One-pot synthesis of pyrrolo[1,2-c]quinazolinone derivatives

Article abstract of DOI:10.1055/s-0034-1379183

A fast and simple one-pot synthesis of pyrrolo[1,2-c]-quinazolinones is reported. The tandem Suzuki coupling of N-Boc-pyrrol-2-yl boronic acid and ortho-substituted aminoaryl halogenides with subsequent cyclization of the third ring yields a variety of pyrroloquinazolinone scaffolds in good to moderate yields. The palladium-catalyzed cross-coupling reaction is applicable to a wide range of substituted aminoaryl halogenides.

Full text of DOI:10.1055/s-0034-1379183

LETTER
▌2769
letter
One-Pot Synthesis of Pyrrolo[1,2-c]quinazolinone Derivatives
Synthesis of Pyrrolo[1,2-c]quinazolinone Derivatives
Matija Petrovčić, Marija Alešković, Kata Mlinarić-Majerski*
Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička Cesta 54, 10 000 Zagreb, Croatia
Fax +385(1)4680195; E-mail: majerski@irb.hr
Received: 25.07.2014; Accepted after revision: 29.08.2014
reaction steps.4 Later, Bandurco et al. synthesized a series
of substituted pyrrolo[1,2-c]quinazolinones in extremely
variable yields by condensing the appropriate quinazoli-
none with α-haloketones.3a Two pyrrolo[1,2-c]quinazoli-
Abstract: A fast and simple one-pot synthesis of pyrrolo[1,2-c]-
quinazolinones is reported. The tandem Suzuki coupling of N-Boc-
pyrrol-2-yl boronic acid and ortho-substituted aminoaryl halo-
genides with subsequent cyclization of the third ring yields a variety
of pyrroloquinazolinone scaffolds in good to moderate yields. The none derivatives were prepared from acetylindole in eight
reaction steps and were analyzed by X-ray diffraction.5 In
addition, a pyrrolo[1,2-c]quinazolinone derivative was
palladium-catalyzed cross-coupling reaction is applicable to a wide
range of substituted aminoaryl halogenides.
Key words: pyrrolo[1,2-c]quinazolinones, Suzuki coupling, palla-
dium catalysis, tandem reaction, heterocycles
isolated as an intermediate in the synthesis of tricyclic
guanidines6 or via tandem aza-Wittig–carbodiimide elec-
trocyclization, wherein a key step for the formation of the
third ring is a TBAF-promoted intramolecular cycliza-
Quinazolines and quinazolinones are common structural tion.7 Recently, Lubell and Dörr published a synthesis of
motifs found in naturally occurring heterocycles.1 They various pyrrolo[1,2-c]quinazolinones in five steps starting
are also relevant pharmacophores in medicinal chemistry from N-(Boc)anthranilate.8
due to their diverse biological activities such as anti-in-
Although it is known that the amino group electronically
flammatory, diuretic, and anticonvulsant properties.2 Fur-
deactivates the C–Br bond in the oxidative addition to the
thermore, annulation of a pyrrole ring resulting in the
palladium catalyst,9 there are examples of direct Suzuki
structures, such as pyrrolo[1,2-c]quinazolinone, pyrro-
coupling in the preparation of biaryls and heteroaryls
lo[1,2-c]quinazoline, and pyrrolo[3,2-c]quinoline, leads
to additional biological effects, including antihyperten-
bearing an unprotected NH2 group.10 However, to the best
of our knowledge, palladium-catalyzed coupling reaction
of pyrroles and ortho-substituted anilines has not been re-
sive, cytotoxic, antiviral, antimalarial, and antibacterial
properties.3 Despite these interesting activities, to date
ported to date.
