Regioselective Br?nsted Acid-Catalyzed Annulation of Cyclopropane Aldehydes with N′-Aryl Anthranil Hydrazides: Domino Construction of Tetrahydropyrrolo[1,2- a]quinazolin-5(1 H)ones

Article abstract of DOI:10.1021/acs.joc.9b03170

A highly regioselective synthesis of tetrahydropyrrolo[1,2-a]quinazolin-5(1H)one derivatives was achieved by reacting cyclopropane aldehydes with N′-aryl anthranil hydrazides in the presence of p-toluene sulfonic acid (PTSA). The transformation involves domino imine formation and intramolecular cyclization to form 2-arylcyclopropyl-2,3-dihydroquinolin-4(1H)-one, followed by nucleophilic ring opening of the cyclopropyl ring to form desired tetrahydropyrrolo[1,2-a]quinazolin-5(1H)one in good to excellent yield with complete regioselectivity. This protocol tolerates a great variety of functional groups and thus provides a simple and step-efficient method for pyrroloquinazolinone synthesis.

Full text of DOI:10.1021/acs.joc.9b03170

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Article
Regioselective Brønsted Acid Catalyzed Annulation of
Cyclopropane Aldehydes with N’-Aryl Anthranil Hydrazides: Domino
Construction of Tetrahydropyrrolo[1,2-a]quinazolin-5(1H)ones
Priyanka Singh, Navpreet Kaur, and Prabal Banerjee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03170 • Publication Date (Web): 21 Jan 2020
Downloaded from pubs.acs.org on January 21, 2020
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Regioselective Brønsted Acid Catalyzed Annulation of Cyclopropane Aldehydes
with
Tetrahydropyrrolo[1,2-a]quinazolin-5(1H)ones
Priyanka Singh, Navpreet Kaur, and Prabal Banerjee*
N’-Aryl
Anthranil
Hydrazides:
Domino
Construction
of
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Department of Chemistry, Indian Institute of Technology Ropar, Nangal Road,
Rupnagar, Punjab 140001, India,
Supporting Information
ABSTRACT: A highly regioselective synthesis of tetrahydropyrrolo[1,2-a]quinazolin-
(1H)one derivatives was achieved by reacting cyclopropane aldehydes with N’-aryl
5
anthranil hydrazides in the presence of PTSA (p-toluene sulphonic acid). The
transformation involves domino imine formation and intramolecular cyclization to form
2
-arylcyclopropyl-2,3-dihydroquinolin-4(1H)-one, followed by nucleophilic ring
opening of the cyclopropyl ring to form desired tetrahydropyrrolo[1,2-a]quinazolin-
(1H)one in good to excellent yield with complete regioselectivity. This protocol
5
tolerates a great variety of functional groups and thus provides a simple and step
efficient method for pyrroloquinazolinones synthesis.
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INTRODUCTION
Over the past few decades, nitrogen-containing heterocycles are among the most
remarkable structural motif of pharmaceuticals that have made a significant
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1
contribution to drug discovery. These covers around 59% of the USFDA approved
2
drugs. Considerable interest has been paid towards their advancement due to the
3
associated diverse biological and pharmacological activities. Pyrroloquinazolinones
and its derivatives have been found as an important core of a variety of natural
4
products and biologically important molecules in the past few years. They often
possess a wide array of biological activities like anti-tumor, antihypertensive, and anti-
inflammatory activity. In addition, some of them are used as thrombin receptor
5
antagonists also (Figure 1). Consequently, synthesis of these interesting nitrogen
heterocycles has become a significant segment of synthetic organic and
pharmaceutical chemistry.
O
O
N
O
N
O
N
H N
2
O
S
O
NH
N
N
N
CH3
CH3
Cl
N
H
O
CH3 HN
F
Quinethazone
antihypertensive, diuretic)
Evodiamine
(thermogenic, stimulant)
Tryptanthrin
Afloqualone
(sedative, muscle-relaxant)
(
(COX-2 inhibitor)
Figure 1. Pharmaceutical molecules having 2,3-dihydroquinazolinone and
pyrroloquinazolinones framework.
Over the time, donor acceptor cyclopropanes (DACs) have emerged as an
inimitable three carbon building block in the arena of organic synthesis for the
6
synthesis of a variety of carbo- and heterocycles. Owing to their high ring strain and
vicinal arrangement of electron releasing and electron accepting groups, easy
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cleavage of C-C bond is facilitated. The engendered 1,3-zwitterionic species7
undergoes various transformation such as cycloaddition reactions, ring opening,
rearrangement and ring expansion reactions towards the formation of diverse high-
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value open-chain and cyclic compounds.8
The classical approach for the synthesis of desired quinazolinones is based on
the direct acid catalyzed condensation of 2-nitrobenzamides and 2-aminobenzamide
9
with carbonyl compounds. Moreover, in 2014, Wu et al. documented the cascade
Palladium-catalyzed/C-H activation reaction of 2-amino-N′-arylbenzohydrazides with
10
triethyl orthobenzoates for the formation of indazolo[3,2-b]quinazolinones. Later, in
2015, Schneider et. al. introduced the one pot [3+2] cycloheteroannulation of bis-silyl
dienediolate with 2-aminobenzamide-derived imines to furnish highly substituted
11
pyrrolo[1,2-a]quinazolinones in good yields (Scheme 1A). Recently, our group has
reported the annulation of cyclopropane aldehydes (CAs) with various aryl hydrazines
towards the formation of tetrahydropyridazine derivatives under Lewis acid catalysis
12
13
(
Scheme 1B). Envisioned by our previous work on cyclopropanes and synthetic
utility of donor acceptor cyclopropanes (DACs) and hydrazides we thought to utilize
cyclopropane aldehydes and N’-aryl benzohydrazides as building block for the
synthesis of pyrroloquinazoline derivatives using facile reaction conditions (Scheme
1C).
In pursuit of discovering a simple and facile route for the synthesis of designed
nitrogen heterocycles, the use of domino reactions can particularly be an attractive
process. Domino reactions involve several bond-forming reactions in a one-pot
operation and allow the highly efficient synthesis of complex molecules starting from
simple substrates.14 They feature operational simplicity, improvement of efficiency,
15
avoidance of toxic reagents and the reduction of waste. The quality and importance
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of a domino reaction can be associated with the number of bonds generated and
16
complexity increased in the process. Hence, performing the reaction of CAs with N’-
aryl anthranil hydrazides in domino fashion can be a useful platform for the simple and
efficient construction of designed pyrroloquinazolinone derivatives in step economic
manner.
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To the best of our knowledge, no previous report for the synthesis of
pyrroloquinazolinones through annulation of CAs with hydrazides have been reported
so far. Therefore, keeping these reactivities in mind, herein, we report a Bronsted acid
catalyzed regioselective annulation of CAs and N’-aryl anthranil hydrazides to furnish
tetrahydropyrrolo[1,2-a]quinazolin-5(1H)ones along with a broad substrate scope.
Scheme 1. Reactivity of benzohydrazides/hydrazines with different aldehydes
A. Previous reports
Wu et. al.10
O
H
O
N
R2
N
C(OEt)3
N
H
R2
Pd(OAc) , AgOAc
N
R1
R3
2
N
R1
+
R3
NH2
AcOH, 120 C, 48 h
Schneider et. al.11
O
N
O
OTMS
OEt
1) 20 mol% Sm(OTf)3
2) 1 equiv DNBSA
O
NH2
NH
CO Et
2
+
+
NH2
R1
H
CH Cl /t-BuOH (2:1)
2
2
OTMS
-20 °C
R1
B. Our previous work12
Ar1
Ar2
Ar2 NH
Lewis acid, MS
DCM, rt
+
Ar1
CHO
NH2
N
N
C. This work
O
N
O
H
H
N
N
Ar2
Ar2
Acid catalyst
DCM, rt
N
N
+
H
Ar1
CHO
NH2
Ar1
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RESULT AND DISCUSSION
To evaluate our hypothesis, we started the investigation with cyclopropane aldehyde
a and anthranil hydrazide 2a as model substrate, and the results are summarized in
1
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Table 1. Knowledge gained from the success of our recent studies on the reactivity of
CAs with N-benzyl amines and aryl hydrazine derivatives12,17 drove us to start this
optimization with different Brønsted acids at room temperature. At first, we started with
the reaction of 1a and 2a in the presence of 30 mol% of acetic acid in ethanol; the
desired cycloadduct 3aa was obtained in 10% yield (Table 1, entry 1). Different
Brønsted acids were then examined for the following transformation in
dichloromethane. To our delight, in the presence of 30 mol% of PTSA (p-toluene
sulphonic acid) reaction got completed in 10 h, affording the final cycloadduct 3aa with
85% yield (Table 1, entry 2). When we proceeded to use TFA (trifluoroacetic acid)
and triflic acid, the reaction got completed in 8 h and 4 h, respectively. In both cases,
the reaction yield got decreased to 70% and 60%, respectively, which may be due to
the decomposition of the cyclopropane aldehyde during the reaction (Table 1, entry
3-4). Further, on moving to CSA (camphor sulphonic acid), reaction yield got increased
to 80%. Whereas on using 2,4-DNBSA (2,4-dinitrobenzene sulphonic acid) for the
transformation, meagre amount of compound 3aa was obtained with a yield of 10%
(Table 1, entry 5-6). Conducting the reaction with a catalyst loading of 20% decreased
the yield to 75% while increasing the catalyst loading from 50 to 100 mol%, increased
the yield of the final product 3aa to 90% within the same duration of time (10 h) (Table
1, entry 7-9).
