FeCl3-mediated three-component cascade reaction: An effective approach to the construction of highly functionalized pyrrolo[1,2-c] quinazolinones

Article abstract of DOI:10.1002/chem.201304028

An unexpected FeCl₃-mediated three-component cascade reaction has been used to construct structurally diverse pyrrolo[1,2-c]quinazolinone derivatives with potential biological activities. This method has advantages of mild conditions, simple work-up, as well as wide substrate scope, which makes it a powerful approach to the synthesis of diverse pyrrolo[1,2-c]quinazolinones. This cascade reaction involves 1,3-dipolar cycloaddition between azomethine ylides and allenoates, followed by intramolecular nucleophilic addition in the presence of FeCl₃. The obtained products could be easily transformed into derivatives with the pyrrolo[2,3-c]quinazoline alkaloid skeleton. An iron trigger: An FeCl₃-triggered three-component domino strategy enables access to highly functionalized pyrrolo[1,2-c]quinazolinones in a single step (see scheme, MS=molecular sieves). The obtained products can be used as building blocks in the synthesis of diverse, potentially biologically active nitrogen-containing heterocycles. This method features mild conditions, a simple work-up, as well as a wide substrate scope. Copyright

Full text of DOI:10.1002/chem.201304028

DOI: 10.1002/chem.201304028
Full Paper
&
Domino Reactions
FeCl3-Mediated Three-Component Cascade Reaction: An Effective
Approach to the Construction of Highly Functionalized
Pyrrolo[1,2-c]quinazolinones
Hu-Fei Zheng,[a] Zhi-Hua Yu,[a] Wei Yuan,[a] Zi-Long Tang,[c] John Clough,[b] Yu-Cheng Gu,[b]
and De-Qing Shi*[a]
Abstract: An unexpected FeCl3-mediated three-component
cascade reaction has been used to construct structurally di-
verse pyrrolo[1,2-c]quinazolinone derivatives with potential
biological activities. This method has advantages of mild
conditions, simple work-up, as well as wide substrate scope,
which makes it a powerful approach to the synthesis of di-
verse pyrrolo[1,2-c]quinazolinones. This cascade reaction in-
volves 1,3-dipolar cycloaddition between azomethine ylides
and allenoates, followed by intramolecular nucleophilic addi-
tion in the presence of FeCl3. The obtained products could
be easily transformed into derivatives with the pyrrolo[2,3-
c]quinazoline alkaloid skeleton.
Introduction
Pyrroloquinazoline and pyrroloquinazolinone are important
structural skeletons in a diverse range of natural occurring al-
kaloids and pharmacologically active molecules. For example,
(À)-martinellic acid and (+)-martinelline (Figure 1), which were
isolated from an ethanolic extract of Martinella iquitosensis
roots, have been shown to possess antagonist properties
against bradykinin receptors,[1] and are used to cure conjuncti-
vitis caused by infection from microorganisms in South Ameri-
ca.[2] Pyrroloquinazoline or pyrroloquinazolinone derivatives
possess versatile biological activities such as antitumor,[3]
potent gastric (H+/K+)-ATPase inhibitor,[4] anti-inflammatory,[5]
and antihypertensive activities.[6] The important medicinal
properties and unique tricyclic skeleton of (À)-martinellic acid
and (+)-martinelline have made the synthesis of pyrroloquina-
zoline or pyrroloquinazolinone architectures more attractive,
and numerous synthetic methods, such as condensing quina-
zolines or quinazolinones with a-halopyruvates or a-haloke-
tones,[7] intramolecular cyclization reaction,[8] 1,3-dipolar cyclo-
Figure 1. Pyrroloquinazoline or pyrroloquinazolinone structural motif in nat-
ural alkaloids and artificial bioactive molecules.
addition,[9] the Fischer indole synthesis,[10] transition-metal-
mediated reactions,[11] aryl radical cyclization,[12] Diels–Alder re-
actions,[13] electrocyclization,[14] and others,[15] have been well-
established. However, these methods usually require stepwise
chemical processes or are limited by the availability of the
starting materials. In addition, only the Fisher indole synthesis
generates completely aromatized pyrroloquinolines and this
requires high temperature (2508C).
1,3-Dipolar cycloadditions of azomethine ylides to give elec-
tron-deficient olefins have been well explored and provide an
effective method with which to access pyrrolidine-containing
compounds (Scheme 1a).[16] In this context, most of the dipo-
larophiles used are electron-deficient alkenes,[17] imines,[18] and
alkynes,[19] and there are only a few examples of 1,3-dipolar cy-
cloadditions involving 2,3-butadienoates with azomethine
ylides.[20] Very recently, Gong and co-workers reported the first
1,3-dipolar cycloaddition between 2,3-butadienoates and azo-
methine ylides, which was used to acess 3-methylenepyrroli-
dine derivatives with excellent enantioselectivity with a chiral
bisphosphoric acid as the catalyst[20a] (Scheme 1b), and subse-
[a] H.-F. Zheng, Dr. Z.-H. Yu, W. Yuan, Prof. Dr. D.-Q. Shi
Key Laboratory of Pesticide and Chemical Biology
Ministry of Education, College of Chemistry
Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (P.R. China)
E-mail: chshidq@mail.ccnu.edu.cn
[b] J. Clough, Y.-C. Gu
Syngenta Jealott’s Hill International Research Centre
Bracknell, Berkshire RG42 6EY (UK)
[c] Prof. Dr. Z.-L. Tang
College of Chemistry and Chemical Engineering
Hunan University of Science and Technology
Xiangtan, Hunan 411201 (P.R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304028.
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Table 1. Optimization of the reaction conditions.[a]
Entry
Solvent Base
Catalyst
Time [h]
Yield [%][b]
4a 5a
6a
1[c]
2[d]
3[e]
4[f]
5
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DMF
CH3CN
THF
CH2Cl2
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
none
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
36
24
24
24
24
28
24
24
24
36
24
24
24
36
24
30
20 trace
trace 20
58
20
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
18
trace
0
40
60
75
76
38
23
20
19
40
45
45
55
60
57
60
30
35
6[g]
7
0
12
13
20
Scheme 1. 1,3-Dipolar cycloaddition reactions between azomethine ylides
and dipolarophiles.
8
9
quently applied to the kinetic resolution of racemic 2,3-buta-
dienoate.[20b] Due to their low price, nontoxicity, and environ-
mentally friendly nature, iron(III) catalysts have received consid-
erable attention from chemists during the last few years.[21]
However, to the best of our knowledge, the use of an FeCl3-
mediated cascade reaction with azomethine ylides and 2,3-bu-
tadienoates to construct the pyrrolo[1,2-c]quinazolinone deriv-
atives has not been studied. As part of our ongoing interest in
developing concise, convenient, and environmentally benign
methods for the synthesis of important biologically active ni-
trogen-containing heterocycles,[22] herein we report an unpre-
cedented cascade process involving 2,3-butadienoates, isatins,
and glycinate or a-amino ketone hydrogen chloride salts
under mild conditions that provides a highly efficient synthetic
route to structurally diverse pyrrolo[1,2-c]quinazolinones
(Scheme 1c).
