20; detection at 227 nm. tR (R) = 7.0
min, tR (S) = 5.6 min, ee > 99%.
(S)-3-hydroxy-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one
((S)-Vasicinone,
dihydropyrrolo[2,1-b]quinazolin-9(1H)-one
5ac)
and
(S)-2-hydroxy-2,3-
((S)-
Isovasicinone, 5ac’)
50 mL round bottom flask with magnetic stirring bar was
charged with (S)-1-(2-aminobenzyl)pyrrolidin-3-ol (3ac)
(preparation is described above) (740 mg, 100 mol%, 3.85
mmol), then potassium iodide (191 mg, 30 mol%, 1.15 mmol),
70% water solution of tert-butyl hydroperoxide (5.27 mL, 1000
mol%, 38.5 mmol) and 5 mL of distilled water were added
under air atmosphere. Stirring was continued overnight.
The reaction mixture was transferred to a round-bottom flask
and quenched with conc. HCl (1 mL) and distilled water (50
mL) (to pH 1-2). This mixture was extracted with
dichloromethane (3×50 mL). The water layer was separated.
NaOH solution was added to the water layer up to pH 12. It was
extracted with dichloromethane (4×50 mL). The organic layer
was dried using anhydrous Na2SO4, and solvent was
evaporated.
1H NMR (400 MHz, Chloroform-d) δ 8.50 – 8.39 (m, 3H), 8.11
(d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.89 – 7.79 (m,
2H), 7.72 – 7.63 (m, 1H), 7.57 (t, J = 7.5 Hz, 1H), 5.33 (s, 2H).
13C{1H} NMR (101 MHz, Chloroform-d) δ 160.8, 152.7, 151.3,
149.6, 149.5, 134.7, 131.7, 130.8 (2C), 129.6, 128.9 (2C),
128.7, 128.1, 127.6, 126.6, 121.4, 47.5.
NMR spectra are in accordance with literature data. 27
The resulting mixture was purified using preparative flash
chromatograph InterChim PuriFlash in DCM – MeOH binary
system (isocratic elution 3% MeOH for 20 min, then gradient
to 10% MeOH for 20 min), Rf of 5ac is 0.50 in 10:1
DCM:MeOH and Rf of 5ac’ 0.45 in 10:1 DCM:MeOH) to get
109 mg of 5aс (14%) as a white solid and 86 mg of 5ac’ (11%)
as an off-white solid.
Rutaecarpine (8)
The synthesis was done according to procedures, described by
Fang and Zhou.28 For the preparation of phenyldiazonium
chloride, to a cooled solution of aniline hydrochloride (120 mg,
0.94 mmol, 110 mol%) in 20% hydrochloric acid (2 mL) a
solution of sodium nitrite (65 mg, 0.94 mmol, 110 mol%) in
water (2 mL) was added dropwise at 0°C. The reaction mixture
was stirred for 15 min and diluted with acetic acid (4 mL) and
then was adjusted to pH=4 using sodium acetate (0.8g). After
(S)-Vasicinone 5ac: Melting point 200-201°C. (lit. melting
point 200-201°C).15 ([α]D20 = -32°, 3.1 mg/mL in CHCl3).
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that a solution of the quinazolinone (170 mg, 0.85 mmol, 110 A round-bottom flask (2 L) was charged with the mixture of 4aa
1
2
3
4
5
6
7
8
mol%) in 50% acetic acid (5 mL) was added to this solution of
phenyldiazonium chloride dropwise at 0°C over a period of 15
min. The reaction mixture was stirred for 3 h at 5 °C. The
mixture was then allowed to stay overnight in a refrigerator. The
precipitated crystals were collected and washed with water,
dried in vacuum to obtain crude product (E)-6-(2-
phenylhydrazono)-8,9-dihydro-6Hpyrido[2,1-b]quinazolin-
11(7H)-one 245 mg, 95% yield, it was used directly without
further purification.