For further optimization, PTSA was chosen as the most promising catalyst for
the cycloaddition of 1a and 2a, and a variety of solvents were then screened. In the
presence of alcoholic solvents like ethanol and methanol, yield got decreased due to
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the incomplete conversion of intermediate bicyclic compound 4 to the final cycloadduct
3
aa (Table 1, entry 10-11). The incomplete conversion was also noticed in the case
of ACN, THF, DCE, and toluene, leading to the decreased yield of the final compound
aa (Table 1, entry 12-15). No formation of the final cycloadduct was observed when
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the 1a and 2a were made to react in the absence of catalyst (Table 1, entry 16).
Thereupon, on the basis of the above optimization results, we choose 30 mol% PTSA
in DCM solvent at room temperature as an optimal reaction condition for the annulation
of 1a with 2a.
Table 1. Optimization of reaction conditionsa
O
O
H
H
N
N
CHO
N
Catalyst
N
+
H
Solvent, rt
O
NH2
N
1a
2a
O
3aa
S. No. Catalystb
Loading
Solventc Time (h) dr ratio Yield (%)d
(mol%)
1
2
3
4
5
6
7
8
9
1
AcOH
PTSA
TFA
Triflic acid
CSA
2,4-DNBSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
30
30
30
30
30
30
20
50
EtOH
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
EtOH
MeOH
ACN
12
10
08
04
10
14
10
10
10
12
12
12
12
12
12
24
20:80
34:66
33:67
30:70
33:67
20:80
32:68
34:66
35:65
25:75
25:75
25:75
25:75
30:70
25:75
10
85
70
60
80
10
75
87
90
45
45
53
50
60
30
0
1 equiv
30
0
11
30
30
30
30
30
-
12
13
14
15
PTSA
PTSA
PTSA
No catalyst
THF
DCE
Toluene
DCM
16
-
a
b
Reactions were carried out with 1.2 equiv of 1a and 1 equiv of 2a. AcOH = acetic
acid, TFA = trifluoro acetic acid, PTSA = p-toluene sulphonic acid, CSA = camphor
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sulphonic acid, 2,4-DNBSA = 2,4-dinitro benzenesulphonic acid. cDCM =
dichloromethane, EtOH = ethanol, MeOH = methanol, ACN = acetonitrile, THF =
d
tetrahydrofuran, DCE = dichloroethane. Isolated yield.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
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5
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5
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6
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0
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2
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6
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8
9
0
1
2
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4
5
6
7
8
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Using the optimized reaction conditions, we further checked the generality of
the method with a variety of aryl substituted CAs 1a-k having different steric and
electronic properties with hydrazide 2a (Table 2). Both electron-rich and electron-
deficient aromatic groups were found similarly viable for the following transformation,
affording the desired product in good to excellent yields (70-85%). Substrates bearing
unsubstituted phenyl 1b and 4-methyl substituents 1c took a comparatively longer time
to complete the annulation as compared to the substrate having 3,4-dimethoxy groups
on the phenyl ring 1d with almost similar yields. Perhaps this may be due to the high
electron donating capability of the two methoxy groups, which makes the cyclopropane
aldehyde 1d more active as compared to other carbaldehydes (1a-1c). On the
contrary, substrates with fluoro 1e, chloro 1f, and bromo 1g substituent at the 4-
position of the aryl group displayed a similar reactivity for the ensuing annulation by
furnishing the products in good yields. Other aromatic analogs like 2-naphthyl 1h and
cinnamyl 1i groups with extended π-system were also checked for the reaction. The
reaction with 2-naphthyl cyclopropane aldehyde 1h was done at reflux conditions to
afford the desired adduct with slightly lesser yield (78%). In addition, 2-furyl substituted
CA 1j was also examined, it resulted in the construction of final adduct in a longer time
but with comparatively good yield. Starting with the fused cyclopropane aldehyde 1k,
octahydroindolo[1,2-a]quinazolin-5(6H)-one 3ka with fused [6-6-5-6] tetracyclic
framework was obtained at reflux conditions in good yield (70%). In total, we have
subjected 11 different CAs for following cycloaddition reaction, thereby demonstrating
the good functional group tolerance for the transformation. The geometry of both the
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
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diastereoisomers (trans and cis) of 3aa was established on the basis of NOE
experiment.
Table 2. Scope investigation with regard to cyclopropane aldehydea,b
0
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2
3
4
5
6
7
8
9
0
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2
3
4
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9
0
O
O
N
O
H
H
N
H
N
N
N
PTSA (30 mol%)
dry DCM, rt
N
N
+
H
H
+
H
CHO
Ar
NH2
N
1
2a
Ar
Ar
H
H
3
(trans)
minor
3' (cis)
major
O
N
N
O
N
O
O
N
H
H
N
H
H
N
N
N
N
N
N
N
MeO
MeO
3
aa
3ba
3ca
3da
MeO
Me
8
5%, 10 h, 34:66
83%, 10 h, 35:65
80%, 11 h, 32:68
81%, 9 h, 40:60
O
N
O
N
O
O
N
H
H
N
H
H
N
N
N
N
N
N
N
N
F
Cl
Br
3ga
3hac
3
ea
3fa
8
2%, 11 h, 35:65
82%, 10 h, 35:65
81%, 11 h, 35:65
7
8%, 14 h, 36:64
O
N
O
N
O
H
N
H
N
H
N
N
N
N
N
O
3kac
3ia
3ja
79%, 11 h, 35:65
82%, 12 h, 35:65
70%, 18 h, 30:70
aUnless otherwise specified all the reactions were carried out in DCM at rt with 1.2
b
equiv of 1 and 1 equiv of 2a in the presence of PTSA (30 mol%). Isolated yield.
cReaction was performed at reflux conditions.
Later on, the generality and viability of the reaction was explored with respect
to N’-aryl substituted anthranil hydrazides/amides 2a-i by reacting them with 4-
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methoxyphenyl cyclopropane aldehyde 1a (Table 3). To our delight, benzohydrazide
derivatives bearing electron releasing substituents like 4-methyl 2a and 4-isopropoyl
2b on N’-phenyl ring, afforded the cycloadduct with appreciable yields. While anthranil
hydrazides having N’-phenyl ring substituted with deactivating groups like 4-fluoro 2d,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4-chloro 2e, and 4-bromo 2f rendered in the formation of the final product with good
yields. Further, N’-benzyl substituted hydrazide 2g led to the amalgamation of
cycloadduct 3ag with a diastereomeric ratio of 20:80 in 81% yield. The stereochemistry
of both the diastereoisomers were fixed on the basis of the single crystal X-ray
analysis. In order to check the effect/utility of hydrazides for the following
transformation, benzamides 2i and 2h were used in place of hydrazides. Both N-
benzyl anthranilamide (2h) and N-phenyl anthranilamide (2i) resulted in the formation
of final tricyclic tetrahydropyrroloquinazolin-5-one derivatives 3ah and 3ai,
respectively, in good yields with a diastereomeric ratio of approximately 3:1. However,
the separation of diastereomeric mixture in both the cases was not feasible via thin
layer and column chromatography and the mixture was isolated as such from the
column without separation. The relative configuration of both the diastereomers (cis
and trans) was established on the basis of the NOE experiment data of 3aa and 3aa’
and was further supported by the X-ray structural analysis of both the diastereomers
of 3ag (see supporting information Figure S1 and S2). Therefore, configuration of both
the diastereomers for all the synthesized cycloadducts was set on the basis of
structural analogy.