10[h]
11
12
13
14
15
16
17
18
19
28
16
9
15
toluene Et3N
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
K2CO3
pyridine FeCl3
DBU
DMAP
Et3N
Et3N
Et3N
Et3N
FeCl3
FeCl3
Cu(OAc)2 24
AgOAc
ZnCl2
CuI
12
10
trace
trace
25
24
24
24
0
14
[a] Reaction conditions (unless otherwise noted): 1a (0.5 mmol), 2a
(0.75 mmol), 3a (0.75 mmol), base (1.0 mmol), catalyst (0.25 mmol), 3 ꢁ
molecular sieve (100 mg), solvent (4.0 mL), stirred at 658C. Bn=benzyl.
[b] Isolated yield based on 1a. [c] Stirred at room temprature. [d] FeCl3
(0.2 equiv), room temperature. [e] FeCl3 (0.2 equiv), stirred at 408C.
[f] FeCl3 (0.2 equiv). [g] Et3N (3.0 equiv) was added. [h] Stirred at 408C.
Results and Discussion
Initially, we investigated the reaction involving 1-benzyl isatin
(1a), methyl glycinate hydrochloride (2a), and ethyl 2,3-buta-
dienoate (3a) in the presence of Et3N (2.0 equiv) and 3 ꢁ mo-
lecular sieve (100 mg) in MeOH (4.0 mL) at room temperature,
and found that the expected [3+2] cycloaddition product 4a
(30%) and the endocyclic isomer 5a (20%) could be isolated
(Table 1, entry 1); the structure of 5a was unambiguously es-
tablished by X-ray crystallographic analysis.[23] When 0.5 equiva-
lents FeCl3 were added as the catalyst, the yield of 4a in-
creased to 58% and, unexpectedly, another product pyrrolo-
[1,2-c]quinazolinone 6a was also isolated in 20% yield (Table 1,
entry 2); the structure of 6a was unambiguously determined
by X-ray crystallographic analysis (Figure 2).[23] The results indi-
cated that the yield of 6a increased with increasing amount of
FeCl3 and with higher reaction temperature (Table 1, entries 3–
5). On the other hand, increasing the amount of Et3N
(3.0 equiv) did not improve the yield of 6a significantly
(Table 1, entry 6). We then investigated the effect of solvents
Figure 2. X-ray crystal structure of compound 6a.
and bases on this cascade reaction in the presence of
50 mol% FeCl3 (Table 1, entries 5 and 7–15) and found that
methanol was the most effective solvent and Et3N was more
suitable base. Encouraged by these interesting findings, a varie-
ty of Lewis acids were then examined (Table 1, entries 5 and
16–19); the results showed that, with the exception of ZnCl2,
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To further evaluate the generality of this cascade annulation,
a series of allenoates and allenone were also investigated
(Table 3, entries 1–5). Firstly, methyl 2,3-butadienoate was also
good candidate, giving 6p in 83% yield (Table 3, entry 1),
whereas the yield decreased slightly when benzyl 2,3-butadie-
Table 2. Scope of the reaction with respect to istains and amino esters.[a]
Table 3. The cascade annulation of allenoates and alkynoates.[a]
Entry
R1
R2
R3
Time
[h]
Product
Yield
[%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14[c]
15[d]
16
Bn
H
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
24
24
24
24
24
48
24
24
24
24
18
24
24
24
24
24
6a
6b
6c
6d
6e
n.r.
6 f
6g
6h
6i
6j
6k
6l
6m
6n
6o
75
78
64
60
58
n.r.
79
69
65
80
78
65
72
69
61
52
CH3
Allyl
propargyl
H
Boc
Bn
Bn
Bn
Bn
Bn
Entry
3
Time Product
[h]
Yield
[%][b]
1
3b 22
6p 83
5-F
5-Cl
5-Br
5-CH3
5-OCH3
6-Cl
7-F
H
2
3
4
3c 12
3d 18
3e 24
6q 56
6r 85
4b 78
Bn
Bn
Bn
Bn
H
H
OiPr
Ph
Bn
[a] Reaction conditions (unless indicated otherwise):
1
(0.5 mmol),
2
(0.75 mmol), 3a (0.75 mmol), Et3N (3.0 equiv), FeCl3 (0.5 equiv), 3 ꢁMS
(100 mg), MeOH (4 mL), 658C. Bn=benzyl. [b] Isolated yield based on 1;
n.r.=no reaction. [c] EtOH was used as solvent due to ester exchange of
2b. [d] iPrOH was used as solvent.
the addition of a Lewis acid was beneficial to the formation of
pyrrolo[1,2-c]quinazolinone 6a (Table 1, entry 18). The results
also showed that Cu(OAc)2 and AgOAc were effective catalysts,
and that FeCl3 was the most effective for the formation of
pyrrolo[1,2-c]quinazolinone 6a.
5
6
7
3 f 24
3g 18
3h 24
4c 75
6s 63
6t 68
With the optimized conditions in hand, we explored the
substrate scope of the cascade reaction with regard to isatin
derivatives 1, glycine ester or a-amino ketone hydrochloride 2,
and ethyl 2,3-butadienoate 3a (Table 2). Firstly, with 2a and 3a
used as a representative partner, a variety of isatin derivatives
1 were investigated, as shown in Table 2; remarkably, the de-
sired products 6 were obtained in moderate to excellent
yields, irrespective of the nature of the protecting group at the
N-1 position of the isatin derivatives 1 (Table 2, entries 1–4) or
the electronic properties of the substituent on the aromatic
ring of 1 (Table 2, entries 7–13). Moreover, when simple isatin
was used, the reaction also occured and gave the correspond-
ing product 6e in modest yield (Table 2, entry 5). However,
when a Boc-protected isatin was used, no pyrrolo[1,2-c]quina-
zolinone derivative was observed (Table 2, entry 6), which
might be due to the difficultly of forming the corresponding
azomethine ylide. Secondly, a variety of glycinate and a-amino
ketone hydrochlorides 2a–d also gave satisfactory results
(Table 2, entries 14–16). Increasing the size of the ester group
of the glycinate esters had a negative effect on the reaction
(Table 2, entries 13–15).
8
9
3i 24
6a 60
3j 22
6u 55
[a] Reaction conditions (unless indicated otherwise): 1a (0.5 mmol), 2a
(0.75 mmol), 3 (0.75 mmol), Et3N (1.0 mmol), FeCl3 (0.25 mmol), 3ꢁ MS
(100 mg), MeOH (4 mL), stirred at 658C. [b] Isolated yield based on 1a.
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noate was used (Table 3, entry 2). Interestingly, 3,4-pentadien-
2-one was also a suitable substrate in this cascade process,
with 6r being isolated in 85% yield (Table 3, entry 3). However,
when 2-methyl-2,3-butadienoate 3e was used, only the [3+2]
cycloadditon product 4b was isolated (Table 3, entry 4), and
when 4-methyl-2,3-butadienoate 3 f was used the [3+2] cyclo-
additon product 4c was obtained in good yield with excellent
stereoselectivity (Table 3, entry 5).
A variety of alkynoates and alkynone were also investigated.
As shown in Table 3, all were effective candidates, giving the
corresponding products 6a and 6s–u in moderate yields
(Table 3, entries 6–9). It was found that increasing the steric
bulk of the substituent on the alkynoates had a negative
impact on these cascade reactions.
Scheme 3. Control experiments.