and 3aa (12.6 g, 46.8 mmol of 4aa, 9.2 mmol of 3aa) at a ratio
of 5/1 (4aa/3aa). Acetone (800 mL) was added. KMnO4 (100
g, 650 mmol) was grinded into powder and added to the reaction
mixture. It was refluxed for 1 h under air atmosphere. Then the
reaction mixture was filtered to remove MnO2. The orange
solution was evaporated under reduced pressure. The reaction
mixture (14.5 g) contained the target compound (5aa) and the
product of condensation between two molecules of acetone
according to 1H NMR spectra in the ratio (1/1 molar ratio). The
side product was evaporated under reduced pressure in high
vacuum. Absence of the product of condensation between two
molecules of acetone was confirmed by GCMS analysis. The
yield of target compound 5aa (53% normalized by the starting
o-nitrobenzaldehide) was determined by 1H NMR with DMF as
an internal standard. The product was used in the next stage
without purification. Some additional considerations are
provided in general procedure B.
9
The obtained hydrazone (200 mg, 0.65 mmol) was added to
polyphosphoric acid (1 g) at 160-180°, and the reaction mixture
was stirred for 60 minutes. pH of the cooled, diluted (with 20
mL of water) reaction mixture was adjusted to 5 with 25%
aqueous ammonia solution and extracted by ethyl acetate (20
mL x 3), the organic phase was dried by anhydrous Na2SO4.
Solvent was removed and the residue was purified by column
cromatofraphy on silica gel using hexane and ethyl acetate (4:1)
to obtain Rutaecarpine: yellow solid, mp: 255 - 258 °C (lit. mp:
257 - 259 °C), 167 mg, 83% yield.29
1H NMR (600 MHz, d6-DMSO) δ 11.60 (s, 1H), 8.06 (d, J = 7.9
Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.55
(d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.40 (t, J = 7.6 Hz,
1H), 7.22 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 4.35 (t, J
= 6.9 Hz, 2H), 3.08 (t, J = 6.9 Hz, 2H).
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60
Step 2. Synthesis of Isaindigotone (9)
The synthetic procedure was similar to described by Jahng.30 A
round-bottom flask (250 mL) was charged with
deoxyvasicinone from the previous step (6.5 g, 35 mmol, 100
mol%), 4-hydroxy-3,5-dimethoxybenzaldehyde (12.7 g, 70
mmol, 200 mol%), AcONa (573 mg, 7 mmol, 20 mol%) and
AcOH (70 mL) under air atmosphere. The reaction mixture was
refluxed for 15 h and then stirred for 48 h to get easy to handle
precipitate. The precipitate was filtered, washed with cool
EtOH and dried under reduced pressure. The product was
obtained as a yellow solid (9.5 g) in 81% yield with 99% purity,
thus it does not require any additional purification. Melting
point 264-270°C (lit. data 248-249°C).31
13C{1H} NMR (151 MHz, d6-DMSO) δ 161.72, 147.86, 145.70,
139.25, 135.34, 127.46, 127.21, 127.18, 126.91, 125.73,
125.55, 121.01, 120.70, 120.68, 118.82, 113.21, 41.62, 19.46.
NMR spectra are in accordance with literature data. 28
Isaindigotone (9)
Total yield of Isaindigatone (normalized to the starting o-
nitrobenzaldehyde) = 43%.
Step 1.1. Synthesis of a mixture of 3aa and 4aa
1H (400 MHz, d6-DMSO) δ: 9.17-8.77 (br s, 1H), 8.12 (d, J =
8.2 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.68-7.66 (m, 2H), 7.45
(t, 7.5 Hz, 1H), 6.95 (s, 2H), 4.18 (t, J = 6.9 Hz, 2H), 3.84 (s,
6H), 3.38-3.30 (m, 2H).
13C{1H} NMR (151 MHz, d6-DMSO) δ: 160.2, 156.1, 149.5,
148.0, 137.1, 134.2, 130.0, 129.3, 126.8, 125.8, 125.7, 125.6,
120.4, 107.7, 56.0, 44.1, 24.9.