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 3. Scope investigation with regard to anthranil hydrazidea,b
O
O
N
R
N
R
H
N
O
H
R
N
CHO
PTSA (30 mol%)
dry DCM, rt
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
H
H
H
MeO
NH2
1a
2
MeO
MeO
3
(trans)
minor
3' (cis)
major
O
O
H
O
N
H
H
N
N
N
N
N
N
Me
Me
N
Me
N
F
3
ab
3ac
3ad
MeO
MeO
MeO
7
8%, 9 h, 35:65
79%, 10 h, 34:66
80%, 11 h, 34:66
O
N
O
N
O
N
H
N
H
N
H
N
N
N
N
Cl
Br
MeO
MeO
MeO
3ae
3af
3ag
81%, 10 h, 35:65
81%, 10 h, 33:67
81%, 10 h, 20:80
O
N
O
N
N
N
MeO
MeO
3ah
3ai
81%, 8 h, 50:50
81%, 9 h, 30:70
aUnless otherwise specified all the reactions were carried out in DCM at rt with 1.2
b
equiv of 1a and 1 equiv of 2 in the presence of PTSA (30 mol%). Isolated yield.
Finally, in order to better understand the proposed annulation mechanistically,
several control experiments were carried out. Firstly, to check the inevitability of acid
catalyst for the transformation, the annulation reaction of N’-phenyl anthranil hydrazide
2a with 4-methoxyphenyl CA 1a was executed in the absence of PTSA. The formation
1
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of bicyclic product 4 with diastereomeric ratio of 1:1 with 60% yield was only perceived
in 14 h, indicating the importance of acid catalyst for the formation of final cycloadduct
(Scheme 2a). Further, the obtained dihydroquinazolin-4-one 4 was then treated with
PTSA (30 mol%) in DCM for 10 h and led to the construction of tetrahydropyrrolo[1,2-
a]quinazolin-5(1H)-one 3aa with 90% yield (Scheme 2b). Indicating that the reaction
of anthranil hydrazides 1 with cyclopropane aldehydes 2 proceeds through the
formation of dihydroquinazoli-4-one intermediate 4 first, followed by the formation of
the final tricyclic adduct 3. Next, to validate the formation of tetrahydropyrrolo[1,2-
a]quinazolin-5(1H)-ones 3 over hexahydro-10H-pyridazino[6,1-b]quinazolin-10-one 6,
N-methyl substituted anthranil hydrazide 2j made to react with cyclopropane aldehyde
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1a in the presence of PTSA. The following reaction resulted in the formation of bicyclic
adduct 5 only, ruling out the possibility of formation [6-6-6] fused tricyclic adduct 6
(Scheme 2c). This may be due to the reduced kinetic favourability for the formation of
6-membered ring over the 5-membered ring. The structure and configuration of the
formed bicyclic adduct 5 was also confirmed by X-ray structure analysis (see
supporting information Figure S3). It was also further supported by the reaction of 2-
amino benzamide 2i with cyclopropane aldehyde 1a, the construction of final
tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-ones 3ai was observed with 81% yield
(Scheme 2d).
On the basis of the above results, we have proposed a plausible mechanism,
as shown in scheme 3, for the following annulation reaction. The reaction proceeds
through the formation of intermediate imine A via the reaction of cyclopropane
aldehyde 1 with anthranil hydrazide 2. Formed imine A then undergoes intramolecular
cyclization with N-atom of the hydrazide linkage and leads to the formation of
intermediate dihydroquinazolin-4-ones B with intact cyclopropane ring. The structure
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
of the formed bicyclic intermediate B is confirmed by H and 13C NMR spectra.
Cyclopropyl ring of the intermediate B then undergoes nucleophilic ring opening and
cyclization with the N-atom of the quinazoline ring rather than N’-atom of the phenyl
ring, which eventually leads to the construction of the final cycloadduct 3. The nitrogen
atom of N’-phenyl group of intermediate B does not participate in the final cyclization,
eliminating the formation of tricyclic compound 6.
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2: Control Experiments
a)
O
H
N
O
H
N
N
N
+
H
CHO
DCM, rt
14 h, 60%
N
H
NH2
O
2a
1a
O
4
b)
O
O
H
H
N
N
N
N
PTSA (30 mol%)
DCM, rt
N
N
10 h, 90%
H
O
O
4
3aa
c)
O
O
H
N
H
N
PTSA (30 mol%)
N
N
H
+
1a
H
H
DCM, rt
10 h, 86%
N
NH
CH3
CH3
H
2j
O
5
d)
O
N
O
N
PTSA (30 mol%)
N
H
+
1a
DCM, rt
9 h, 81%
NH2
2i
O
3ai
1
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Scheme 3: Proposed Mechanism
O
H
N
N
Ar2
H
O
N
O
H
H
NH2
Intramolecular
cyclization
N
N
Ar2
Ar2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
2
H
Ar1
CHO
Ar1
- H2O
N
H
Imine formation
1
A
Ar1
B
Nucleophilic
ring opening
PTSA
Ar2
O
O
H
Ar1
N
N
Ar2
N
N
N
N
H
Ar1
6
(not observed)
3
Having plenty of cycloadduct in hand, following cycloaddition was carried out in
one pot via in situ generations of anthranil hydrazide 2a in the reaction mixture starting
from Isatoic anhydride 7 (1 equiv) and phenyl hydrazine 8 (1 equiv) under reflux
conditions in dry ACN. After the complete consumption of phenyl hydrazine 8 in
reaction mixture, as observed from thin layer chromatography. CA 1a (1.1 equiv) and
PTSA (30 mol%) were then added to the reaction mixture and refluxed for overnight
till completion of reaction. The desired cycloadduct 3aa was obtained in 50% yield with
dr 30:70 (Scheme 4).
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 4: One pot sequential synthesis of 3aa
O
O
H
H
N
N
N
O
NH2
+
H
dry ACN, reflux, 8 h
NH2
N
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
7
8
2a
O
H
N
CHO
N
MeO
N
1a
PTSA, dry ACN,
reflux, overnight
MeO
3
aa
dr 30:70
0% yield
5
Further to check synthetic potentiality of the synthesized tetrahydropyrrolo[1,2-
a]quinazolin-5(1H)one derivates, debenzylation of the compound 3ag was performed
in the presence of H2 and Pd/C to provide the corresponding 4-amino-
tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one 9. The obtained free NH group of
2
compound 9 can be further utilized for post functionalization of the tetrahydropyrrolo
quinazolin-5-one derivatives (Scheme 5).
Scheme 5: Debenzylation of 3ag
O
N
O
N
H
N
NH2
N
H , Pd/C
N
2
MeOH, rt, 12 h
73%
MeO
MeO
3ag
9
To investigate the stereospecificity of the ring opening process, an
enantioenriched cyclopropane carbaldehyde 1b was employed in the mentioned
reaction (Scheme 6). Formation of the enantioenriched annulated product 3ba and
1
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3
ba’ with 86% and 88% ee, respectively, established that the reaction proceeds in a
stereospecific manner (see supporting information pp-S228 for details).
Scheme 6: Stereospecificity of the ring opening
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
H
O
N
H
N
O
N
H
H
N
N
N
PTSA
H
CHO
N
+
H
N
+
DCM, rt,
NH2
12 h
H
H
8
4% yield
dr 3:7
1b
2a
(88% ee)
3ba
3ba'
(88% ee)
(86% ee)
Gram scale synthesis for the proposed annulation using 4-methoxyphenyl
cyclopropane aldehyde 1a and N’-phenyl anthranil hydrazide 2a as substrate was also
performed (Scheme 7). To our delight final product 3aa was obtained with excellent
yield (81% yield), indicating the importance of proposed protocol for larger scale
syntheses.