The obtained pyrrolo[1,2-c]quinazolinones 6, could be used
as useful building blocks in organic synthesis and were easily
transformed into diverse potential biologically active heterocy-
cles (Scheme 2). Firstly, pyrrolo[1,2-c]quinazolinone 6a could
To gain some insights into the unexpected cascade reaction,
the following experiments were conducted (Scheme 3). Com-
pound 4a could be converted into the endocyclic isomer 5a
(25%) and 6a (42%) in the presence of Et3N at 658C. However,
when FeCl3 (50 mol%) was added, 4a was converted into 6a
in 90% yield. These results clearly indicated that FeCl3 played
a vital role in the transformation process from 4a into 6a.
Based on the above experimental results and on other con-
trol experiments, a plausible mechanism of FeCl3-mediated
three-component cascade reaction between azomethine ylides
and allenoates has been proposed as depicted in Scheme 4.
Firstly, the FeIII-ion-stabilized azomethine ylide 9, generated in
situ from the substituted isatin 1a and primary a-amino acid
methyl ester 2a, reacted with ethyl 2,3-butadienoate 3a to fur-
nish the 1,3-diplar cycoloaddition product 4a. Secondly, con-
version of exocyclic 4a into endocyclic 5a can occur via inter-
mediates 10 and 11 under reflux conditions. It is reasonable
that 4a could convert into 10 and 11 through keto–enol tauto-
merism and proton transfer under the basic conditions. Subse-
quently, 11 could transform into 14 after several rounds of
proton transfer. Finally, product 6a forms through intramolecu-
lar nitrogen anion nucleophilic attack of the carbonyl group, si-
Scheme 2. Synthetic transformation of pyrrolo[1,2-c]quinazolinones.
be readily transformed into pyrrolo[3,2-c]quinazoline derivative
7a in one pot; this product not only exhibits important biolog-
ical activities but also constitutes the core structural element
of many natural alkaloids (Figure 1).[1,3–6,24] Moreover, the intro-
duction of propargyl-protected
isatin as a substrate not only ef-
fectively allowed the construc-
tion of pyrrolo[1,2-c]quinazolin-
one derivatives, but also in-
creased the complexity of the
products and the synthetic ap-
plication. Transformations based
on alkynes have been the sub-
ject of many intensive studies,
with azide–alkyne Huisgen cyclo-
addition being an extremely
powerful approach in combina-
torial chemistry and drug discov-
ery.[25] As expected, in the pres-
ence of sodium ascorbate and
CuSO4, 6d could be conviently
transformed into the desired tri-
azole compound 7b in 68%
yield.
Scheme 4. A plausible mechanism to account for the cascade annulation.
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Chem. Eur. J. 2014, 20, 1711 – 1719
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multaneously activated by Fe3+ ion, followed by release of
a proton.
Compounds 4b and 4c were synthesized according to the proce-
dure described for 6, except that 2-methly-2,3-butadienoate (3e)
or 4-methly-2,3-butadienoate (3 f) was used.
3’-Ethyl 5’-methyl 1-benzyl-4’-methylene-2-oxospiro[indoline-
3,2’-pyrrolidine]-3’,5’-dicarboxylate (4a): Yield: 30%; white solid;
m.p. 130–1318C. H NMR (600 MHz, CDCl3): d=7.23–7.34 (m, 6H),
Conclusion
1
7.17 (t, J=7.8 Hz, 1H), 7.00 (t, J=7.5 Hz, 1H), 6.70 (d, J=7.8 Hz,
1H), 5.77 (s, 1H), 5.57 (s, 1H), 4.99 (d, J=15.6 Hz, 1H), 4.83 (d, J=
16.2 Hz, 1H), 4.68 (d, J=5.4 Hz, 1H), 4.15–4.19 (m, 1H), 4.06–4.10
(m, 1H), 3.87 (s, 3H), 3.69 (s, 1H), 1.18 ppm (t, J=6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=174.5, 170.3, 168.9, 143.3, 141.8,
135.3, 131.1, 129.1, 128.6, 127.4, 127.1, 122.8, 122.6, 113.4, 109.2,
68.7, 63.0, 61.1, 58.2, 52.6, 43.7, 13.7 ppm; MS (EI, 70 eV): m/z=420
(1.5) [M]+, 374 (3.1), 361 (51.2), 347 (6.3), 315 (17.5), 287 (11.0), 197
(12.3), 181 (3.3), 91 (100); HRMS (ESI): m/z calcd for C24H25N2O5:
421.1758 [M+H]+; found: 421.1765.
We have developed an unprecedented FeCl3-triggered, three-
component domino strategy to access highly functionalized
pyrrolo[1,2-c]quinazolinones in moderate to excellent yields.
Based on previous reports and on our own inverstigations,
a plausible mechanism has been proposed. The obtained prod-
ucts were used as useful building blocks in the synthesis of
a diverse range of potentially biologically active heterocycles.
This method has advantages of mild conditions and simple
work-up as well as wide substrate scope, which makes this ap-
proach powerful for the synthesis of diverse pyrrolo[1,2-c]qui-
nazolinones. Further investigation on the pharmacological ac-
tivities of these compounds is underway. The development of
more sophisticated and powerful cascade reactions is ongoing
in our laboratory and will be reported in due course.
(Z)-3’-Ethyl 5’-methyl 1-benzyl-4’-ethylidene-2-oxospiro[indoline-
3,2’-pyrrolidine]-3’,5’-dicarboxylate (4b): Yield: 75%; white solid;
1
m.p. 163–1648C. H NMR (600 MHz, CDCl3): d=7.25–7.32 (m, 5H),
7.16 (t, J=7.2 Hz, 2H), 6.97 (t, J=7.2 Hz, 1H), 6.70 (d, J=8.4 Hz,
1H), 6.18 (q, J=6.0 Hz, 1H), 5.06 (d, J=15.6 Hz, 2H), 4.81 (d, J=
15.6 Hz, 1H), 4.68 (s, 1H), 4.21–4.24 (m, 1H), 4.13–4.16 (m, 1H),
3.87 (s, 3H), 3.63 (s, 1H), 1.71 (d, J=6.0 Hz, 3H), 1.24 ppm (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=173.5, 170.4, 169.6,
140.9, 136.9, 135.0, 132.9, 128.9, 128.6, 127.5, 126.9, 124.1, 123.1,
122.1, 109.4, 69.8, 63.8, 61.2, 55.6, 52.6, 43.8, 15.7, 13.8 ppm; MS
(EI, 70 eV): m/z=434 (3.0) [M]+, 388 (4.8), 375 (90), 361 (5.4), 329
(23.9), 301 (30.1), 211 (17.3), 193 (6.3), 149 (4.4), 129 (2.9), 92 (9.9),
91 (100); HRMS (ESI): m/z calcd. for C25H27N2O5: 435.1914 [M+H]+;
found: 435.1920.