only a few examples of the pyrrolo[1,2-c]quinazolinone
We have shown that the Suzuki reaction between various
synthesis are known in the literature. They usually involve
ortho-substituted arylhalides and N-Boc-pyrrol-2-yl bo-
multistep synthetic procedures with tedious isolation of
ronic acid gives 2-[(2-substituted)phenyl]pyrrole deriva-
intermediate compounds. Cotter et al. published a synthe-
tives, and we found that o-bromoaniline under the same
sis of 7-hydroxy-2-methylpyrrolo[1,2-c]quinazolinone
reaction conditions yields pyrrolo[1,2-c]quinazolinone 1
as a product of cross-coupling reaction followed by intra-
starting from 2-amino-3-hydroxyacetophenone in three
X
Z
X
Z
NH2
X
Z
Z
Y
Br
Pd(PPh3)4, Cs2CO3
Y
Y
Y
B(OH)2
+
+
NH
N
N
O
N
– t-BuOH
toluene–MeOH (10:1)
reflux, 24 h
H2N
H2N
Ot-Bu
NH
1–10
Boc
X
12a–j
Y = H
O
11
1a–10a
12a X = H
Z = H
Z = H
Z = H
Z = Me
1
2
3
4
5
6
7
8
9
X = H
Y = H
X = Me Y = H
X = i-Pr Y = H
X = Me Y = H
X = H
X = NO2 Y = H
X = H Y = Cl
X = NO2 Y = H
Z = H
Z = H
Z = H
1a X = H Y = H Z = H
3a X = i-Pr Y = H Z = H
5a X = H Y = NO2 Z = H
I1–I10
12b X = Me Y = H
12c X = i-Pr Y = H
12d X = Me Y = H
Y = NO2 Z = H
12f X = NO2 Y = H
Z = Me
12e X = H
Y = NO2 Z = H
Z = NO2
Z = H
Z = Cl
Z = Cl
Z = F
Z = NO2
Z = H
Z = Cl
Z = Cl
Z = F
12g X = H
Y = Cl
12h X = NO2 Y = H
7a X = H Y = Cl Z = H
8a X = NO2 Y = H Z = Cl
12i X = F
12j X = F
Y = H
Y = H
X = F
Y = H
Y = H
10 X = F
Scheme 1
SYNLETT 2014, 25, 2769–2772
Advanced online publication: 07.10.2014
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3
6
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5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1379183; Art ID: st-2014-d0627-l
© Georg Thieme Verlag Stuttgart · New York

2770
M. Petrovčić et al.
LETTER
molecular cyclization.11 Herein, we demonstrate that the Formation of the Boc-protected intermediate through the
above-mentioned one-pot tandem reaction can be applied cross-coupling reaction is most probably the slowest step.
to the preparation of a series of new pyrrolo[1,2- The yields of the tandem process vary from moderate to
c]quinazolinones 1–10 (Scheme 1). The results of the em- good. Cross-coupling reactions of arylhalogenides substi-
ployed tandem reactions are presented in Table 1.
tuted with electron-donating groups gave tricyclic prod-
ucts in moderate yields (Table 1, entries 2–4), and in one
example, the cross-coupled product that had not under-
gone the cyclization step was also isolated (Table 1, entry
3). Since its formation was not observed in all cases it is
obvious that the electron-donating substituent on the ani-
line increases the nucleophilicity of the amine and thus
helps the cyclization step to occur. On the other hand, in
the reactions with electron-withdrawing substituents, that
should facilitate the oxidative addition of palladium16 and
enhance yields, it was not observed (Table 1, entries 5–
10). However, it is known that very strong electron-with-
drawing substituents may enhance the acidity and coordi-
nation of the amine group to the palladium catalyst,
preventing the oxidative addition and resulting in a lower
yield of cross-coupling reaction.9,16 Therefore, in the reac-
tions conducted with dihalogen-substituted anilines the
yields were very different (Table 1, entries 9 and 10).
Thus, in the reaction with 2-bromo-5-chloro-3-fluoroani-
line (12i) we isolated 80% of the tricylic product; whereas
in the reaction with 2-bromo-3,5-difluoroaniline (12j) it
dropped to a moderate yield of 38%. The rather poor
yields observed in the cross-coupling reactions with nitro
anilines 12e and 12f could be explained by solubility
problems (Table 1, entries 5 and 6). During the workup of
the reaction in entries 5, 6, and 8 (Table 1), a fine emulsion
was formed, resulting in difficulties in isolation of the
products.
Table 1 Synthesis of Quinazolinones 1–10 via Suzuki Coupling Re-
action and Intramolecular Cyclization Sequencea
Entry
Aniline
Isolated compounds
Recovered aniline Yield of
Yield of
(%)
1–10 (%)
1a–10a (%)
1
2
12a
12b
12c
12d
12e
12f
12g
12h
12i
21
25
25
37
11
35
15
53
–
1 27
2 37
3 31
4 29
5 23
6 22
7 11
8 11c
9 80
10 38
1a 22
3a 4
5a 3
3
4
5
6
7
7a 8b
8a 7d
8
9
10
12j
–
a Isolated yield.
b Isolated with 10% of impurities.
c In mixture with 8a.
d In mixture with 8.