Scheme 7: Gram scale synthesis
O
H
O
N
H
N
N
PTSA
CHO
N
+
H
N
DCM, rt,
12 h
MeO
NH2
1a
2a
(0.93 g, 5.28 mmol)
(1 g, 4.40 mmol)
MeO
3aa
dr 30:70
(1.37 gm, 3.55 mmol)
81%
CONCLUSION
In conclusion, we have developed a simple and efficient step economic method for the
synthesis of tetrahydropyrrolo[1,2-a]quinazolin-5(1H)one derivatives by reacting
cyclopropane aldehydes and N’-aryl anthranil hydrazides with complete
1
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
regioselectivity. The reaction follows a domino sequence of imination/intramolecular
cyclization/nucleophilic ring opening. A wide range of cyclopropane aldehydes and
hydrazides have been screened for the synthesis of highly functionalized
pyrroloquinazolinone derivatives with good to excellent yields.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EXPERIMENTAL SECTION
General information. All solvents and reagents were obtained from commercial
sources and were purified following the standard procedure prior to use. The
developed chromatogram was analyzed by UV lamp (254 nm) or p-anisaldehyde
solution. Products were purified by flash chromatography on silica gel (mesh size 230–
1
13
4
00). Unless otherwise specified, all the H NMR and C NMR spectra were recorded
1
13
in CDCl . Chemical shifts of H NMR and C NMR spectra are expressed in parts per
3
million (ppm). All coupling constants are absolute values and are expressed in Hertz.
The description of the signals includes the following: s = singlet, d = doublet, dd =
doublet of doublet, t = triplet, dt = doublet of triplet, q = quartet, br = broad, and m =
13
multiplet. All C spectra were recorded with broadband proton decoupling.
Isatoic anhydride 7, N-methyl isatoic anhydride, base free phenyl hydrazine
derivatives were obtained according to the reported procedures.18-20
General Procedure for the preparation of trans-2-arylcyclopropanealdehydes
(
1a-j)12,13c,17 For the reaction schemes, see Scheme S1 in the Supporting Information.
1) To a mixture of triethyl phosphonoacetate (22.0 mmol, 1.1 equiv.), DBU (0.70
mmol, 0.035 equiv.), and finely ground K CO (40 mmol, 2 equiv.) was added
2
3
ArCHO (20 mmol, 1 equiv.), and the resulting mixture was stirred using a magnetic
stirrer for 4 h at room temperature under argon atmosphere. Ethyl acetate was
added to the crude mixture and the solid was filtered off. The solid was rinsed with
1
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ethyl acetate, and the combined filtrate was concentrated. The resulting oil was
distilled under reduced pressure using a bulb-to-bulb apparatus (10 mm Hg/240
°C) to give corresponding alkene (yield 84%) (E:Z =99:1).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
) A suspension of TMSOI (16.8 mmol, 1.2 equiv.) and NaH (21 mmol, 1.5 equiv.) in
anhydrous DMSO (15 mL) was stirred for 1 h. A DMSO solution (15 mL) of alkene
(14 mmol, 1 equiv.) was added at 0 °C. The reaction mixture was stirred at 55 °C
for 24 h. Another suspension of TMSOI (4.2 mmol, 0.3 equiv.) and NaH (4.2 mmol,
0.3 equiv.) in DMSO (10 mL) was added to the reaction mixture and reaction was
stirred at 65°C for 84 h. The solution was poured into a brine solution and extracted
with ethyl acetate. The combined organic layer was washed with water and dried
over MgSO4, concentrated and purified by silica gel column to afford
corresponding cyclopropane derivative as a white solid (60-80%yield).
3) To a stirred solution of LAH (1.35 mmol, 1.5 equiv.) in 7 mL diethyl ether was added
dropwise a solution of cyclopropane ester (0.90 mmol, 1equiv.) in 3 mL diethyl
ether under N atmosphere. After the addition was completed the reaction mixture
2
was refluxed for another 6 h. The reaction mixture was then cooled to rt, and the
excess LAH was destroyed by ethyl acetate. 15 mL of 10% H SO4 and 8 mL of
2
ether was added, and the aqueous layer was extracted several times with diethyl
ether. The combined organic layer was washed with water and 5% NaHCO , dried
3
over MgSO and concentrated in a rotary evaporator (90-95% yield). Without any
4
further purification, the crude material (a colorless oil) was used for the next step.
) To a solution of cyclopropane alcohol (6.8 mmol, 1 equiv.) in dry DCM (14 mL),
PCC (13.6 mmol, 2 equiv.) was added in a portion-wise manner through a solid
4
addition tube under N atmosphere. After 3h reaction mixture was filtered through
2
a small plug of celite and concentrated in vacuo. The crude mixture was purified
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1
2
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2
2
2
2
2
2
2
2
3
3
3
3
3
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3
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3
4
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4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
by silica gel column chromatography using ethyl acetate in hexane as an eluent.
Starting from aryl aldehyde the 2-arylcyclopropanecarbaldehydes was obtained in
40-50% overall yield.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
trans-2-(4-Methoxyphenyl)cyclopropane-1-carbaldehyde
(1a).12
4-Methoxy
benzaldehyde (1.0 g, 7.35 mmol), 1a (0.62 g, 3.53 mmol), 48% overall yield, white
1
solid. H NMR (400 MHz): δ 9.30 (d, J = 4.9 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 6.83 (d,
J = 8.7 Hz, 2H),3.79 (s, 3H), 2.62-2.55 (m, 1H), 2.12-2.06 (m, 1H), 1.73-1.67 (m, 1H),
1
.51-1.45 (m, 1H).
trans-2-Phenylcyclopropane-1-carbaldehyde (1b).12 Benzaldehyde (1.0 g, 9.43
1
mmol), 1b (0.69 g, 4.72 mmol), 50% overall yield, white solid. H NMR (400 MHz): δ
9
.32 (d, J = 4.5 Hz, 1H), 7.32-7.27 (m, 2H), 7.25-7.20 (m, 1H), 7.13-7.09 (m, 2H), 2.66-
2.60 (m, 1H), 2.20-2.14 (m, 1H), 1.76-1.71 (m, 1H), 1.56-1.51 (m, 1H).
trans-2-(p-Tolyl)cyclopropane-1-carbaldehyde (1c).17 4-Methylbenzaldehyde (1.0 g,
1
8
.32 mmol), 1c (0.64g, 3.99 mmol), 48% overall yield, white solid. H NMR (400 MHz):
δ 9.30 (d, J = 4.5 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.2 Hz, 2H), 2.63-2.57
m, 1H), 2.32 (s, 3H), 2.16-2.10 (m, 1H), 1.74-1.68 (m, 1H), 1.54-1.48 (m, 1H).
(
trans-2-(3,4-Dimethoxyphenyl)cyclopropane-1-carbaldehyde (1d).12 3,4-Dimethoxy
benzaldehyde (1.0 g, 6.02 mmol), 1d (0.53 g, 2.59 mmol), 43% overall yield, white
1
solid. H NMR (400 MHz): δ 9.31 (d, J = 4.5 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.69-
6
.64 (m, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 2.63−2.58 (m, 1H), 2.15−2.08 (m, 1H),
1.73−1.67 (m, 1H), 1.53−1.47 (m, 1H).
trans-2-(4-Fluorophenyl)cyclopropane-1-carbaldehyde (1e).12 4-Fluorobenzaldehyde
1
(
1.0 g, 8.06 mmol), 1e (0.66 g, 4.03 mmol), 50% overall yield, white solid. H NMR
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(
400 MHz): δ 9.33 (d, J = 4.5 Hz, 1H), 7.11−7.05 (m, 2H), 7.01-6.95 (m, 2H), 2.65−2.58
m, 1H), 2.15−2.09 (m, 1H), 1.75−1.69 (m, 1H), 1.51−1.45 (m, 1H).
(
trans-2-(4-Chlorophenyl)cyclopropane-1-carbaldehyde (1f).17 4-Chlorobenzaldehyde
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
5
5
6
0
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4
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0
1
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1
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9
0
1
2
3
4
5
6
7
8
9
0
1
(1.0 g, 7.11 mmol), 1e (0.70 g, 3.88 mmol), 55% overall yield, white solid. H NMR
(
400 MHz): δ 9.33 (d, J = 4.5 Hz, 1H), 7.26 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.4 Hz,
H), 2.62-2.56 (m, 1H), 2.17-2.11 (m, 1H), 1.76-1.70 (m, 1H), 1.52-1.46 (m, 1H).
trans-2-(4-Bromophenyl)cyclopropane-1-carbaldehyde 4-Bromo
(1g).13c
2
benzaldehyde (1.0 g, 5.40 mmol), 1g (0.8 g, 3.57 mmol), 66% overall yield, white solid.