Experimental Section
General information
Unless otherwise noted, all the reactions were conducted under
a dry N2 atmosphere. All solvents were treated according to gener-
al methods. Column chromatography purifications were performed
using 200–300 mesh silica gel, and reactions were monitored by
thin-layer chromatography (TLC). Melting points were determined
with a WRS-1B digital melting-point apparatus, and the values are
3’-Ethyl 5’-methyl 1-benzyl-3’-methyl-4’-methylene-2-oxospir-
o[indoline-3,2’-pyrrolidine]-3’,5’-dicarboxylate (4c): Yield: 78%;
white solid; m.p. 118–1198C. 1H NMR (600 MHz, CDCl3): d=7.25–
7.34 (m, 5H), 7.16 (t, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.98 (t,
J=7.8 Hz, 1H), 6.72 (d, J=7.8 Hz, 1H), 5.74 (s, 1H), 5.29 (s, 1H),
5.08 (d, J=15.6 Hz, 1H), 4.78 (d, J=9.6 Hz, 1H), 4.74 (d, J=15.0 Hz,
1H), 4.18–4.25 (m, 2H), 3.88 (s, 3H), 1.27 (t, J=7.2 Hz, 3H),
1.02 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=173.7, 171.8, 169.8,
150.0, 141.7, 135.0, 129.3, 128.7, 128.3, 127.2, 126.7, 123.5, 122.4,
111.4, 109.1, 73.2, 64.1, 61.1, 58.5, 52.2, 43.5, 18.2, 13.4 ppm; HRMS
(ESI): m/z calcd for C25H27N2O5: 435.1914 [M+H]+; found: 435.1918.
1
uncorrected. H and 13C NMR spectra were recorded with a Varian
Mercury PLUS 400 or a Varian Mercury PLUS 600 spectrometer in
CDCl3 or [D6]DMSO. Chemical shifts (d) are reported in parts per
million (ppm) relative to the singlet (0 ppm) for tetramethylsilane
(TMS). Data are reported as follows: chemical shift, multiplicity (s=
singlet, d=doublet, t=triplet, q=quartet, dd=doublet of dou-
blets, and m=multiplet), integration, and coupling constant (Hz).
13C NMR chemical shifts are reported in ppm from CDCl3 (taken as
77.0 ppm). Mass spectra were measured with a Finnigan TRACEMS
2000 (EI-MS) spectrometer. X-ray diffraction analysis was carried
out with a Bruker APEX-II CCD X-ray diffraction instrument. HRMS
were recorded with an IonSpec FT-ICR mass spectrometer with ESI
resource. Allenoates[26] and substituted isatins[27] were synthesized
according to the reported methods. Other chemicals were pur-
chased from commercial suppliers and used without further purifi-
cation.
3’-Ethyl 5’-methyl 1-benzyl-4’-methyl-2-oxo-3’,4’-dihydrospiro[in-
doline-3,2’-pyrrole]-3’,5’-dicarboxylate (5a): Yield: 20%; white
solid; m.p. 161–1628C. 1H NMR (600 MHz, CDCl3): d=7.38 (d, J=
7.2 Hz, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.28 (d, J=7.2 Hz, 1H), 7.16–
7.18 (m, 1H), 6.93 (d, J=4.8 Hz, 2H), 6.71 (d, J=8.4 Hz, 1H), 5.26
(d, J=15.6 Hz, 1H), 4.67 (d, J=15.6 Hz, 1H), 4.11–4.16 (m, J=
7.5 Hz, 1H), 3.89 (s, 3H), 3.75–3.79 (m, 1H), 3.61–3.65 (m, 1H), 3.58
(d, J=7.8 Hz, 1H), 1.55 (d, J=7.2 Hz, 3H), 0.46 ppm (t, J=7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=174.8, 172.8, 169.2, 162.0,
142.9, 135.1, 130.0, 128.5, 127.6, 127.3, 125.9, 124.1, 122.8, 109.3,
81.3, 60.8, 56.9, 52.7, 46.8, 44.1, 17.1, 13.0 ppm; MS (EI, 70 eV): m/
z=420 (25.7) [M]+, 347 (13.9), 315 (24.6), 301 (3.9), 225 (16.1), 198
(5.8), 105 (3.9), 91 (100); HRMS (ESI): m/z calcd for C24H25N2O5:
412.1758 [M+H]+; found: 421.1760.
General procedure for the synthesis of 4a or 5a
Under a nitrogen atmosphere, to a 10 mL flask equipped with
a reflux condenser was added 1 (0.5 mmol), 2 (0.75 mmol), 3
(0.75 mmol), 3 ꢁ molecular sieve (100 mg), Et3N (1.0 mmol), and
MeOH (4.0 mL). This solution was stirred at room temperature for
36 hours until either the reaction reached completion or no further
product was formed (reaction monitored by TLC). The reaction
mixture was concentrated under reduced pressure, then the crude
product was purified by flash chromatography on silica gel (silica:
200–300; petroleum ether/ethyl acetate 12:1 to 6:1) to afford the
desired products 4a (30%) and 5a (20%) as white solids.
General procedure for the synthesis of pyrrolo[1,2-c]quina-
zolinones 6
Under a nitrogen atmosphere, to a 10 mL flask equipped with
a reflux condenser was added isatin derivative 1 (0.5 mmol), a-
amino acid ester or a-amino ketone hydrochloride 2 (0.75 mmol),
2,3-butadienoate 3 (0.75 mmol), FeCl3 (0.25 mmol), 3 ꢁ molecular
Chem. Eur. J. 2014, 20, 1711 – 1719
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Full Paper
sieve (100 mg), Et3N (1.0 mmol), and MeOH (4.0 mL). The mixture
was stirred at 658C for 12–24 h until 1 was completely consumed
(reaction monitored by TLC). The reaction mixture was concentrat-
ed under reduced pressure and the crude product was purified by
column chromatography (petroleum ether/ethyl acetate 12:1 to
6:1) to give the corresponding product 6 as a white solid.
207 (24.7), 195 (10.0), 168 (5.2), 140 (15.7), 103.5 (12.3); HRMS (ESI):
m/z calcd for C17H17N2O5: 329.1143 [M+H]+; found: 329.1144.
1-Ethyl 3-methyl 6-benzyl-9-fluoro-2-methyl-5-oxo-5,6-dihydro-
pyrrolo[1,2-c]quinazoline-1,3-dicarboxylate (6 f): Yield: 79%;
white solid; m.p. 172–1738C. 1H NMR (600 MHz, CDCl3): d=8.72–
8.70 (m, 1H), 7.32 (t, J=7.5 Hz, 2H), 7.26 (t, J=7.2 Hz, 1H), 7.22 (d,
J=7.2 Hz, 2H), 7.14–7.04 (m, 2H), 5.48 (s, 2H), 4.47 (q, J=7.0 Hz,
2H), 3.97 (s, 3H), 2.39 (s, 3H), 1.45 ppm (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=164.9, 163.0, 159.3, 156.9, 145.3, 134.9, 130.7,
130.5, 128.8, 128.5, 127.6, 126.2, 121.5, 117.2, 116.9, 116.7, 116.6,
115.6, 115.5, 113.7, 113.0, 112.7, 61.0, 52.7, 47.7, 14.1, 11.6 ppm; MS
(EI, 70 eV): m/z=436 (26.5) [M]+, 422 (1.4), 404 (25.5), 391 (3.5), 377
(4.6), 303 (2.0), 225 (1.3), 92 (8.2), 91 (100); HRMS (ESI): m/z calcd
for C24H22FN2O5: 437.1507 [M+H]+; found: 437.1513.