The best yields were achieved when the reaction was con-
ducted with 5 mol% of Pd(PPh3)4 in a 10:1 mixture of tol-
uene and methanol with Cs2CO3 as a base.12 In all
experiments, except entries 9 and 10 (Table 1), some start-
ing aniline was recovered together with the quinazolinone
product. However, in entries 1, 3, 5, 7, and 8 (Table 1), be-
sides the quinazolinone product and the recovered aniline,
the cross-coupling products 1a, 3a, 5a, 7a, and 8a, respec-
tively, were formed. Furthermore, in entries 1 and 2 (Ta-
ble 1) traces of di-tert-butyl 1H,1′H-2,2′-bipyrrole-1,1′-
dicarboxylate (13)13 were detected.
In conclusion, we have shown that the palladium-cata-
lyzed coupling of o-bromoaniline and N-Boc-pyrrol-2-yl
boronic acid can be applied for the one-pot preparation of
a series of pyrrolo[1,2-c]quinazolinones 1–10. The reac-
tion employs commercially available pyrrole boronic acid
and various o-bromoanilines, with both electron-with-
drawing and electron-donating groups. However, a direct
correlation with respect to the substituent influence on
cross-coupling and/or cyclization reaction cannot be
made. The application of these tandem reactions for the
construction of the pyrrolobenzodiazocine or pyrroloben-
zodiazepinone derivatives is under current investigation.
The formation of 1–10 involves a palladium-catalyzed
cross-coupling reaction between 11 and 12, the formation
of intermediates I1–I10, and subsequent nucleophilic at-
tack of the amino group to the Boc-carbonyl (Scheme 1).
Formation of compounds 1a–10a is the result of the Boc
deprotection of the intermediate compounds I1–I10 under
the basic reaction conditions.14 Moreover, since the reac-
tion is carried out in refluxing toluene, thermal deprotec-
tion is also possible.15 On the other hand, the byproduct
bipyrrole 13 results from a competitive homocoupling re-
action that uses up the starting boronic acid 11. To mini-
mize the formation of the byproduct 13, the addition time
of 11 to the refluxing reaction mixture was extended to
seven hours, with subsequent refluxing for another 17
hours.
Acknowledgment
We thank the Ministry of Science Education and Sports of the Re-
public of Croatia (grant No. 098-0982933-2911, KMM) and the
Croatian Academy of Sciences and Arts (grant awarded to M.A.)
for financial support. The authors also thank Dr. N. Basarić for hel-
pful discussion.
References and Notes
(1) (a) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62,
9787. (b) Eguchi, S. Top. Heterocycl. Chem. 2006, 6, 113.
(c) Brown, D. J. Quinazolines, Supplement I,The Chemistry
of Heterocyclic Compounds; Vol.55; John Wiley and Sons:
Chichester, 1996.
Synlett 2014, 25, 2769–2772
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Pyrrolo[1,2-c]quinazolinone Derivatives
2771
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Hz, 1 H), 7.89–7.92 (m, 1 H), 11.48 (br s, 1 H).
Compound 1a: white crystals. 1H NMR (600 MHz, CDCl3):
δ = 3.94 (s, 2 H), 6.30–6.33 (m, 1 H), 6.40–6.44 (m, 1 H),
6.75–6.77 (m, 1 H), 6.79–6.83 (m, 1 H), 6.85–6.87 (m, 1 H),
7.06–7.10 (m, 1 H), 7.24 (s, 1 H), 8.58 (br s, 1 H).
9-Methylpyrrolo[1,2-c]quinazolin-5(6H)-one (2)
Purified by chromatography with a mixture CH2Cl2–MeOH
(98:2). Fractions were rechromatographed using 0 → 35%
Et2O in CH2Cl2 as eluent to obtain analytically pure 2.
Analytical Data
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Dommisse, R. A.; Lemière, G. L. F.; Košmrlj, J.; Mátyus, P.
Tetrahedron 2004, 60, 2283.