1H NMR (400 MHz): δ 9.31 (d, J = 4.3 Hz, 1H), 7.39 (d, J = 8.6 Hz, 2H), 6.97 (d, J =
8
.7 Hz, 2H), 2.6-2.54 (m, 1H), 2.16-2.09 (m, 1H), 1.75-1.69 (m, 1H), 1.50-1.45 (m, 1H).
trans-2-(Naphthalen-2-yl)cyclopropane-1-carbaldehyde (1h).12 2-Naphthaldehyde
1
(1.0 g, 6.40 mmol), 1h (0.65 g, 3.31 mmol), 52% overall yield, off white solid. H NMR
(400 MHz): δ 9.37 (d, J = 4.5 Hz, 1H), 7.81-7.74 (m, 3H), 7.58 (s, 1H), 7.49-7.41 (m,
2
H),7.20 (dd, J = 8.4, 1.8 Hz, 1H), 2.82-2.76 (m, 1H), 2.30-2.23 (m, 1H), 1.83-1.77 (m,
1
H), 1.69-1.62 (m, 1H).
17
trans-2-Styrylcyclopropane-1-carbaldehyde (1i). trans-Cinnamaldehyde (1.0 g, 7.56
1
mmol), 1i (0.62 g, 3.60 mmol), 47% overall yield, off white solid. H NMR (400 MHz):
δ 9.24 (d, J = 4.58 Hz, 1H), 7.32-7.29 (m, 4H), 6.56 (d, J = 15.57 Hz, 1H), 5.76 (dd, J
=
15.57, 8.52 Hz, 1H), 2.33-2.25 (m, 1H), 2.08-2.01 (m, 1H), 1.66-1.60 (m, 1H), 1.34-
.28 (m, 1H).
1
12
trans-2-(Furan-2-yl)cyclopropane-1-carbaldehyde (1j). Furan-2-carbaldehyde (1.0 g,
1
10.41 mmol), 1j (0.64 g, 4.69 mmol), 45% overall yield, pale yellow oil. H NMR (400
MHz): δ 9.36 (d, J = 4.3 Hz, 1H), 7.27−7.25 (m, 1H), 6.30−6.28 (m, 1H), 6.10 (d, J =
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.3 Hz, 1H), 2.65−2.59 (m, 1H), 2.32−2.26 (m, 1H), 1.69−1.64 (m, 1H), 1.62−1.56 (m,
1H).
17
General procedure for preparation of bicyclo[4.1.0]heptane-7-carbaldehyde (1k). For
the reaction scheme, see Scheme S2 in the Supporting Information. To a suspension
of cyclohexene (2.36 g, 28.7 mmol) and Rh (OAc) (40 mg, 0.09 mmol) in CH Cl (10
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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8
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0
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7
8
9
0
2
4
2
2
mL) at room temperature was added ethyl diazoacetate (3.28 g, 28.7 mmol) via
syringe pump and over the course of 12 hours. Once the addition was complete, the
green mixture was stirred for another 12 hours, and then filtered through a short pad
of celite. The filtrate was concentrated in a rotary evaporator. The crude mixture was
separated by flash chromatography using ethyl acetate/hexane as eluent.
The reduction of cyclopropane carboxylate to cyclopropyl methanol and the oxidation
of cyclopropyl methanol to cyclopropane aldehyde was carried out following the
general procedure described in the preparation of trans-2-aryl cyclopropane
aldehydes.
Bicyclo[4.1.0]heptane-7-carbaldehyde (1k).17 Cyclohexene (2.36 g, 28.7 mmol), 1k
1
(1.60 g, 12.9 mmol), 45% overall yield, colorless oil. H NMR (400 MHz): δ 9.00 (d, J
=
1
5.49 Hz, 1H), 1.96-1.84 (m, 2H), 1.77-1.64 (m, 4H), 1.38 (t, J = 4.36 Hz, 1H), 1.34-
.24 (m, 2H), 1.23-1.14 (m, 2H).
General Procedure for the preparation of anthranil hydrazides (2a-j)21c For the
reaction scheme, see Scheme S3 in the Supporting Information. To a mixture of isatoic
anhydride/N-methyl isatoic anhydride (0.61 mmol, 1 equiv.) and hydrazine/aniline
derivatives (0.67 mmol, 1.1 equiv.) in ethanol (5 mL), catalytic amount of glacial acetic
acid (2 drops) was added. The mixture was heated under reflux for 2 hours,
concentrated to its half volume, and then cooled. The separated solid was filtered and
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crystallized from aqueous ethanol to give the titled compounds in 75-85% yield. Solid
obtained was used as such for further reaction.
2
-Amino-N'-phenylbenzohydrazide (2a):10 Isatoic anhydride (0.20 g, 1.22 mmol),
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1
1
1
1
1
1
1
1
2
2
2
2
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9
0
phenylhydrazine (0.14 g, 1.34 mmol), 2a (0.25 g, 1.10 mmol), 82% yield, yellow solid.
1H NMR (400 MHz): δ 7.76 (s, 1H), 7.48 (d, J = 8.18 Hz, 1H), 7.30-7.22 (m, 3H), 6.96-
6.89 (m, 3H), 6.74-6.66 (m, 2H), 6.27 (s, 1H), 5.56 (s, 2H).
2
-amino-N'-(p-tolyl)benzohydrazide (2b) 10 Isatoic anhydride (0.10 g, 0.61 mmol), 4-
methylphenylhydrazine (0.081 g, 0.67 mmol), 2b (0.12 g, 0.50 mmol), 82% yield,
1
yellow solid. H NMR (400 MHz, CDCl ): δ 7.83 (s, 1H), 7.47 (d, J = 8.37 Hz, 1H),
3
7.29-7.23 (m, 1H), 7.05 (d, J = 8.28 Hz, 2H), 6.85 (d, J = 8.28 Hz, 2H), 6.72-6.66 (m,
2H), 5.86 (s, 2H), 2.26 (s, 3H).
10
2
-amino-N'-(4-isopropylphenyl)benzohydrazide (2c): Isatoic anhydride (0.10 g, 0.61
mmol), 4-isopropoylphenylhydrazine (0.11 g, 0.67 mmol), 2b (0.14 g, 0.52 mmol), 85%
1
yield, yellow solid. H NMR (400 MHz): δ 7.72 (s, 1H), 7.46 (dd, J = 8.25, 1.34 Hz, 1H),
7
.28-7.23 (m, 2H), 7.10 (d, J = 8.46 Hz, 2H), 6.87 (d, J = 8.49 Hz, 2H), 6.71-6.66 (m,
H), 5.56 (s, 2H), 2.86-2.76 (m, 1H), 1.19 (d, J = 6.86 Hz, 6H).
2
2
-amino-N'-(4-fluorophenyl)benzohydrazide (2d):10 Isatoic anhydride (0.10 g, 0.61
mmol), 4-fluorophenylhydrazine (0.085 g, 0.67 mmol), 2d (0.11 g, 0.44 mmol), 74%
1
yield, yellow solid. H NMR (400 MHz): δ 7.80 (s, 1H), 7.47 (d, J = 7.92 Hz, 1H), 7.30-
7.27 (m, 1H), 6.98-6.86 (m, 4H), 6.73-6.67 (m, 2H), 6.26 (s, 1H), 5.57 (s, 2H).
2
-amino-N'-(4-chlorophenyl)benzohydrazide (2e):10 Isatoic anhydride (0.10 g, 0.61
mmol), 4-chlorophenylhydrazine (0.096 g, 0.67 mmol), 2e (0.13 g, 0.49 mmol), 82%
1
yield, yellow solid. H NMR (400 MHz): δ 7.72 (s, 1H), 7.48 (dd, J = 8.49, 1.30 Hz, 1H),
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.31-7.26 (m, 1H), 7.20 (d, J = 8.70 Hz, 2H), 6.88 (d, J = 8.70 Hz, 2H), 6.73-6.68 (m,
2H), 5.59 (s, 2H).
2
-amino-N'-(4-bromophenyl)benzohydrazide (2f):21a Isatoic anhydride (0.10 g, 0.61
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
mmol), 4-bromophenylhydrazine (0.12 g, 0.67 mmol), 2f (0.14 g, 0.46 mmol), 75%
1
yield, yellow solid. H NMR (400 MHz): δ 7.72 (s, 1H), 7.48 (d, J = 8.39 Hz, 1H), 7.37-
7.27 (m, 1H), 6.83 (d, J = 8.72 Hz, 2H), 6.73-6.68 (m, 2H), 6.24 (s, 1H), 5.54 (s, 2H).
2
-amino-N'-benzylbenzohydrazide (2g):10 Isatoic anhydride (0.40 g, 2.45 mmol),
benzylhydrazine (0.33 g, 2.69 mmol), 2g (0.50 g, 2.07 mmol), 85% yield, white solid.