1-Ethyl 3-methyl 6-benzyl-2-methyl-5-oxo-5,6-dihydropyrrolo-
[1,2-c]quinazoline-1,3-dicarboxylate (6a): Yield: 75%; white solid;
m.p. 172–1738C. 1H NMR (600 MHz, CDCl3): d=8.81 (d, J=8.4 Hz,
1H), 7.36–7.30 (m, 3H), 7.26–7.22 (m, 4H), 7.18 (d, J=8.4 Hz, 1H),
5.50 (s, 2H), 4.46 (q, J=7.0 Hz, 2H), 3.97 (s, 3H), 2.39 (s, 3H),
1.44 ppm (t, J=6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=165.1,
162.9, 145.4, 135.1, 134.2, 131.4, 129.5, 128.6, 128.4, 127.3, 126.3,
126.2, 123.0, 120.8, 114.9, 114.1, 112.8, 60.8, 52.4, 47.2, 14.0,
11.4 ppm; MS (EI, 70 eV): m/z=418 (16.8) [M]+, 385 (8.8), 359 (1.9),
286 (3.2), 207 (3.2), 169 (2.8), 140 (3.5), 129 (5.4), 92 (7.9), 91 (100);
HRMS (ESI): m/z calcd for C24H23N2O5: 419.1601 [M+H]+; found:
419.1605.
1-Ethyl 3-methyl 6-benzyl-9-chloro-2-methyl-5-oxo-5,6-dihydro-
pyrrolo[1,2-c]quinazoline-1,3-dicarboxylate (6g): Yield: 69%;
1
white solid; m.p. 167–1688C. H NMR (600 MHz, CDCl3): d=8.90 (s,
1H), 7.31 (t, J=7.5 Hz, 2H), 7.26–7.24 (m, 2H), 7.21 (d, J=7.8 Hz,
2H), 7.09 (d, J=8.4 Hz, 1H), 5.47 (s, 2H), 4.47 (q, J=7.0 Hz, 2H),
3.97 (s, 3H), 2.39 (s, 3H), 1.46 ppm (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=164.8, 162.9, 145.2, 134.8, 132.9, 130.0, 129.5,
128.8, 128.7, 127.6, 126.3, 126.1, 121.5, 116.4, 115.5, 113.6, 61.2,
52.7, 47.6, 14.1, 11.6 ppm; MS (EI, 70 eV): m/z=452 (23.3) [M]+, 420
(19.9), 407 (3.2), 393 (4.2), 319 (1.6), 257 (1.7), 210 (1.4), 92 (7.8), 91
(100); HRMS (ESI): m/z calcd for C24H22ClN2O5: 453.1212 [M+H]+;
found: 453.1219.
1-Ethyl 3-methyl 2,6-dimethyl-5-oxo-5,6-dihydropyrrolo[1,2-c]-
quinazoline-1,3-dicarboxylate (6b): Yield: 78%; white solid; m.p.
142–1438C. 1H NMR (600 MHz, CDCl3): d=8.82 (d, J=7.8 Hz, 1H),
7.50–7.48 (m, 1H), 7.29–7.24 (m, 2H), 4.45 (q, J=7.2 Hz, 2H), 3.98
(s, 3H), 3.70 (s, 3H), 2.36 (s, 3H), 1.43 ppm (t, J=6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=165.2, 163.1, 144.9, 135.0, 131.3,
129.6, 128.2, 126.3, 123.0, 120.7, 114.0, 113.9, 112.6, 60.8, 52.5, 31.0,
14.1, 11.5 ppm; MS (EI, 70 eV): m/z=342 (100) [M]+, 311 (23.7), 297
(28.3), 284 (26.7), 256 (7.1), 238 (46.7), 209 (14.4), 181 (5.6), 140
(6.1), 132 (13.7); HRMS (ESI): m/z calcd for C18H19N2O5: 343.1288
[M+H]+; found: 343.1290.
1-Ethyl 3-methyl 6-benzyl-9-bromo-2-methyl-5-oxo-5,6-dihydro-
pyrrolo[1,2-c]-quinazoline-1,3-dicarboxylate (6h): Yield: 65%;
1
white solid; m.p. 176–1778C. H NMR (600 MHz, CDCl3): d=9.03 (d,
1-Ethyl 3-methyl 6-allyl-2-methyl-5-oxo-5,6-dihydropyrrolo[1,2-
c]quinazoline-1,3-dicarboxylate (6c): Yield: 64%; white solid; m.p.
132–1338C. 1H NMR (600 MHz, CDCl3): d=8.81 (s, J=8.4 Hz, 1H),
7.45 (t, J=7.5 Hz, 1H), 7.27–7.24 (m, 2H), 5.94 (dd, J=5.4, 5.4 Hz,
1H), 5.27 (d, J=10.8 Hz, 1H), 5.21 (d, J=17.4 Hz, 1H), 4.89 (s, 2H),
4.45 (q, J=7.0 Hz, 2H), 3.97 (s, 3H), 2.37 (s, 3H), 1.43 ppm (t, J=
6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=165.2, 163.0, 144.9,
134.3, 131.4, 130.8, 129.6, 128.4, 126.5, 123.1, 120.8, 117.7, 114.8,
114.2, 112.8, 60.9, 52.6, 46.1, 14.1, 11.5 ppm; MS (EI, 70 eV): m/z=
368 (100) [M]+, 354 (9.1), 337 (20.1), 323 (19.2), 307 (12.6), 264
(29.2), 223 (13.1), 207 (10.9), 195 (8.6), 179 (8.3), 167 (7.2), 140
(16.7); HRMS (ESI): m/z calcd for C20H21N2O5: 369.1445 [M+H]+;
found: 369.1444.
J=7.8 Hz, 1H), 7.43–7.41 (m, 1H), 7.31 (t, J=7.5 Hz, 2H), 7.27–7.25
(m, 1H), 7.21 (d, J=7.2 Hz, 2H), 7.04 (d, J=9.0 Hz, 1H), 5.46 (s, 2H),
4.48 (q, J=7.2 Hz, 2H), 3.97 (s, 3H), 2.39 (s, 3H), 1.46 ppm (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=164.7, 162.9, 145.2,
134.7, 133.3, 132.3, 129.8, 129.0, 128.8, 127.6, 126.3, 121.5, 116.7,
116.3, 115.9, 113.6, 61.2, 52.7, 47.6, 14.1, 11.6 ppm; MS (EI, 70 eV):
m/z=498 (12.4) [M+2]+, 497 (2.8) [M+1]+, 496 (11.8) [M]+, 466
(11.5), 437 (2.6), 194 (1.2), 140 (1.0), 92 (6.8), 91 (100); HRMS (ESI):
m/z calcd for C24H22BrN2O5: 497.0707 [M+H]+; found: 497.0705.
1-Ethyl 3-methyl 6-benzyl-2,9-dimethyl-5-oxo-5,6-dihydropyr-
rolo[1,2-c]quinazoline-1,3-dicarboxylate (6i): Yield: 80%; white
1
solid; m.p. 170–1718C. H NMR (600 MHz, CDCl3): d=8.56 (s, 1H),
7.30 (t, J=7.5 Hz, 2H), 7.25 (t, J=7.2 Hz, 1H), 7.22 (d, J=7.8 Hz,
2H), 7.15 (d, J=8.4 Hz, 1H), 7.06 (d, J=9.0 Hz, 1H), 5.47 (s, 2H),
4.46 (q, J=7.2 Hz, 2H), 3.96 (s, 3H), 2.38 (s, 3H), 2.37 (s, 3H),
1.44 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=165.3,
163.1, 145.5, 135.3, 132.8, 132.3, 131.5, 130.8, 128.7, 128.6, 127.4,
126.4, 126.3, 120.9, 115.0, 114.1, 112.8, 60.9, 52.6, 47.3, 20.9, 14.2,
11.5 ppm; MS (EI, 70 eV): m/z=432 (51.2) [M]+, 418 (5.5), 401
(12.7), 400 (41.0), 399 (29.4), 387 (4.8), 373 (7.1), 299 (3.4), 181 (3.5),
92.1 (6.0), 91 (100); HRMS (ESI): m/z calcd for C25H25N2O5: 433.1758
[M+H]+; found: 433.1765.