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J.; Laitila, M.; Haukka, M.; Pursiainen, J. Eur. J. Inorg.
Chem. 2008, 397. (g) Youn, S. W.; Bihn, J. H. Tetrahedron
Lett. 2009, 50, 4598.
Grey powder; mp 255–258 °C; IR (KBr): ν = 2921, 1701,
1508, 1411, 721 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.35
(s, 3 H), 6.66 (t, J = 3.3 Hz, 1 H), 6.97 (dd, J1 = 3.5 Hz, J2 =
1.5 Hz, 1 H), 7.13–7.16 (m, 2 H), 7.58 (dd, J1 = 3.0 Hz, J2 =
1.5 Hz, 1 H), 7.73 (s, 1 H), 11.40 (br s, 1 H). 13C NMR (75
MHz, CDCl3): δ = 20.5 (CH3), 104.3 (CH), 113.7 (CH),
114.1 (C), 115.3 (CH), 115.4 (CH), 122.0 (CH), 128.8 (CH),
129.2 (C), 130.3 (C), 132.1 (C), 145.4 (C). HRMS: m/z [M]+
calcd for C12H10N2O: 198.0788; found: 198.0788.
9-Isopropylpyrrolo[1,2-c]quinazolin-5(6H)-one (3) and
4-Isopropyl-2-(1H-pyrrol-2-yl)aniline (3a)
Purified by chromatography with a mixture CH2Cl2–MeOH
(99:1). Fractions were rechromatographed using CH2Cl2–
Et2O (7:3) as eluent to obtain analytically pure compounds.
Analytical Data
Compound 3: grey powder; mp 170–173 °C. IR (KBr): ν =
2954, 1701, 1508, 1407, 715 cm–1. 1H NMR (300 MHz,
DMSO-d6): δ = 1.23 (s, 3 H), 1.26 (s, 3 H), 2.94 (sept, J =
6.9 Hz, 1 H), 6.66 (t, J = 3.3 Hz, 1 H), 7.03 (dd, J1 = 3.5 Hz,
J2 = 1.5 Hz, 1 H), 7.15–7.24 (m, 2 H), 7.57 (dd, J1 = 3.0 Hz,
J2 = 1.5 Hz, 1 H), 7.76–7.78 (m, 1 H), 11.40 (br s, 1 H). 13
NMR (75 MHz, DMSO-d6): δ = 23.9, 33.1, 104.3, 113.7,
114.2, 115.3, 115.5, 119.4, 125.9, 129.4, 130.7, 143.3,
145.5. HRMS: m/z [M]+ calcd for C14H14N2O: 226.11;
found: 226.1101.
C
Compound 3a: white crystals; mp 90–91 °C. IR (KBr): ν =
3384, 3305, 3178, 2962, 1500, 825, 725 cm–1. 1H NMR (300
MHz, CDCl3): δ = 1.21 (s, 3 H), 1.23 (s, 3 H), 2.82 (sept, J
= 6.9 Hz, 1 H), 3.81 (br s, 2 H), 6.31 (dd, J1 = 5.8 Hz, J2 =
2.8 Hz, 1 H), 6.39–6.45 (m, 1 H), 6.71 (d, J = 8.2 Hz, 1 H),
6.84–6.88 (m, 1 H), 6.96 (dd, J1 = 2.2 Hz, J2 = 8.2 Hz, 1 H),
7.11 (d, J = 2.2 Hz, 1 H), 8.68 (br s, 1 H). 13C NMR (75 MHz,
CDCl3): δ = 24.1 (2 × CH3), 33.2 (CH), 107.2 (CH), 109.2
(CH), 116.7 (CH), 117.7 (CH), 119.6 (C), 125.7 (CH), 126.3
(CH), 129.9 (C), 139.7 (C), 140.9 (C). HRMS: m/z [M]+
calcd for C13H16N2: 200.1308; found: 200.1311.
(11) Alešković, M.; Basarić, N.; Mlinarić-Majerski, K.