1H NMR (400 MHz): δ 7.60 (s, 1H), 7.42-7.24 (m, 6H), 7.22-7.15 (m, 2H), 6.67 (d, J =
8.07 Hz, 1H), 6.59 (t, J = 7.57 Hz, 1H), 5.39 (s, 2H), 4.04 (s, 2H).
2
-amino-N-benzylbenzamide (2h):21b Isatoic anhydride (0.10 g, 0.61 mmol),
1
benzylamine (0.072 g, 0.67 mmol), 2h (0.12 g, 0.53 mmol), 87% yield, white solid. H
NMR (400 MHz): δ 7.37-7.27 (m, 6H), 7.20 (t, J = 7.78 Hz, 1H), 6.69 (d, J = 8.29 Hz,
1H), 6.63 (t, J = 7.78 Hz, 1H), 6.33 (s, 1H), 5.57 (s, 2H), 4.60 (s, 2H).
2
-amino-N-phenylbenzamide (2i):21b Isatoic anhydride (0.10 g, 0.61 mmol), aniline
1
(0.063 g, 0.67 mmol), 2i (0.11 g, 0.51 mmol), 85% yield, white solid. H NMR (400
MHz): δ 7.75 (s, 1H), 7.56 (d, J = 8.20 Hz, 2H), 7.47 (d, J = 8.25 Hz, 1H), 7.40-7.34
m, 2H), 7.28=7.23 (m, 1H), 7.15 (t, J = 7.46 Hz, 1H), 6.74-6.66 (m, 2H), 5.49 (s, 2H).
2-(methylamino)-N'-phenylbenzohydrazide (2j):21c N-Methylisatoic anhydride (0.10 g,
(
0.56 mmol), phenylhydrazine (0.067 g, 0.62 mmol), 2j (0.11 g, 0.45 mmol), 81% yield,
1
white solid. H NMR (400 MHz): δ 7.29 (s, 1H), 7.50 (dd, J = 8.03, 1.57 Hz, 1H), 7.45-
7.36 (m, 2H), 7.28-7.22 (m, 2H), 6.96-6.89 (m, 3H), 6.70 (d, J = 8.39 Hz, 1H), 6.63 (t,
J = 7.70 Hz, 1H) 6.23 (s, 1H), 2.84 (d, J = 4.22 Hz, 3H).
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Representative procedure for the Bronsted acid catalysed annulation of
cyclopropanealdehydes (1) and anthranil hydrazides (2). For the reaction scheme,
see Scheme S4 in the Supporting Information. A round bottom flask equipped with
magnetic stirrer bar was charged with PTSA (0.066 mmol, 0.3 equiv). A solution of
1
1
1
1
1
1
1
1
1
1
2
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cyclopropane
carbaldehyde
(0.26
mmol,
1.2
equiv),
and
anthranil
hydrazides/benzamides (0.22 mmol, 1 equiv) in DCM (1 mL) was added to it, and the
mixture was stirred at room temperature till the completion of reaction (as monitered
by TLC). The excess of the solvent was evaporated on a rotary evaporator. The crude
mixture obtained was further purified by column chromatography on silica gel using
ethyl acetate/hexane as eluent.
In case of aldehydes 3h and 3k reaction was done at reflux conditions using DCM as
solvent at 50 °C (oil bath temperature).
1-(4-Methoxyphenyl)-4-(phenylamino)-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-
5(1H)-one (3aa and 3aa’): Reaction time: 10 h, 1a (46.48 mg, 0.26 mmol), 2a (50 mg,
0.22 mmol), 3aa and 3aa’ (72 mg, 0.187 mmol), 85% yield.
3
aa: white crystalline solid, 24.5 mg, R = 0.60 (EtOAc:Hexane = 2.5:7.5), mp 129-131
f
1
°
C. H NMR (400 MHz): δ 7.94 (dd, J = 7.84, 1.23 Hz, 1H), 7.27-7.15 (m, 5H), 6.98-
6.88 (m, 5H), 6.81 (t, J = 7.22 Hz, 1H), 6.44 (s, 1H), 6.40 (d, J= 8.25 Hz, 1H), 5.58 (dd,
J = 6.19, 2.68 Hz, 1H), 5.02 (dd, J = 7.63, 2.27 Hz, 1H), 3.82 (s, 3H), 2.76-2.63 (m,
13
1
1H), 2.50-2.40 (m, 1H), 2.32-2.21 (m ,1H), 1.93-1.84 (m, 1H); C{ H} NMR (100 MHz):
δ 158.8, 148.3, 146.2, 146.1, 135.2, 134.2, 129.29, 129.2, 126.7, 121.6, 118.8, 115.5,
114.6, 114.2, 114.1, 77.05, 66.4, 55.4, 34.0, 29.1; IR (neat): 3053, 2928, 1666, 1605,
+
1492, 1378, 1263, 732; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N O
24
24
3
2
386.1863; Found 386.1865.
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3
aa’: white crystalline solid, 47.5 mg, R = 0.50 (EtOAc:Hexane = 2.5:7.5), mp 132-
f
1
133 °C. H NMR (400 MHz): δ 7.94 (dd, J = 7.66, 1.39 Hz, 1H), 7.38-7.33 (m, 2H),
7.28-7.18 (m, 4H), 7.07-7.01 (m, 2H), 6.95-6.88 (m, 3H), 6.78 (t, J = 7.49 Hz, 1H), 6.50
0
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2
3
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1
2
3
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(s, 1H), 6.34 (d, J = 8.36 Hz, 1H), 5.28-5.20 (m, 1H), 4.85 (dd, J = 9.2, 1.91 Hz, 1H),
13
1
3.80 (s, 3H), 2.54-2.32 (m, 2H), 2.30-2.22 (m, 1H), 2.00-1.93 (m ,1H); C{ H} NMR
(100 MHz): δ 158.9, 146.2, 134.8, 134.2, 129.6, 129.2, 127.1, 121.5, 118.2, 115.6,
1
1
3
14.3, 114.2, 113.0, 111.3, 77.5, 60.6, 55.3, 32.6, 28.7; IR (neat): 3053, 2954, 1667,
+
605, 1492, 1263, 732; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N O
24
24
3
2
86.1863; Found 386.1860.
-Phenyl-4-(phenylamino)-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one
1
(3ba and 3ba’): Reaction time: 10 h, 1b (38.56 mg, 0.26 mmol), 2a (50 mg, 0.22
mmol), 3ba and 3ba’ (65 mg, 0.182 mmol), 83% yield.
3ba: white crystalline solid, 23 mg, R = 0.55 (EtOAc:Hexane = 2.5:7.5), mp 139-141
f
1
°
C. H NMR (400 MHz): δ 7.95 (d, J = 7.70 Hz, 1H), 7.41-7.35 (m, 2H), 7.33-7.17 (m,
6H), 6.99-6.90 (m, 3H), 6.82 (t, J = 7.52 Hz, 1H), 6.45 (s, 1H), 6.39 (d, J = 8.16 Hz,
1
1
1
H), 5.64-5.57 (m, 1H), 5.07 (d, J = 7.20 Hz, 1H), 2.81-2.68 (m, 1H), 2.51-2.42 (m,
13
1
H), 2.33-2.21 (m ,1H), 1.97-1.88 (m, 1H); C{ H} NMR (100 MHz): δ 148.3, 146.1,
43.2, 134.3, 129.2, 128.9, 127.3, 125.6, 121.6, 118.9, 115.5, 114.6, 114.1, 77.1, 66.9,
33.9, 29.1; IR (neat): 3054, 1661, 1603, 1491, 1382, 1264, 732; HRMS (ESI-TOF) m/z:
+
[
M+H] Calcd for C H N O 356.1757; Found 356.1749.
23
22
3
3ba’: white crystalline solid, 42 mg, R = 0.41 (EtOAc:Hexane = 2.5:7.5), mp 140-141
f
1
°
C. H NMR (400 MHz): δ 7.96 (d, J = 7.91 Hz, 1H), 7.48-7.43 (m, 2H), 7.41-7.35 (m,
2H), 7.32-7.18 (m, 4H), 7.08-7.02 (m, 2H), 6.92 (t, J = 7.41 Hz, 1H), 6.78 (t, J = 7.59
Hz, 1H), 6.54 (s, 1H), 6.34 (d, J = 8.27 Hz, 1H), 5.31-5.21 (m, 1H), 4.90 (d, J = 9.10
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Hz, 1H), 2.58-2.31 (m, 2H), 2.31-2.24 (m, 1H), 2.06-1.97 (m ,1H); C{ H} NMR (100
MHz): δ 148.3, 146.2, 142.8, 134.2, 129.7, 129.2, 128.9, 127.5, 126.0, 121.5, 118.3,
115.6, 114.2, 113.0, 77.6, 61.1, 32.5, 28.7; IR (neat): 3054, 1664, 1603, 1491, 1378,
1
1
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1
1
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2
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0
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0
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0
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7
8
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0
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0
+
1
263, 732; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N O 356.1757; Found
23
22
3
3
56.1764.