1-Ethyl 3-methyl 2-methyl-5-oxo-6-(prop-2-yn-1-yl)-5,6-dihydro-
pyrrolo;[1,2-c]quinazoline-1,3-dicarboxylate (6d): Yield: 60%;
1
white solid; m.p. 185–1868C. H NMR (600 MHz, CDCl3): d=8.81 (d,
J=8.4 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.31
(t, J=7.8 Hz, 1H), 5.04 (s, 2H), 4.45 (q, J=7.0 Hz, 2H), 3.97 (s, 3H),
2.36 (s, 3H), 2.31 (s, 1H), 1.43 ppm (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=165.3, 163.0, 144.7, 133.6, 131.4, 129.9, 128.8,
126.7, 123.7, 121.0, 114.7, 114.4, 113.3, 73.6, 61.0, 52.7, 33.6, 29.6,
14.2, 11.6 ppm; MS (EI, 70 eV): m/z=366 (100) [M]+, 335 (22.0), 321
(17.1), 308 (15.8), 262 (32.2), 223 (6.5), 195 (7.9), 179 (7.4), 167 (4.9),
140 (12.5); HRMS (ESI): m/z calcd for C20H19N2O5: 367.1288 [M+H]+;
found: 367.1289.
1-Ethyl 3-methyl 6-benzyl-9-methoxy-2-methyl-5-oxo-5,6-dihy-
dropyrrolo[1,2-c]quinazoline-1,3-dicarboxylate (6j): Yield: 78%;
white solid; m.p. 165–1668C. 1H NMR (600 MHz, CDCl3): d=8.56–
8.544 (m, 1H), 7.30 (t, J=7.5 Hz, 2H), 7.26–7.21 (m, 3H), 7.09 (d, J=
9.6 Hz, 1H), 6.94–6.92 (m, 1H), 5.47 (s, 2H), 4.45 (q, J=7.0 Hz, 2H),
3.97 (s, 3H), 3.85 (s, 3H), 2.39 (s, 3H), 1.43 ppm (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=165.4, 163.3, 155.3, 145.4, 135.3,
131.6, 128.8, 128.4, 127.5, 126.3, 121.1, 117.6, 116.3, 115.2, 109.7,
61.0, 55.5, 52.7, 47.5, 14.2, 11.8 ppm; MS (EI, 70 eV):
m/z=448 (79.2) [M]+, 434 (5.2), 416 (31.2), 389 (11.4), 357 (36.2),
253 (9.5), 225 (7.2), 197 (4.0), 92 (10.9), 91 (100); HRMS (ESI): m/z
calcd for C25H25N2O6: 449.1707 [M+H]+; found: 449.1713.
1-Ethyl 3-methyl 2-methyl-5-oxo-5,6-dihydropyrrolo[1,2-c]quina-
zoline-1,3-dicarboxylate (6e): Yield: 58%; white solid; m.p. 205–
2068C. 1H NMR (600 MHz, CDCl3): d=10.63 (s, 1H), 8.77 (d, J=
8.4 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 7.17 (d,
J=7.8 Hz, 1H), 4.46 (q, J=7.0 Hz, 2H), 3.98 (s, 3H), 2.39 (s, 3H),
1.44 ppm (t, J=6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=165.2,
163.1, 146.0, 133.3, 132.7, 129.8, 129.1, 126.2, 123.6, 120.0, 115.5,
113.4, 113.2, 61.0, 52.6, 14.2, 11.7 ppm; MS (EI, 70 eV): m/z=328
(100) [M]+, 314 (14.4), 297 (24.6), 283 (23.1), 270 (20.1), 224 (60.7),
Chem. Eur. J. 2014, 20, 1711 – 1719
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Full Paper
1-Ethyl
3-methyl
6-benzyl-8-chloro-2-methyl-5-oxo-5,6-
199–2008C. 1H NMR (600 MHz, CDCl3): d=8.80 (d, J=8.4 Hz, 1H),
7.35 (t, J=7.5 Hz, 1H), 7.31 (t, J=7.5 Hz, 2H), 7.25–7.23 (m, 4H),
7.18 (d, J=8.4 Hz, 1H), 5.49 (s, 2H), 3.98 (s, 3H), 3.97 (s, 3H),
2.38 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=165.6, 162.9, 145.4,
135.1, 134.3, 131.6, 129.7, 128.7, 128.5, 127.4, 126.4, 126.3, 123.2,
120.9, 114.9, 114.1, 112.6, 52.5, 51.7, 47.3, 11.4 ppm; MS (EI, 70 eV):
m/z=404 (35.7) [M]+, 372 (27.4), 345 (2.8), 285 (3.0), 207 (1.7), 179
(2.0), 168 (2.6), 140 (1.9), 92 (9.1), 91 (100); HRMS (ESI): m/z calcd
for C23H21N2O5: 405.1445 [M+H]+; found: 405.1453.
dihydropyrrolo[1,2-c]quinazoline-1,3-dicarboxylate (6k): Yield:
65%; white solid; m.p. 195–1978C. H NMR (600 MHz, CDCl3): d=
1
8.87 (d, J=8.4 Hz, 1H), 7.34 (t, J=7.5 Hz, 2H), 7.29–7.18 (m, 5H),
5.45 (s, 2H), 4.44 (q, J=7.0 Hz, 2H), 3.97 (s, 3H), 2.39 (s, 3H),
1.43 ppm (t, J=7.2 Hz, 3H); C13 NMR (100 MHz, CDCl3): d=165.1,
162.9, 145.4, 135.5, 134.6, 131.0, 129.0, 128.1, 127.8, 126.4, 123.6,
121.3, 115.1, 113.3, 112.9, 61.1, 52.7, 47.6, 14.2, 11.7 ppm; MS (EI,
70 eV): m/z=455 (2.2) [M+1]+, 452 (24.9) [M]+, 452 (24.9), 420
(21.6), 393 (2.7), 257 (1.5), 207 (4.5), 196 (1.8), 92 (7.5), 91 (100);
HRMS (ESI): m/z calcd for C24H22ClN2O5: 453.1212 [M+H]+; found:
453.1214.
1-Benzyl 3-methyl 6-benzyl-2-methyl-5-oxo-5,6-dihydropyrrolo-
[1,2-c]quinazoline-1,3-dicarboxylate (6q): Yield: 56%; white solid;
m.p. 163–1648C. 1H NMR (600 MHz, CDCl3): d=8.72 (d, J=8.4 Hz,
1H), 7.47 (d, J=7.8 Hz, 2H), 7.40 (t, J=7.2 Hz, 2H), 7.37 (d, J=
7.2 Hz, 1H), 7.33–7.12 (m, 8H), 5.49 (s, 2H), 5.44 (s, 2H), 3.96 (s,
3H), 2.35 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=165.1, 163.0,
145.5, 135.3, 135.2, 134.4, 131.7, 129.8, 128.8, 128.7, 128.6, 128.3,
127.5, 126.6, 126.3, 123.2, 121.1, 115.0, 114.2, 112.6, 66.9, 52.6, 47.5,
11.6 ppm; MS (EI, 70 eV): m/z=480 (15.3) [M]+, 448 (7.6), 389 (3.6),
346 (2.1), 314 (1.6), 140 (1.0), 129 (2.5), 92 (8.7), 91 (100); HRMS
(ESI): m/z calcd for C29H25N2O5: 481.1758 [M+H]+; found: 481.1767.