J. Heterocycl. Chem. 2011, 48, 1329.
(12) General Procedure
To a stirred solution of the corresponding aniline (1 mmol),
Cs2CO3 (2 mmol), and Pd(PPh3)4 (5 mol%) in toluene (20
mL) at reflux and under nitrogen atmosphere, a solution of
N-Boc-pyrrol-2-yl boronic acid17 (1 mmol) in a mixture of
toluene (10 mL) and MeOH (3 mL) was added over 7 h. The
mixture was stirred at reflux for 17 h, cooled, and the MeOH
was removed under reduced pressure. To the resultant
toluene suspension H2O (30 mL) was added, and the layers
were separated. The water layer was extracted with CH2Cl2
(3 × 25 mL; or EtOAc for compound 5), the combined
organic extracts were washed with H2O (30 mL), dried over
MgSO4, filtered, and the solvent was evaporated under
reduced pressure. The residue was purified by column
chromatography on silica gel using a suitable eluent as
indicated below.
7,9-Dimethylpyrrolo[1,2-c]quinazolin-5(6H)-one (4)
Purified by chromatography with a mixture CH2Cl2–Et2O
(7:3).
Analytical Data
Grey powder; mp 254–256 °C. IR (KBr): ν = 3224, 2916,
1689, 1498, 1348, 719 cm–1. 1H NMR (300 MHz, DMSO-
d6): δ = 2.30 (s, 3 H), 2.37 (s, 3 H), 6.65 (t, J = 3.3 Hz, 1 H),
6.94 (dd, J1 = 3.5 Hz, J2 = 1.5 Hz, 1 H), 6.98 (s, 1 H), 7.56–
7.59 (m, 2 H), 10.55 (br s, 1 H). 13C NMR (75 MHz, DMSO-
d6): δ = 17.5 (CH3), 20.4 (CH3), 104.1 (CH), 113.9 (CH),
114.2 (C), 115.2 (CH), 119.9 (CH), 123.9 (C), 128.7 (C),
129.4 (C), 130.1 (CH), 131.8 (C), 145.8 (C). HRMS: m/z
[M]+ calcd for C13H12N2O: 212.0944; found: 212.0936.
8-Nitropyrrolo[1,2-c]quinazolin-5(6H)-one (5) and
5-Nitro-2-(1H-pyrrol-2-yl)aniline (5a)
Pyrrolo[1,2-c]quinazolin-5(6H)-one (1) and
2-(1H-Pyrrol-2-yl)aniline (1a)11
Purified by chromatography with a mixture of n-hexane–
Et2O (3:2).
The general workup procedure was slightly changed because
of solubility problems. In this case, product 5a was extracted
from the water layer with CH2Cl2 and 5 with EtOAc.
Chromatography with a mixture CH2Cl2–MeOH (99:1)
furnished analytically pure 5a and chromatography with a
mixture CH2Cl2–EtOAc (9:1) furnished pure 5.
Analytical Data
Compound 1: grey powder. 1H NMR (300 MHz, DMSO-d6):
δ = 6.67 (t, J = 3.3 Hz, 1 H), 7.01 (dd, J1 = 3.5 Hz, J2 = 1.5
Hz, 1 H), 7.18–7.36 (m, 3 H), 7.59 (dd, J1 = 3.1 Hz, J2 = 1.5
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2769–2772

2772
M. Petrovčić et al.
Analytical Data
LETTER
Analytical Data
Compound 5: yellow crystals; mp 312–313 °C. IR (KBr): ν
= 3255, 1720, 1521, 1340, 723 cm–1. 1H NMR (300 MHz,
DMSO-d6): δ = 6.78 (dd, J1 = 3.1 Hz, J2 = 3.6 Hz, 1 H), 7.30
(dd, J1 = 3.6 Hz, J2 = 1.5 Hz, 1 H), 7.74 (dd, J1 = 3.1 Hz, J2
= 1.5 Hz, 1 H), 8.01 (dd, J1 = 8.7 Hz, J2 = 2.2 Hz, 1 H), 8.06–
White crystals; mp 236–238 °C. IR (KBr): ν = 3247, 1698,
1573, 1499, 724 cm–1. 1H NMR (300 MHz, DMSO-d6): δ =
6.73 (t, J = 3.3 Hz, 1 H), 7.17 (dd, J1 = 3.6 Hz, J2 = 1.5 Hz,
1 H), 7.44 (dd, J1(HF) = 8.5 Hz, J2 = 2.7 Hz, 1 H), 7.67 (dd, J1
= 3.1 Hz, J2 = 1.5 Hz, 1 H), 7.87 (dd, J1(HF) = 9.1 Hz, J2 = 2.7
Hz, 1 H), 10.91 (br s, 1 H). 13C NMR (75 MHz, DMSO-d6):
δ = 107.0 (CH), 107.4 (d, JCF = 24.6 Hz, CH), 114.4 (CH),
8.08 (m, 1 H), 8.14 (d, J = 8.7 Hz, 1 H), 11.87 (br s, 1 H). 13
C
NMR (75 MHz, DMSO-d6): δ = 108.6, 110.7, 114.7, 117.8,
117.9, 119.8, 122.9, 127.6, 132.6, 145.0, 145.4. HRMS: m/z
[M + H]+ calcd for C11H8N3O3: 230.0561; found: 230.0565.