-(Phenylamino)-1-(p-tolyl)-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one
4
(
3ca and 3ca’): Reaction time: 11 h, 1c (84.58 mg, 0.52 mmol), 2a (100 mg, 0.44
mmol), 3ca and 3ca’ (130 mg, 0.35 mmol), 80% yield.
1
3ca: light yellow semisolid, 42 mg, R = 0.65 (EtOAc:Hexane = 2.5:7.5). H NMR (400
f
MHz): δ 7.94 (dd, J = 7.84, 1.79 Hz, 1H), 7.27-7.12 (m, 7H), 6.98-6.89 (m, 3H), 6.81
(
t, J = 7.32 Hz, 1H), 6.42 (s, 1H), 6.40 (d, J = 8.22 Hz, 1H), 5.58 (dd, J = 6.29, 2.82
Hz, 1H), 5.04 (dd, J = 7.84, 2.18 Hz, 1H), 2.76-2.63 (m, 1H), 2.48-2.39 (m, 1H), 2.38-
13
1
2
.20 (m ,4H), 1.93-1.85 (m, 1H); C{ H} NMR (100 MHz): δ 148.3, 146.2, 140.2, 137.0,
1
34.2, 129.6, 129.28, 129.25, 125.5, 121.6, 118.7, 115.4, 114.5, 114.1, 77.07, 66.6,
34.0, 29.1, 21.1; IR (neat): 3270, 2922, 1658, 1602, 1490, 1381, 1264, 734; HRMS
+
(
ESI-TOF) m/z: [M+H] Calcd for C H N O 370.1914; Found 370.1912.
24
24
3
1
3
ca’: light yellow semisolid, 88 mg, R = 0.55 (EtOAc:Hexane = 2.5:7.5). H NMR (400
f
MHz): δ 7.94 (dd, J = 7.75, 1.59 Hz, 1H), 7.35-7.31 (m, 2H), 7.28-7.16 (m, 7H), 7.07-
.01 (m, 2H), 6.92 (t, J = 7.41 Hz, 1H), 6.77 (t, J = 7.80 Hz, 1H), 6.49 (s, 1H), 6.34 (d,
7
J = 8.29 Hz, 1H), 5.29-5.20 (m, 1H), 4.87 (d, J = 9.10 Hz, 1H), 2.53-2.22 (m, 6H), 2.01-
1
1
.94 (m ,1H); 13C{ H} NMR (100 MHz): δ 146.2, 139.8, 137.2, 134.2, 129.6, 129.2,
1
25.9, 121.5, 118.2, 114.2, 113.0, 77.3, 60.9, 32.5, 28.7, 21.1; IR (neat): 3054, 1664,
+
1604, 1491, 1381, 1264, 732; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N O
24
24
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370.1914; Found 370.1928.
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-(3,4-Dimethoxyphenyl)-4-(phenylamino)-2,3,3a,4-tetrahydropyrrolo[1,2-a]
quinazolin-5(1H)-one (3da and 3da’): Reaction time: 09 h, 1d (108.9 mg, 0.52 mmol),
2a (100 mg, 0.44 mmol), 3da and 3da’ (148 mg, 0.356 mmol), 81% yield.
0
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3da: white solid, 59 mg, R = 0.55 (EtOAc:Hexane = 2.5:7.5), mp 164-165 °C. H NMR
f
(
400 MHz): δ 7.95 (d, J = 7.70 Hz, 1H), 7.25-7.19 (m, 3H), 6.99-6.89 (m, 3H), 6.88-
.74 (m, 4H), 6.43 (d, J = 8.16 Hz, 1H), 6.40 (s, 1H), 5.58 (d, J = 6.68 Hz, 1H), 5.00
d, J = 7.20 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 2.77-2.63 (m, 1H), 2.51-2.40 (m, 1H),
6
(
13
1
2
1
1
.34-2.21 (m ,1H), 1.98-1.85 (m, 1H). C{ H} NMR (100 MHz): δ 149.4, 148.2, 146.2,
46.1, 135.7, 134.3, 129.3, 129.2, 121.6, 119.0, 117.6, 115.6, 114.8, 114.1, 111.3,
08.7, 77.3, 77.1, 66.8, 56.0, 34.0, 29.1. IR (neat): 3054, 2930, 1658, 1603, 1491,
+
1263, 733; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N O 416.1969; Found
25
26
3
3
4
16.1982.
da’: white solid, 89 mg, R = 0.54 (EtOAc:Hexane = 2.5:7.5), mp 165-166 °C. H NMR
1
3
f
(
400 MHz): δ 7.94 (dd, J = 7.78, 1.35 Hz, 1H), 7.24-7.18 (m, 3H), 7.06-7.01 (m, 2H),
7.01-6.94 (m, 2H), 6.91 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.78 (t, J = 7.5 Hz,
H), 6.47 (s, 1H), 6.35 (d, J = 8.2 Hz, 1H), 5.26-5.19 (m, 1H), 4.82 (dd, J = 9.0, 2.0
1
1
3
1
Hz, 1H), 3.86 (s, 3H), 2.53-2.34 (m, 2H), 2.30-2.23 (m, 1H), 2.01-1.94 (m ,1H). C{ H}
NMR (100 MHz): δ 149.4, 148.4, 148.3, 146.2, 135.4, 134.2, 129.6, 129.2, 121.6,
118.3, 118.0, 115.5, 114.2, 113.0, 111.3, 108.7, 77.5, 77.3, 60.9, 55.8, 32.5, 28.7. IR
+
(neat): 3057, 2834, 1660, 1603, 1491, 1257, 753; HRMS (ESI-TOF) m/z: [M+H] Calcd
for C H N O 416.1969; Found 416.1967.
25
26
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1-(4-Fluorophenyl)-4-(phenylamino)-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-
5(1H) -one (3ea and 3ea’): Reaction time: 11 h, 1e (86.68 mg, 0.52 mmol), 2a (100
mg, 0.44 mmol), 3ea and 3ea’ (135 mg, 0.36 mmol), 82% yield.
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ea: off white solid, 47 mg, R = 0.56 (EtOAc:Hexane = 2.5:7.5), mp 157-159 °C. H
f
NMR (400 MHz): δ 7.96 (dd, J = 7.73, 1.34 Hz, 1H), 7.27-7.19 (m, 5H), 7.10-7.03 (m,
2H), 6.97-6.90 (m, 3H), 6.84 (t, J = 7.42 Hz, 1H), 6.44 (s, 1H), 6.37 (d, J = 8.19 Hz,
1
1
1
1
1
1
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1
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4
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0
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0
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0
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H), 5.57 (dd, J = 6.22, 2.74 Hz, 1H), 5.04 (brd, J = 7.56 Hz, 1H), 2.78-2.67 (m, 1H),
13
1
2
.51-2.43 (m, 1H), 2.30-2.19 (m ,1H), 1.92-1.84 (m, 1H). C{ H} NMR (100 MHz): δ
163.3, 160.8, 146.0, 138.9, 134.3, 129.3, 129.2, 127.2, 127.1, 121.6, 119.1, 115.9,
1
15.7, 114.6, 114.1, 77.0, 66.4, 34.0, 29.0. IR (neat): 3269, 3049, 2873, 1658, 1602,
+
1
491, 1222, 750; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H FN O 374.1663;
23
21
3
Found 374.1667.