1-Ethyl 3-methyl 6-benzyl-7-fluoro-2-methyl-5-oxo-5,6-dihydro-
pyrrolo[1,2-c]quinazoline-1,3-dicarboxylate (6l): Yield: 72%;
white solid; m.p. 150–1518C. H NMR (600 MHz, CDCl3): d=8.51 (d,
1
J=8.4 Hz, 1H), 7.26 (t, J=7.2 Hz, 2H), 7.22 (d, J=6.6 Hz, 1H), 7.19
(d, J=7.8 Hz, 2H), 7.17–7.08 (m, 2H), 5.63 (s, 2H), 4.45 (q, J=
7.0 Hz, 2H), 3.95 (s, 3H), 2.40 (s, 3H), 1.43 ppm (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=165.1, 162.5, 151.5, 149.0, 145.8,
136.4, 130.9, 129.8, 128.4, 127.2, 126.4, 124.3, 123.3, 122.3, 121.6,
117.6, 117.4, 113.8, 61.1, 52.5, 50.3, 50.1, 14.1, 11.5 ppm; MS (EI,
70 eV): m/z=436 (18.3) [M]+, 404 (36.1), 377 (3.6), 303 (6.3), 92
(8.6), 91 (100); HRMS (ESI): m/z calcd for C24H22FN2O5: 437.1507
[M+H]+; found: 437.1511.
Methyl 1-acetyl-6-benzyl-2-methyl-5-oxo-5,6-dihydropyrrolo[1,2-
c]quinazoline-3-carboxylate (6r): Yield: 85%; white solid; m.p.
200–2018C. 1H NMR (600 MHz, CDCl3): d=8.11 (d, J=7.8 Hz, 1H),
7.34 (t, J=7.2 Hz, 1H), 7.31 (d, J=7.8 Hz, 2H), 7.25–7.18 (m, 5H),
5.50 (s, 2H), 3.98 (s, 3H), 2.63 (s, 3H), 2.36 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=199.7, 162.8, 145.6, 135.2, 134.4, 129.6, 128.8,
127.5, 126.6, 126.3, 125.3, 123.4, 122.7, 121.0, 115.3, 114.2, 52.6,
47.4, 32.2, 11.0 ppm; MS (EI, 70 eV): m/z=388 (30.4) [M]+, 356
(16.3), 329 (2.5), 265 (3.0), 207 (1.2), 128 (1.8), 92 (8.4), 91 (100);
HRMS (ESI): m/z calcd for C23H21N2O4: 389.1496 [M+H]+; found:
389.1496.
Diethyl 6-benzyl-2-methyl-5-oxo-5,6-dihydropyrrolo[1,2-c]quina-
zoline-1,3-dicarboxylate (6m): Yield: 69%; white solid; m.p. 116–
1
117 8C. H NMR (600 MHz, CDCl3): d=8.81 (d, J=7.8 Hz, 1H), 7.34 (t,
J=7.8 Hz, 1H), 7.31 (t, J=7.5 Hz, 2H), 7.26–7.22 (m, 4H), 7.18 (d,
J=8.4 Hz, 1H), 5.49 (s, 2H), 4.47–4.42 (m, 4H), 2.40 (s, 3H), 1.44 (t,
J=7.2 Hz, 3H), 1.38 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=165.3, 162.5, 145.6, 135.3, 134.5, 131.5, 129.7, 128.8,
128.6, 127.5, 126.6, 126.4, 123.2, 121.4, 115.0, 114.4, 113.0, 61.7,
60.9, 47.5, 14.2, 14.1, 11.5 ppm; MS (EI, 70 eV): m/z=432 (26.5)
[M]+, 385 (16.5), 360 (14.5), 195 (2.0), 181 (2.0), 140 (2.8), 129 (3.2),
92 (11), 91 (100); HRMS (ESI): m/z calcd for C25H25N2O5: 433.1758
[M+H]+; found: 433.1765.
1-Ethyl 3-methyl 6-benzyl-5-oxo-5,6-dihydropyrrolo[1,2-c]quina-
zoline-1,3-dicarboxylate (6s): Yield: 63%; white solid; m.p. 166–
1688C. 1H NMR (600 MHz, CDCl3): d=9.54 (d, J=7.8 Hz, 1H), 7.53
(s, 1H), 7.41 (t, J=7.5 Hz, 1H), 7.33–7.22 (m, 6H), 7.23 (d, J=8.4 Hz,
1H), 5.53 (s, 2H), 4.40 (q, J=7.2 Hz, 2H), 3.96 (s, 3H), 1.42 ppm (t,
J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=63.7, 161.8, 145.7,
135.1, 134.8, 130.5, 128.9, 128.1, 127.6, 126.4, 123.5, 122.9, 122.4,
114.9, 114.6, 112.3, 60.9, 52.7, 47.7, 14.3 ppm; MS (EI, 70 eV): m/z=
404 (16.7) [M]+, 390 (5.9), 372 (16.0), 358 (5.5), 271 (5.3), 165 (1.4),
92 (8.1), 91 (100); HRMS (ESI): m/z calcd for C23H21N2O5: 405.1445
[M+H]+; found: 405.1448.
1-Ethyl 3-isopropyl 6-benzyl-2-methyl-5-oxo-5,6-dihydropyrrolo-
[1,2-c]quinazoline-1,3-dicarboxylate (6n): Yield: 61%; white solid;
m.p. 98–1008C. 1H NMR (600 MHz, CDCl3): d=8.80 (d, J=8.4 Hz,
1H), 7.35–7.25 (m, 6H), 7.22 (t, J=7.5 Hz, 1H), 7.17 (d, J=8.4 Hz,
1H), 5.49 (s, 2H), 5.30–5.32 (m, 1H), 4.48 (q, J=7.0 Hz, 2H), 2.40 (s,
3H), 1.43 (t, J=7.2 Hz, 3H), 1.38 ppm (d, J=6.0 Hz, 6H); 13C NMR
(100 MHz, CDCl3): d=165.3, 161.9, 145.5, 135.3, 134.5, 131.4, 129.6,
128.7, 128.3, 127.4, 126.5, 126.4, 123.1, 121.7, 114.9, 114.4, 112.9,
69.4, 60.9, 47.4, 21.7, 14.2, 11.4 ppm; MS (EI, 70 eV): m/z=446
(20.3) [M]+, 386 (20.0), 360 (19.8), 285 (3.5), 207 (2.2), 140 (2.6), 92
(9.6), 91 (100); HRMS (ESI): m/z calcd for C26H27N2O5: 447.1914
[M+H]+; found: 447.1916.