Some additional general details are provided in general
procedure B. A dry Schlenk tube (250 mL) with a magnetic
stirring bar was flushed with argon
3
times. 2-
Nitrobenzaldehyde (9.97 g, 100 mol%, 66 mmol), iron
pentacarbonyl (27 mL, 300 mol%, 198 mmol) and THF (132
mL) were added. The reaction mixture was frozen with liquid
nitrogen up to a solid state. Pyrrolidine (27 mL, 500 mol%, 330
mmol) was added under argon atmosphere to the frozen
mixture. Then it was slowly warmed up to -20oC and stirred at
this temperature overnight. Slow warming up is highly
important, see general procedure B. After that the mixture was
warmed up to room temperature and stirred for 2 hours. Then it
was transferred into a beaker (500 mL), 200 mL of distilled
water and 60 mL conc. HCl were added. Reaction mixture was
transferred into a separating funnel (1 L). Acidic water layer
was extracted with CH2Cl2 (2*300 mL). Then organic layer was
washed with acidic water (1*200 mL). NaOH was added to the
water layer up to pH 12. The mixture was cooled to room
temperature and CH2Cl2 (400 mL) was added. Mixture was
stirred for 1 hour and then filtered via Schott’s filter with cotton
to separate the solution from insoluble iron hydroxides. Organic
layer was separated; water layer was extracted with CH2Cl2
(3*200 mL). Combined organic layers were dried over
anhydrous Na2SO4 and solvent was removed under reduced
pressure. NMR analysis with 1,4-dinitrobenzene as an internal
standard showed that organic residue contains 4aa (71%), and
3aa (14%). This mixture (12.6 g) was used in the next stage
without purification.
NMR spectra are in accordance with literature data. 32
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures, compounds characterization, copies of
all relevant spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
* denis.chusov@gmail.com
ACKNOWLEDGMENT
This work was supported by the RFBR (grant number 18-33-
20065) and the Council of the President of the Russian Federation
(Grant for Young Scientists No. MK-1736.2019.3), NMR studies
were performed with the financial support from Ministry of Science
and Higher Education of the Russian Federation using the
equipment of Center for molecular composition studies of INEOS
RAS.
Step 1.2. Synthesis of deoxyvasicinone 5aa
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Chusov D. Synthesis of Nitriles from Aldehydes with
REFERENCES
Elongation of the Molecule with Two Carbon Atoms.
European J. Org. Chem. 2019, 2019, 32–35. (b) Li Y., Dang
J., Liang Q., Yin L. Thermal-Responsive Carbon Monoxide
(CO) Delivery Expedites Metabolic Exhaustion of Cancer
Cells toward Reversal of Chemotherapy Resistance. ACS
Central Science 2019, 5, 6, 1044-1058.
1
2
3
4
5
6
(1) (a) Amin, A. H.; Mehta, D. R. A Bronchodilator Alkaloid
(Vasicinone) from Adhatoda Vasica Nees. Nature 1959, 184,
1317. (b) Sharma, P. C.; Kaur, G.; Pahwa, R.; Sharma, A.;
Rajak, H. Quinazolinone Analogs as Potential Therapeutic
Agents. Curr. Med. Chem. 2011, 18, 4786–4812.
(2) Mhaske, S. B.; Argade, N. P. The Chemistry of Recently
Isolated Naturally Occurring Quinazolinone Alkaloids.
Tetrahedron 2006, 62, 9787–9826.
(8) Nguyen, Q.; Nguyen, T.; Driver, T. G. Iron(II) Bromide-
Catalyzed Intramolecular C–H Bond Amination [1,2]-Shift
Tandem Reactions of Aryl Azides. J. Am. Chem. Soc. 2013,
135, 620–623.
7
8
9
(3) (a) Darras, F. H.; Pockes, S.; Huang, G.; Wehle, S.; Strasser,
A.; Wittmann, H.-J.; Nimczick, M.; Sotriffer, C. A.; Decker,
M. Synthesis, Biological Evaluation, and Computational
Studies of Tri- and Tetracyclic Nitrogen-Bridgehead
Compounds as Potent Dual-Acting AChE Inhibitors and HH3
Receptor Antagonists. ACS Chemical Neuroscience 2014, 5,
225–242. (b) Wang, Y.-Q.; Huang, Z.-L.; Chen, S.-B.; Wang,
C.-X.; Shan, C.; Yin, Q.-K.; Ou, T.-M.; Li, D.; Gu, L.-Q.; Tan,
J.-H.; Huang, Z.-S. Design, Synthesis, and Evaluation of New
Selective NM23-H2 Binders as c-MYC Transcription
Inhibitors via Disruption of the NM23-H2/G-Quadruplex
Interaction. J. Med. Chem. 2017, 60, 6924–6941. (c) Qian, P.;
Deng, Y.; Mei, H.; Han, J.; Zhou, J.; Pan, Y. Visible-Light
Photoredox Catalyzed Oxidative/Reductive Cyclization
Reaction of N-Cyanamide Alkenes for the Synthesis of
Sulfonated Quinazolinones. Org. Lett. 2017, 19, 4798–4801.