1
3
ea’: off white solid, 88 mg, R = 0.50 (EtOAc:Hexane = 2.5:7.5), mp 160-161 °C. H
f
NMR (400 MHz): δ 7.96 (dd, J = 7.74, 1.34 Hz, 1H), 7.44-7.37 (m, 2H), 7.28-7.19 (m,
3
H), 7.10-7.00 (m, 4H), 6.93 (t, J = 7.37 Hz, 1H), 6.80 (t, J = 7.46 Hz, 1H), 6.49 (s,
H), 6.30 (d, J = 8.40 Hz, 1H), 5.28-5.20 (m, 1H), 4.88 (dd, J = 9.20, 1.70 Hz, 1H),
1
13
1
2.57-2.45 (m, 1H), 2.42-2.24 (m, 2H), 2.00-1.93 (m, 1H); C{ H} NMR (100 MHz): δ
1
63.3, 160.9, 146.0, 138.4, 134.2, 129.7, 129.3, 127.5, 127.5, 121.6, 118.5, 115.9,
1
15.7, 114.2, 112.9, 77.5, 60.5, 32.5, 28.6. IR (neat): 3275, 3049, 2873, 1663, 1604,
+
1
492, 1223, 752; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H FN O 374.1663;
23 21
3
Found 374.1666.
1-(4-Chlorophenyl)-4-(phenylamino)-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin
-
5
(1H)-one (3fa and 3fa’): Reaction time: 10 h, 1f (93.61 mg, 0.52 mmol), 2a (100 mg,
.44 mmol), 3fa and 3fa’ (140 mg, 0.36 mmol), 82% yield.
fa: off white solid, 49 mg, R = 0.70 (EtOAc:Hexane = 2.5:7.5), mp 154-155 °C. H
0
1
3
f
NMR (400 MHz): δ 7.95 (dd, J = 7.76, 1.39 Hz, 1H), 7.37-7.31 (m, 2H), 7.27-7.18 (m,
H), 6.97-6.89 (m, 3H), 6.85 (t, J = 7.24 Hz, 1H), 6.41 (s, 1H), 6.36 (d, J = 8.05 Hz,
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H), 5.57 (dd, J = 6.36, 2.63 Hz, 1H), 5.02 (dd, J = 5.93, 2.26 Hz, 1H), 2.79-2.67 (m,
13
1
1H), 2.52-2.43 (m, 1H), 2.30-2.18 (m ,1H), 1.91-1.83 (m, 1H); C{ H} NMR (100 MHz,
CDCl ): δ 148.2, 145.9, 141.8, 134.3, 133.1, 129.34, 129.3, 127.0, 121.6, 119.2, 115.7,
3
0
1
2
3
4
5
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0
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0
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0
114.6, 114.1, 113.6, 77.0, 66.5, 33.9, 29.0; IR (neat): 3270, 3049, 2872, 1658, 1602,
+
1488, 1264, 733; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H ClN O 390.1368;
23
21
3
Found 390.1375.
1
3fa’: off white solid, 91 mg, R = 0.60 (EtOAc:Hexane = 2.5:7.5), mp 158-159 °C. H
f
NMR (400 MHz): δ 7.96 (dd, J = 7.77, 1.56 Hz, 1H), 7.40-7.32 (m, 4H), 7.28-7.20 (m,
3
H), 7.05-6.99 (m, 2H), 6.93 (t, J = 7.36 Hz, 1H), 6.81 (t, J = 7.36 Hz, 1H), 6.49 (s,
H), 6.29 (d, J = 8.12 Hz, 1H), 5.28-5.21 (m, 1H), 4.87 (dd, J = 9.34, 1.68 Hz, 1H),
1
13
1
2.56-2.46 (m, 1H), 2.42-2.24 (m, 2H), 2.00-1.92 (m, 1H); C{ H} NMR (100 MHz): δ
148.2, 145.9, 141.3, 134.2, 133.2, 129.8, 129.3, 129.1, 127.4, 121.6, 118.6, 115.8,
114.2, 112.9, 77.6, 60.5, 32.4, 28.6; IR (neat): 3271, 3049, 2877, 1660, 1603, 1489,
+
1298, 751; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H ClN O 390.1368; Found
23
21
3
390.1370.
1-(4-Bromophenyl)-4-(phenylamino)-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-
5(1H)-one (3ga and 3ga’): Reaction time: 11 h, 1g (118.36 mg, 0.52 mmol), 2a (100
mg, 0.44 mmol), 3ga and 3ga’ (154 mg, 0.356 mmol), 81% yield.
ga: light yellow solid, 54 mg, R = 0.65 (EtOAc:Hexane = 2.5:7.5), mp 155-157 °C.
3
f
1H NMR (400 MHz): δ 7.95 (dd, J = 7.78, 1.34 Hz, 1H), 7.50 (d, J = 8.48 Hz, 2H), 7.27-
7
.21 (m, 3H), 7.15 (d, J = 8.48 Hz, 2H), 6.97-6.90 (m, 3H), 6.85 (t, J = 7.68 Hz, 1H),
.42 (s, 1H), 6.35 (d, J = 8.2 Hz, 1H), 5.56 (dd, J = 6.27, 2.61 Hz, 1H), 5.01 (dd, J =
6
7.94, 2.64 Hz, 1H), 2.78-2.67 (m, 1H), 2.51-2.43 (m, 1H), 2.29-2.18 (m ,1H), 1.91-1.83
13
1
(m, 1H); C{ H} NMR (100 MHz): δ 148.2, 145.9, 142.4, 134.3, 132.0, 129.34, 129.3,
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27.4, 121.6, 121.1, 119.3, 115.7, 114.6, 114.1, 77.0, 66.6, 33.8, 29.0; IR (neat): 3053,
+
1661, 1604, 1489, 1263, 732; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H BrN O
23
21
3
434.0863; Found 434.0891.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
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2
2
2
2
2
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6
7
8
9
0
3ga’: light yellow solid, 100 mg, R = 0.55 (EtOAc:Hexane = 2.5:7.5), mp 156-157 °C.
f
1H NMR (400 MHz): δ 7.96 (dd, J = 7.79, 1.36 Hz, 1H), 7.50 (d, J = 8.15 Hz, 2H), 7.32
(d, J = 8.20 Hz, 2H), 7.28-7.19 (m, 3H), 7.01 (d, J = 8.02 Hz, 2H), 6.93 (t, J = 7.33 Hz,
1
H), 6.81 (t, J = 7.47 Hz, 1H), 6.54 (s, 1H), 6.29 (d, J = 8.20 Hz, 1H), 5.29-5.19 (m,
H), 4.85 (dd, J = 9.20, 1.45 Hz, 1H), 2.57-2.45 (m, 1H), 2.41-2.24 (m, 2H), 2.00-1.92
1
1
3
1
(m, 1H). C{ H} NMR (100 MHz): δ 148.2, 145.9, 141.9, 134.2, 132.1, 129.8, 129.3,
127.7, 121.6, 121.3, 118.6, 115.8, 114.1, 112.9, 77.5, 60.5, 32.3, 28.6;IR (neat): 3053,
+
2986, 1667, 1605, 1490, 1263, 732; HRMS (ESI-TOF) m/z: [M+H] Calcd for
C H BrN O 434.0863; Found 434.0856.
23
21
3
1-(Naphthalen-2-yl)-4-(phenylamino)-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-
5(1H)-one (3ha and 3ha’): Reaction time: 14 h, 1h (103.6 mg, 0.52 mmol), 2a (100
mg, 0.44 mmol), 3ha and 3ha’ (139 mg, 0.34 mmol), 78% yield.
ha: yellow solid, 50 mg, R = 0.45 (EtOAc:Hexane = 2.5:7.5) , mp 149-150 °C. H
1
3
f
NMR (400 MHz): δ 7.96 (dd, J = 7.82, 1.58 Hz, 1H), 7.89-7.78 (m, 3H), 7.68 (s, 1H),
7
.51-7.45 (m, 2H), 7.38 (dd, J = 8.56, 1.54 Hz, 1H), 7.27-7.22 (m, 3H), 7.20-7.15 (m,
H), 6.99-6.89 (m, 3H), 6.82 (t, J = 7.58 Hz, 1H), 6.42 (t, J = 4.41 Hz, 1H), 5.68 (dd, J
1
= 6.25, 2.53 Hz, 1H), 5.23-5.19 (m, 1H), 2.84-2.72 (m, 1H), 2.53-2.44 (m, 1H), 2.35-
13
1
2.24 (m ,1H), 2.03-1.95 (m, 1H); C{ H} NMR (100 MHz): δ 148.3, 146.2, 140.6, 134.3,
132.8, 129.3, 129.0, 127.9, 127.8, 126.5, 126.0, 124.1, 123.9, 121.6, 119.0, 115.6,
114.8, 114.1, 77.2, 67.2, 33.7, 29.1; IR (neat): 3053, 1661, 1603, 1491, 1384, 1264,
+
732; HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N O 406.1914; Found 406.1927.
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