Methyl 1-acetyl-6-benzyl-5-oxo-5,6-dihydropyrrolo[1,2-c]quina-
zoline-3-carboxylate (6t): Yield: 68%; white solid; m.p. 156–
1578C. 1H NMR (600 MHz, CDCl3): d=9.50 (d, J=7.8 Hz, 1H), 7.46
(s, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.33–7.25 (m, 6H), 7.23 (d, J=8.4 Hz,
1H), 5.53 (s, 2H), 3.97 (s, 3H), 2.66 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=194.0, 161.7, 145.6, 135.0, 134.8, 133.8, 131.0, 128.9,
127.9, 127.6, 126.4, 123.5, 123.0, 122.2, 120.5, 114.8, 114.7, 52.8,
47.8, 30.4 ppm; MS (EI, 70 eV): m/z=374 (30.4) [M]+, 342 (30.2),
351 (3.0), 271 (4.6), 171 (1.8), 129 (2.2), 92 (8.7), 91 (100); HRMS
(ESI): m/z calcd for C22H19N2O4: 375.1339 [M+H]+; found: 375.1345.
Ethyl 3-benzoyl-6-benzyl-2-methyl-5-oxo-5,6-dihydropyrrolo[1,2-
c]quinazoline-1-carboxylate (6o): Yield: 52%; white solid; m.p.
197–1988C. 1H NMR (600 MHz, CDCl3): d=8.88 (d, J=7.2 Hz, 1H),
7.77 (d, J=7.2 Hz, 2H), 7.54 (t, J=7.2 Hz, 1H), 7.43 (t, J=7.5 Hz,
2H), 7.36 (t, J=7.8 Hz, 1H), 7.28–7.21 (m, 4H), 7.17 (d, J=8.4 Hz,
1H), 7.09 (d, J=7.2 Hz, 2H), 5.34 (s, 2H), 4.49 (q, J=7.0 Hz, 2H),
2.31 (s, 3H), 1.45 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=188.7, 165.6, 145.7, 139.0, 135.1, 134.4, 132.7, 130.9, 129.8,
128.7, 128.5, 128.2, 127.5, 126.5, 126.4, 123.4, 115.1, 114.5, 113.6,
61.0, 47.3, 14.2, 11.6 ppm; MS (EI, 70 eV): m/z=464 (43.8) [M]+, 435
(2.2), 419 (4.1), 359 (5.5), 206 (3.2), 195 (2.3), 165 (2.9), 105 (26.1),
92 (8.6), 91 (100); HRMS (ESI): m/z calcd for C29H25N2O4: 465.1809
[M+H]+; found: 465.1814.
Trimethyl 6-benzyl-5-oxo-5,6-dihydropyrrolo[1,2-c]quinazoline-
1,2,3-tricarboxylate (6u): Yield: 55%; white solid; m.p. 233–2348C.
1H NMR (600 MHz, CDCl3): d=8.06 (d, J=8.4 Hz, 1H), 7.35 (t, J=
7.8 Hz, 1H), 7.32 (d, J=7.8 Hz, 2H), 7.28–7.23 (m, 4H), 7.19 (d, J=
8.4 Hz, 1H), 5.49 (s, 2H), 4.03 (s, 3H), 4.02 (s, 3H), 3.89 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=165.8, 162.2, 162.1, 145.4, 134.7,
133.9, 129.9, 128.9, 127.7, 126.9, 126.3, 125.6, 124.3, 124.2, 118.5,
115.7, 113.8, 111.9, 53.4, 52.9, 52.4, 47.6 ppm, MS (EI, 70 eV): m/z=
448 (17.9) [M]+, 416 (12.2), 329 (1.8), 297 (5.2), 208 (1.9), 121 (2.0),
92 (7.9), 91 (100); HRMS (ESI): m/z calcd for C24H21N2O7: 449.1343
[M+H]+; found: 449.1345.
Dimethyl 6-benzyl-2-methyl-5-oxo-5,6-dihydropyrrolo[1,2-c]qui-
nazoline-1,3-dicarboxylate (6p): Yield: 83%; white solid; m.p.
Chem. Eur. J. 2014, 20, 1711 – 1719
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Yield: 70%; white solid; m.p. 242–2438C. H NMR (400 MHz, CDCl3):
d=13.0 (s, 1H), 12.6 (s, 1H), 8.53 (d, J=7.6 Hz, 1H), 7.38 (t, J=
7.2 Hz, 1H), 7.36–7.18 (m, 7H), 5.55 (s, 2H), 2.7 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=163.0, 160.0, 137.7, 137.5, 135.4,
128.9, 128.7, 126.9, 126.6, 126.5, 123.4, 123.2, 121.9, 115.9, 113.8,
113.2, 40.2, 11.4 ppm; MS (EI, 70 eV): m/z=332 (90.4) [M]+, 313
(17.4), 288 (14.5), 241 (36.1), 223 (58.1), 197 (17.4), 180 (12.8), 91
(100.0); HRMS (ESI): m/z calcd for C27H26N5O5: 333.1234 [M+H]+;
found: 333.1231.
Synthesis of 1-ethyl 3-methyl 6-[(1-benzyl-1H-1,2,3-triazol-4-
yl)methyl]-2-methyl-5-oxo-5,6-dihydropyrrolo[1,2-c]quinazo-
line-1,3-dicarboxylate (7b)
ˇ
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(0.5 mmol),
sodium
ascorbate
(0.02 mmol),
CuSO4·5H2O
(0.04 mmol), and 8.0 mL (DMF/H2O=3:1), and the reaction mixture
was stirred at 30–408C for several hours. Water (25 mL) was added
to the mixture and the crude product was extracted with CH2Cl2
(3ꢂ20 mL). The combined organic phase was washed with brine,
dried over MgSO4, and concentrated under reduced pressure. The
crude product was purified by flash chromatography on silica gel
(silica: 200–300; petroleum ether/ethyl acetate) to afford 7b. Yield:
1
68%; white solid; m.p. 202–2038C. H NMR (600 MHz, CDCl3): d=
8.72 (d, J=8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.53 (s, 1H), 7.49 (t,
J=8.1 Hz, 1H), 7.34–7.25 (m, 4H), 7.23 (d, J=7.2 Hz, 2H), 5.50 (s,
2H), 5.45 (s, 2H), 4.43 (q, J=7.0 Hz, 2H), 3.93 (s, 3H), 2.36 (s, 3H),
1.42 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=165.2,
162.9, 145.3, 143.0, 134.2, 134.1, 131.8, 130.1, 129.1, 129.0, 128.7,
128.1, 126.4, 123.4, 123.3, 120.6, 115.3, 114.1, 113.0, 61.0, 54.1, 52.5,
39.8, 14.2, 11.5 ppm; MS (EI, 70 eV): m/z=499 (60.2) [M]+, 328
(52.9), 296 (37.7), 282 (11.3), 207 (12.8), 143 (10.4), 114 (17.7), 91
(100.0); HRMS (ESI): m/z calcd for C27H26N5O5: 500.1928 [M+H]+;
found: 500.1933.
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Acknowledgements
The authors are grateful to the National Science Foundation of
China (21342004), the Syngenta PhD (postgraduate) Pro-
gramme, and the Open Project of Key Laboratory of Theoreti-
cal Chemistry and Molecular Simulation of Ministry of Educa-
tion, Hunan University of Science and Technology (LKF1206)
for support of this research. The authors would also like to
thank Prof. Dr. W.-J. Xiao, of the same department, for scientific
discussions during the preparation of this manuscript.
Keywords: domino reactions · allenes · azo compounds ·
iron · fused-ring systems
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Received: October 15, 2013
Published online on December 30, 2013
Chem. Eur. J. 2014, 20, 1711 – 1719
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