(d) Lygin, A. V; de Meijere, A. Ortho-Lithiophenyl
Isocyanide: A Versatile Precursor for 3H-Quinazolin-4-Ones
and 3H-Quinazolin-4-Thiones. Org. Lett. 2009, 11, 389–392.
(e) Xie, F.; Chen, Q.-H.; Xie, R.; Jiang, H.-F.; Zhang, M. MOF-
Derived Nanocobalt for Oxidative Functionalization of Cyclic
Amines to Quinazolinones with 2-Aminoarylmethanols. ACS
Catal. 2018, 8, 5869–5874. (f) Liu, Y.; Chen, G.-Q.; Tse, C.-
W.; Guan, X.; Xu, Z.-J.; Huang, J.-S.; Che, C.-M.
[Fe(F20TPP)Cl]‐Catalyzed Amination with Arylamines and
{[Fe(F20TPP)(NAr)](PhI=NAr)}+ Intermediate Assessed by
High‐Resolution ESI‐MS and DFT Calculations Chem. – An
Asian J. 2015, 10, 100–105. (g) Rasapalli, S.; Sammeta, V. R.;
Murphy, Z. F.; Huang, Y.; Boerth, J. A.; Golen, J. A.; Savinov,
S. N. Synthesis of C-Ring-Substituted Vasicinones and
Luotonins via Regioselective Aza-Nazarov Cyclization of
Quinazolinonyl Enones. Org. Lett. 2019, 21, 9824-9828.
(4) (a) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. α-Amination of
Nitrogen Heterocycles: Ring-Fused Aminals. J. Am. Chem.
Soc. 2008, 130, 416–417. (b) Richers, M. T.; Deb, I.;
Platonova, A. Y.; Zhang, C.; Seidel, D. Facile Access to Ring-
Fused Aminals via Direct α-Amination of Secondary Amines
with o-Aminobenzaldehydes: Synthesis of Vasicine,
Deoxyvasicine, Deoxyvasicinone, Mackinazolinone, and
Ruteacarpine. Synthesis 2013, 45, 1730–1748. (c) Richers, M.
T.; Zhao, C.; Seidel, D. Selective Copper(II) Acetate and
Potassium Iodide Catalyzed Oxidation of Aminals to
Dihydroquinazoline and Quinazolinone Alkaloids. Beilstein J.
Org. Chem. 2013, 9, 1194–1201. (d) Paul, A.; Chandak, H. S.;
Ma, L.; Seidel, D. Redox-Annulations of Cyclic Amines with
Ortho-Cyanomethylbenzaldehydes. Org. Lett. 2020, 22, 976-
980.
(9) Podyacheva, E.; Afanasyev, O. I.; Tsygankov, A. A.;
Makarova, M.; Chusov, D. Hitchhiker’s Guide to Reductive
Amination. Synthesis 2019, 51, 2667–2677.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(10) Kim, S. I.; Lee, S. H.; Lee, E. S.; Lee, C. S.; Jahng, Y. New
Topoisomerases Inhibitors: Synthesis of Rutaecarpine
Derivatives and Their Inhibitory Activity against
Topoisomerases. Arch. Pharm. Res. 2012, 35, 785–789.
(11) Wallbaum, S.; Mehler, T.; Martens, J. Decarboxylation of α-
Amino Acids Containing Two and Three Stereogenic Centers:
A Simple One-Step Procedure to Prepare Two Optically Active
β -Amino Alcohols and a Bicyclic Pyrrolidine Derivative.
Synth. Commun. 1994, 24, 1381–1387.