Compound 5a: red crystals; mp 159–161 °C. IR (KBr): ν =
3392, 1618, 1514, 1336, 877, 744 cm–1. 1H NMR (600 MHz,
DMSO-d6): δ = 5.57 (s, 2 H), 6.21–6.23 (m, 1 H), 6.57–6.60
(m, 1 H), 6.94–6.96 (m, 1 H), 7.41–7.46 (m, 2 H), 7.65 (d, J
= 2.2 Hz, 1 H), 11.27 (s, 1 H). 13C NMR (150 MHz, DMSO-
d6): δ = 108.9, 109.1, 109.3, 111.1, 120.2, 124.2, 127.0,
127.5, 145.1; 145.6. HRMS: m/z [M]+ calcd for C10H9N3O2:
203.0688; found: 203.0691.
115.1 (d, JCF = 27.2 Hz, CH), 116.7 (CH), 116.7 (d, JCF
=
11.7 Hz, C), 119.8 (d, JCF = 10.3 Hz, C), 126.1 (d, JCF = 2.2
Hz, C), 127.6 (d, JCF = 3.5 Hz, C), 145.0 (C), 157.2 (d, JCF
241.6 Hz, C). HRMS: m/z [M]+ calcd for C11H6ClFN2O:
236.0153; found: 236.0148.
=
7,9-Difluoropyrrolo[1,2-c]quinazolin-5(6H)-one (10)
Purified by chromatography with a mixture CH2Cl2–MeOH
(99.5:0.5). Fractions were rechromatographed using
CH2Cl2–EtOAc (97:3) as eluent to obtain analytically pure
10.
7,9-Dinitropyrrolo[1,2-c]quinazolin-5(6H)-one (6)
Purified by chromatography with CH2Cl2.
Analytical Data
Analytical Data
White crystals; mp 270–271 °C. IR (KBr): ν = 3087, 1697,
1510, 1400, 1301, 727 cm–1. 1H NMR (600 MHz, DMSO-
d6): δ = 6.71 (t, J = 3.3 Hz, 1 H), 7.14 (dd, J1 = 3.5 Hz, J2 =
1.5 Hz, 1 H), 7.26–7.30 (m, 1 H), 7.67 (dd, J1 = 3.0 Hz, J2 =
1.5 Hz, 1 H), 7.68–7.71 (m, 1 H), 11.56 (br s, 1 H). 13C NMR
(150 MHz, DMSO-d6): δ = 102.2 [dd, J1(CF) = 28.2 Hz, J2(CF)
= 22.0 Hz, CH], 103.8 [dd, J1(CF) = 24.7 Hz, J2(CF) = 3.2 Hz,
CH], 106.7 (CH), 114.0 (CH), 116.7 [dd, J1(CF) = 11.2 Hz,
J2(CF) = 4.7 Hz, C], 117.8 (CH), 117.8 [dd, J1(CF) = 14.2 Hz,
J1(CF) = 2.8 Hz, C], 127.7 (t, JCF = 3.5 Hz, C), 144.8 (C),
148.8 [dd, J1(CF) = 248.4 Hz, J2(CF) = 13.3 Hz, C], 156.6 [dd,
J1(CF) = 240.5 Hz, J2(CF) = 11.4 Hz, C]. 19F NMR (565 MHz,
DMSO-d6): δ = –106.6 (dt, J1 = 9.2 Hz, J2 = 4.5 Hz, 1 F),
–114.4 (m, 1 F). HRMS: m/z [M]+ calcd for C11H6F2N2O:
220.0443; found: 220.0448.
