A novel approach for the synthesis of N -arylpyrroles

Article abstract of DOI:10.1055/s-0029-1218372

Treatment of quinazolin-4(3H)-one bromides with acetylenic dipolarophiles in 1,2-epoxybutane medium gave, in good yields, N-arylpyrroles instead of the corresponding pyrrolo[1,2-a]quinazolines. The structures of the pyrroles were deduced by NMR spectrosco

Full text of DOI:10.1055/s-0029-1218372

3336
LETTER
A Novel Approach for the Synthesis of N-Arylpyrroles
A
N
ew Synthe
l
sis of
N
o
-Arylpyrrol
r
es ea Dumitrascu,a Emilian Georgescu,b Mino R. Caira,*c Florentina Georgescu,b Marcel Popa,a Bogdan Draghici,a
Dan G. Dumitrescua
a
Center of Organic Chemistry ‘C. D. Nenitzescu’, Romanian Academy, Spl. Independentei 202B, Bucharest 060023, Romania
Oltchim Research Center, St. Uzinei 1, Ramnicu Valcea 240054, Romania
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Fax +27(21)6505195; E-mail: Mino.Caira@uct.ac.za
b
c
Received 8 October 2009
Quinazolinium N1-salts are generally unavailable, due to
the decreased reactivity of nitrogen atom N1 as compared
to N3. To overcome this impediment, the starting material
used was 3-methyl-4(3H)-quinazolinone (1), instead of
Abstract: Treatment of quinazolin-4(3H)-one bromides with acet-
ylenic dipolarophiles in 1,2-epoxybutane medium gave, in good
yields, N-arylpyrroles instead of the corresponding pyrrolo[1,2-
a]quinazolines. The structures of the pyrroles were deduced by
NMR spectroscopy and confirmed by X-ray crystal structure analy- quinazoline. Quaternization of nitrogen atom N1 with
sis. The 1H NMR spectra of ethyl esters revealed hindered rotation
about the N–Ar bond.
bromoacetophenones 2 was effected in EtOH or DMF un-
der reflux, resulting in salts 3 in yields exceeding 75%
(Scheme 1).4
Key words: 1,3-dipolar cycloaddition, N-ylide, pyrroles, pyrro-
lo[1,2-a]quinazoline, one-pot reaction
O
O
N
EtOH, reflux
N
Me
N
Me
The syntheses and biological properties of pyrrolo[1,2-
a]quinazolines were reviewed1 in 1991, and an update on
this topic showed that new syntheses and biological inves-
tigations have since been reported.2 The rather scarce lit-
erature data on synthetic strategies for constructing the
pyrrolo[1,2-a]quinazoline skeleton includes a double cy-
clization of anthranilic acid derivatives and two other gen-
eral methods starting from quinazoline or pyrrole
derivatives.1,2
+
BrCH2COAr
N+
Br–
1
2
3
CH2COAr
Scheme 1
Encouraged by the positive results reported previously3f a
simple one-pot reaction between salts 3 and acetylenic di-
polarophiles in 1,2-epoxybutane as reaction medium and
base was employed as the synthetic strategy (Scheme 2).
The reaction mixture was heated under reflux with the aim
of obtaining pyrrolo[1,2-a]quinazolines. However, after
workup of the reaction mixture, instead of the expected
pyrrolo[1,2-a]quinazolines, the corresponding N-substi-
tuted pyrroles 4 were obtained in good yields.5
Given that the synthesis6 and properties7 of variously sub-
stituted pyrroles enjoy intensive study, this method shows
promising results for the synthesis of compounds of this
type.
As N-ylides are generally the most direct synthetic route
for obtaining pyrroloazines, they have been used in two
approaches for the synthesis of pyrrolo[1,2-a]quinazo-
lines.2b,m The first approach employed dichloroquinazo-
linium N-ylides and resulted in a mixture of isomeric
pyrroloquinazolines.2m The second attempt successfully
used unsubstituted quinazolinium N1-ylide for obtaining
a number of tetrahydropyrrolo[1,2-a]quinazolines as well
as one example of an unexpected N-substituted pyrrole
when using DMAD as dipolarophile.2b However, in the
latter case, the authors did not expand this research fur-
ther.
The new series of compounds is presented in Table 1.
The structures of the pyrroles were deduced from IR and
NMR spectra and were confirmed by X-ray analysis of
representative compounds. Initial evidence for the forma-
tion of substituted pyrroles instead of the expected pyrro-
lo[1,2-a]quinazolines was obtained from IR spectroscopy.
The presence of a medium to strong band in the range
3250–3400 cm–1 indicates the presence of the NH group.
Furthermore, the bands of the carbonyl groups are ob-
served in the 1640–1730 cm–1 range.
Our interest in pyrroloazines3 led us to investigate the re-
activity of monosubstituted quinazolinium N1-ylides,
which are more easily available than di- or unsubstituted
N-ylides.
Herein we present a versatile synthesis for tri- and tetra-
substituted pyrroles starting from quinazolinium mono-
substituted N1-salts and acetylenic dipolarophiles in a
‘one-pot’ reaction requiring no special conditions.
The characteristic feature that confirms the pyrrole struc-
tures is the coupling between the NH proton and the N-
methyl group, with a value of 4.9 Hz. In the case of trisub-
stituted pyrroles 4a–l the two protons H-3 and H-5 from
pyrrole appear as two doublets with the coupling constant
SYNLETT 2009, No. 20, pp 3336–3340
Advanced online publication: 18.11.2009
DOI: 10.1055/s-0029-1218372; Art ID: D28509ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