(12) Dieckmann, A.; Richers, M. T.; Platonova, A. Y.; Zhang, C.;
Seidel, D.; Houk, K. N. Metal-Free α-Amination of Secondary
Amines: Computational and Experimental Evidence for
Azaquinone Methide and Azomethine Ylide Intermediates. J.
Org. Chem. 2013, 78, 4132–4144.
(13) Campi, E. M.; Habsuda, J.; Jackson, W. R.; Jonasson, C. A. M.;
Mccubbin, Q. J. The Stereochemistry of Organometallic
Compounds. XLII. The Preparation of [2,1-b]Quinazolines
Involving Rhodium-Catalysed Hydroformylation of 2-Amino-
N-Alkenylbenzylamines. Aust. J. Chem. 1995, 48, 2023–2033.
(14) Späth, E.; Kuffner, F.; Platzer, N. Über Peganin (Vasicin) Und
Seine Derivate. Berichte der Dtsch. Chem. Gesellschaft (A B
Ser.) 1935, 68, 935–940.
(15) Aga, M. A.; Kumar, B.; Rouf, A.; Shah, B. A.; Andotra, S. S.;
Taneja, S. C. Natural (−)-Vasicine as a Novel Source of
Optically Pure 1-Benzylpyrrolidin-3-Ol. Helv. Chim. Acta
2013, 96, 969–977.
(16) Sharma, S.; Kumar, M.; Kumar, V.; Kumar, N. Metal-Free
Transfer Hydrogenation of Nitroarenes in Water with Vasicine:
Revelation of Organocatalytic Facet of an Abundant Alkaloid.
J. Org. Chem. 2014, 79 (19), 9433–9439.
(17) Ahmad, M.; Aga, M. A.; Bhat, J. A.; Kumar, B.; Rouf, A.;
Capalash, N.; Mintoo, M. J.; Kumar, A.; Mahajan, P.; Mondhe,
D. M.; et al. Exploring Derivatives of Quinazoline Alkaloid L-
Vasicine as Cap Groups in the Design and Biological
Mechanistic Evaluation of Novel Antitumor Histone
Deacetylase Inhibitors. J. Med. Chem. 2017, 60, 3484–3497.
(18) Pete, B.; Szántay, C. An Improved Method for the Synthesis of
2-, 3- and 4-Dialkylaminomethylanilines. Arkivoc 2009, 2009,
78–83.
(19) Jumde, V. R.; Cini, E.; Porcheddu, A.; Taddei, M. A Metal-
Catalyzed Tandem 1,4-Benzodiazepine Synthesis Based on
Two Hydrogen-Transfer Reactions. European J. Org. Chem.
2015, 2015, 1068–1074.
(5) (a) Zhou, F.; Wang, D.-S.; Driver, T. G. Palladium-Catalyzed
Formation of N-Heteroarenes from Nitroarenes Using
Molybdenum Hexacarbonyl as the Source of Carbon
Monoxide. Adv. Synth. Catal. 2015, 357, 3463–3468. (b)
Kochetkov, K. A.; Vasil′eva, T. T.; Gasanov, R. G.; Mysova,
N. E.; Bystrova, N. A. The Use of Iron Carbonyls in the C—C
Bond Formation Reactions. Russ. Chem. Bull. 2019, 68, 1301–
1320.
(6) Afanasyev, O. I.; Usanov, D.; Chusov, D. Hydrogen-Free
Reductive Amination Using Iron Pentacarbonyl as a Reducing
Agent. Org. Biomol. Chem. 2017, 15, 10164–10166.
(7) (a) Afanasyev, O. I.; Zarochintsev, A.; Petrushina, T.;
Cherkasova, A.; Denisov, G.; Cherkashchenko, I.; Chusova,
O.; Jinho, O.; Man-Seog, C.; Usanov, D. L.; Semenov S. E.;
(20) Bao, H.; Wang, D.; Wang, X.; Cheng, C.; Li, Y.; Hu, Y.
Hydrogenation
Aminomethyl)Nitrobenzenes
of
(N,N-Disubstituted
(N,N-Disubstituted
to
Aminomethyl)Anilines Catalyzed by Palladium–Nickel
Bimetallic Nanoparticles. RSC Adv. 2015, 5 (58), 47125–
47130.