Orange crystals; mp 291–293 °C. IR (KBr): ν = 3436, 3257,
1718, 1612, 1529, 1307, 750 cm–1. 1H NMR (300 MHz,
DMSO-d6): δ = 6.83 (t, J = 3.3 Hz, 1 H), 7.58 (dd, J1 = 3.6
Hz, J2 = 1.5 Hz, 1 H), 7.77 (dd, J1 = 3.0 Hz, J2 = 1.5 Hz, 1
H), 8.75 (d, J = 2.4 Hz, 1 H), 9,14 (d, J = 2.4 Hz, 1 H), 11.18
(br s, 1 H). 13C NMR (75 MHz, DMSO-d6): δ = 109.4 (CH),
115.3 (CH), 117.8 (CH), 117.9 (C), 118.5 (CH), 122.2 (CH),
126.4 (C), 131.0 (C), 134.6 (C), 141.4 (C), 143.9 (C).
HRMS: m/z [M]+ calcd for C11H6N4O5: 274.0338; found:
274.0333.
8-Chloropyrrolo[1,2-c]quinazolin-5(6H)-one (7) and 5-
Chloro-2-(1H-pyrrol-2-yl)aniline (7a)
Purified by chromatography with a CH2Cl2–EtOAc (96:4).
Analytical Data
(13) Johnson, C. N.; Stemp, G.; Anand, N.; Stephen, S. C.;
Gallagher, T. Synlett 1998, 1025.
(14) Tom, N. J.; Simon, W. M.; Frost, H. N.; Ewing, M.
Tetrahedron Lett. 2004, 45, 905.
(15) Rawal, V. H.; Jones, R. J.; Cava, M. P. J. Org. Chem. 1987,
52, 19.
(16) Hegedus, L. S. Organopalladium Chemistry, In
Organometallics in Synthesis; Schlosser, M., Ed.; John
Wiley and Sons: Chichester, 2002.
(17) N-Boc-pyrrole, N-Boc-pyrrol-2-yl boronic acid, and 2-bromo-
5-chloroaniline were prepared according to the procedures
described in the literature: (a) Grehn, L.; Ragnarsson, U.
Angew. Chem., Int. Ed. Engl. 1984, 23, 296. (b) Martina, S.;
Enkelmann, V.; Wegner, G.; Schlüter, A.-D. Synthesis 1991,
613. (c) Allen, J. R.; Biswas, K.; Bryan, M. C.; Burli, R.;
Cao, G.-Q.; Frohn, M. J.; Golden, J. E.; Mercede, S.;
Peterkin, T.; Pickrell, A. J.; Reed, A.; Tegley, C. M.; Wang,
X. WO 2008076427, 2008.
Compound 7: dark grey powder; mp 257–259 °C. IR (KBr):
ν = 2360, 1710, 1587, 1409, 721 cm–1. 1H NMR (300 MHz,
DMSO-d6): δ = 6.69 (t, J = 3.3 Hz, 1 H), 7.05 (dd, J1 = 3.5
Hz, J2 = 1.5 Hz, 1 H), 7.22–7.27 (m, 2 H), 7.60 (dd, J1 = 3.1
Hz, J2 = 1.5 Hz, 1 H), 7.95 (d, J = 8.2 Hz, 1 H), 11.57 (br s,
1 H). 13C NMR (75 MHz, DMSO-d6): δ = 105.2 (CH), 113.3
(C), 114.0 (CH), 114.8 (CH), 115.9 (CH), 122.9 (CH), 123.9
(CH), 128.3 (C), 131.2 (C), 133.6 (C), 145.2 (C). HRMS:
m/z [M]+ calcd for C11H7ClN2O: 218.0242; found: 218.0249.
7-Chloro-9-nitropyrrolo[1,2-c]quinazolin-5(6H)-one (8)
and 2-Chloro-4-nitro-6-(1H-pyrrol-2-yl)aniline (8a)
Separation of products 8 and 8a was unsuccessful even after
several repeated chromatography. The yields were estimated
from 1H NMR spectroscopic analysis of the mixture of 8
(11%) and 8a (8%).
7-(Chloro-9-fluoropyrrolo[1,2-c]quinazolin-5(6H)-one
(9)
Purified by chromatography with CH2Cl2.
Synlett 2014, 25, 2769–2772
© Georg Thieme Verlag Stuttgart · New York