LETTER
A New Synthesis of N-Arylpyrroles
3337
O
O
O
Me
E1
E2
N
H
NMe
N
Me
Br–
H
not
E1
Et
N+
N
E1
N
O
CH2COAr
E2
ArOC
ArOC
pyrrolo[1,2-a]quinazoline
E2
3
4
Scheme 2
Compound 4h exemplifies the series of trisubstituted pyr-
roles. The CO2Et substituent is coplanar with the pyrrole
ring but the moieties at positions 1 and 2 are twisted out
of the pyrrole ring plane, the relevant torsion angles being
C2–N1–C15–C20 = –51.9(2)° and N1–C2–C6–O7 =
–20.3(2)°, respectively. Furthermore, the plane of the me-
thylaminocarbonyl residue is rotated out of the plane of its
attached phenyl ring [torsion angle C15–C20–C21–O22 =
–38.3(2)°]. This solid-state conformation is associated
with several short intramolecular nonbonded contacts
[C15···O7 = 2.970(1); C2···O22 = 3.010(2); C2···C21 =
3.163(2); C6···C21 = 3.186(2) Å, Figure 1]. Such short
contacts are the probable source of hindered rotation
Table 1 N-Substituted Pyrroles 4
Compd 4 E1
E2
H
H
H
H
H
H
H
H
H
H
H
H
Ar
Mp (°C)
171–172
178–180
Yield (%)
4a
4b
4c
4d
4e
4f
COMe
Ph
57
56
51
75
49
72
60
61
63
52
80
51
53
48
59
67
54
52
COMe
COMe
CO2Me
CO2Me
CO2Me
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
4-ClC6H4
4-MeOC6H4 162–164
Ph
169–170
170–172
195–197
195–196
158–160
168–170
4-ClC6H4
4-MeC6H4
Ph
1
4g
4h
4i
about the N–Ar bond in 4h detected in solution by H
NMR spectroscopy. The specific conformation of 4h ob-
served in the solid state is evidently the result of a com-
promise between intramolecular steric repulsive
interactions and the energetically favorable formation of a
centrosymmetric dimer of 4h (Figure 2) via hydrogen
bonding (N23–H···O7i, with N···O = 2.832(2) Å and angle
N–H···O = 133°, i = ½–x, ½–y, 1–z).
Figure 3 shows the structure and solid-state conformation
of representative compound 4m, which exemplifies the
series of tetrasubstituted pyrroles. When compared with
4h (Figure 1), the effect of additional substitution at posi-
tion 3 is immediately evident, namely rotation of the
CO2Me group at C3 around the bond C3–C28 to an orien-
tation nearly orthogonal to the pyrrole plane in order to re-
duce steric congestion.
4-FC6H4
4-ClC6H4
4j
3-O2NC6H4 165–167
4-O2NC6H4 180–181
4-MeOC6H4 192–194
4k
4l
4m
4n
4o
4p
4q
4r
CO2Me CO2Me Ph
163–165
201–202
198–200
CO2Me CO2Me 4-ClC6H4
CO2Me CO2Me 4-BrC6H4
CO2Me CO2Me 3-O2NC6H4 167–168
CO2Me CO2Me 4-O2NC6H4 258–259
CO2Me CO2Me 4-MeOC6H4 172–173
of 1.6 Hz, whereas in the 1H NMR spectra of tetrasubsti-
tuted pyrroles 4m–r H-5 appears as a sharp singlet. The
main features of the 13C NMR spectra are the presence of
the carbonyl group signals. The pyrrole structure is further
suggested by the signals of the tertiary carbons of the pyr-
role ring, C-3 and C-5 for 4a–l and C-5 for pyrroles 4m–
r, respectively. It is interesting to note that in the 1H NMR
spectra of ethyl esters 4g–l the methylenic protons in the
ethyl group appear as a multiplet instead of a quartet due
to the coupling between the two methylenic protons. The
magnetic nonequivalence of the methylene protons could
be explained by hindered rotation about the N–Ar bonds.
The structures of the pyrroles, deduced from NMR and IR
spectra, were confirmed by single crystal X-ray analysis
of two representative pyrroles, namely 4h and 4m.8
The structure and solid-state conformation of 4h are
shown in Figure 1.
Figure 1 X-ray crystal structure of 4h (E1 = CO2Et, E2 = H, Ar =
4-FC6H4) with thermal ellipsoids drawn at the 50% probability level
Synlett 2009, No. 20, 3336–3340 © Thieme Stuttgart · New York