(21) Sutherell, C. L.; Ley, S. V. On the Synthesis and Reactivity of
2,3-Dihydropyrrolo[1,2-a]Quinazolin-5(1H)-Ones. Synthesis
2017, 49, 135–144.
(22) Jahng, K. C.; Kim, S. I.; Kim, D. H.; Seo, C. S.; Son, J. K.; Lee,
S. H.; Lee, E. S.; Jahng, Y. One-Pot Synthesis of Simple
Alkaloids:
2,3-Polymethylene-4(3H)-
Quinazolinones,
Luotonin A, Tryptanthrin, and Rutaecarpine. Chem. Pharm.
Bull. 2008, 56, 607–609.
ACS Paragon Plus Environment

Page 17 of 17
The Journal of Organic Chemistry
(23) Ojo, B.; Chowdhury, B. K. Synthesis of {2,3-Dihydro-7-
Halopyrrolo-[(2,1-b)]-Quinazolin-9-(1H)-One and 2,3-
Dihydro-5,7-Dihalopyrrolo-[(2,1-b)]-Quinazolin-9-(1H)-
One}: New Analogs of Deoxyvasicinone. Synth. Commun.
2012, 42, 1002–1009.
(24) Zhao, D.; Wang, T.; Li, J.-X. Metal-Free Oxidative Synthesis
of Quinazolinones via Dual Amination of Sp3 C–H Bonds.
Chem. Commun. 2014, 50, 6471–6474.
(25) Kamal, A.; Ramana, K. V.; Rao, M. V. Chemoenzymatic
Synthesis of Pyrrolo[2,1-b]Quinazolinones: Lipase-Catalyzed
Resolution of Vasicinone. J. Org. Chem. 2001, 66, 997–1001.
(26) Chowdhury, B. K.; Afolabi, E. O.; Osuide, G.; Sokomba, E. N.
Synthesis and Biological Activities of Two New Derivatives of
Deoxyvasicine and Deoxyvasicinone. Indian J. Chem. - Sect.
B Org. Med. Chem. 1985, 24, 789–790.
(28) Fang, J.; Zhou, J. Efficient Syntheses of 2,3-Disubstituted
Natural Quinazolinones via Iridium Catalysis. Org. Biomol.
Chem. 2012, 10, 2389–2391.
1
2
3
4
5
6
7
8
(29) Chen, Z.; Hu, G.; Li, D.; Chen, J.; Li, Y.; Zhou, H.; Xie, Y.
Synthesis and Vasodilator Effects of Rutaecarpine Analogues
Which Might Be Involved Transient Receptor Potential
Vanilloid Subfamily, Member 1 (TRPV1). Bioorg. Med.
Chem. 2009, 17, 2351–2359.
(30) Motiur Rahman, A. F. M.; Jeong, B. S.; Kim, D. H.; Park, J.
K.; Lee, E. S.; Jahng, Y. A Facile Synthesis of α,Α′-
Bis(Substituted-Benzylidene)-Cycloalkanones
and
9
Substituted-Benzylidene Heteroaromatics: Utility of NaOAc as
a Catalyst for Aldol-Type Reaction. Tetrahedron 2007, 63
(11), 2426–2431.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(31) Liu, J.-F.; Ye, P.; Sprague, K.; Sargent, K.; Yohannes, D.;
(27) Baguia, H.; Deldaele, C.; Romero, E.; Michelet, B.; Evano, G.
Copper-Catalyzed Photoinduced Radical Domino Cyclization
of Ynamides and Cyanamides: A Unified Entry to Rosettacin,
Luotonin A, and Deoxyvasicinone. Synthesis 2018, 50, 3022–
3030.
Baldino, C. M.; Wilson, C. J.; Ng, S.-C. Novel One-Pot Total
Syntheses
of
Deoxyvasicinone,
Mackinazolinone,
Isaindigotone, and Their Derivatives Promoted by Microwave
Irradiation. Org. Lett. 2005, 7, 3363–3366.
(32) Wu, X.; Qin, G.; Cheung, K. K.; Cheng, K. F. New Alkaloids
from Isatis Indigotica. Tetrahedron 1997, 53, 13323–13328.
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