3338
F. Dumitrascu et al.
LETTER
Despite the similarities in the overall molecular confor-
mations of 4h and 4m, the molecules of 4m do not form
dimers in the crystal. Instead, infinite spirals of molecules
hydrogen bonded head-to-tail propagate parallel to the
21-axis parallel to b. The unique hydrogen bond is N22–
H···O7ii, with N···O = 2.992(2) Å and angle N–H···O =
144°, ii = 1–z, –½+y, ½–z).
The reaction mechanism for formation of the pyrroles 4
implies, in the first step, the attack of the bromide ion from
the salts 3 on the oxirane ring giving the corresponding
alkoxide. Subsequently, the N-ylides 5 are generated in
situ by the action of the alkoxide on bromides 3. The N-
ylide reacts with the activated alkynes to give the corre-
sponding primary cycloadducts 6. Usually, the primary
cycloadducts that result from heteroaromatic N-ylides re-
arrange and aromatize to the corresponding pyrroloazoles
or pyrroloazines.3a In the case of cycloadducts 6, ring
opening occurs with formation of pyrroles 4 (Scheme 3).
Figure 2 Centrosymmetric dimer present in the crystal of 4h
This hypothesis was confirmed in the case of primary cy-
cloadducts of type 6 which in solution and in the presence
of triethylamine gave pyrroles 4 instead of rearrangement
products or the expected pyrrolo[1,2-a]quinazoline. A
similar phenomenon was observed in the case of cycload-
ducts resulting from benzimidazolium N-ylides and acet-
ylenic dipolarophiles: instead of the corresponding
pyrrolo[1,2-a]benzimidazoles, a pyrrole derivative fol-
lowed by recyclization to pyrrolo[1,2-a]quinoxaline was
obtained by ring opening of the primary cycloadduct.9
In the case of 1,3-dipolar cycloaddition between N-ylides
5 and DMAD, the primary cycloadduct of type 6 could be
isolated from the reaction mixture and characterized by IR
and NMR spectroscopy.10 The first evidence is the lack of
a NH group band in the IR spectrum. The structure of the
primary cycloadduct was elucidated by NMR spectrosco-
py. The position of the double bond in the pyrroline ring
was suggested on the basis of the chemical shifts of the es-
ter groups which have very close values. Moreover the
carbonyl group in the aroyl moiety is more deshielded due
to its direct bond to a sp3-carbon atom. The definitive fea-
ture of the 1H NMR spectrum is the long-range coupling
constant J1,3a = 6.0 Hz between H-1 and H-3a of the pyr-
roline ring, which is specific to this type of dihydro deriv-
ative, as previously reported.3a
Figure 3 X-ray crystal structure of 4m (E1 = CO2Me, E2 = CO2Me,
Ar = Ph) with thermal ellipsoids drawn at the 40% probability level
Relevant torsion angles that define the orientations of the
ester groups relative to the pyrrole ring are C5–C4–C24–
O26 = –13.7(2)° and C4–C3–C28–O30 = 108.4(2)°. For
the substituents at positions 1 and 2, the torsion angles are
similar to those adopted in the molecule of 4h (C2–N1–
C14–C19 = –62.8(2)° and N1–C2–C6–O7 = –25.5(2)°,
respectively). In compound 4m, short intramolecular con-
tacts analogous to those observed for 4h include
C14···O7 = 2.873(2), O21···N1 = 2.843(2), and C2···C20 =
3.196(2) Å.
In conclusion, a novel approach to the synthesis of pyr-
roles using monosubstituted quinazolinium N-ylides is
presented. Also, the formation of dihydropyrrolo[1,2-
a]quinazoline as an intermediate in the formation of the
pyrroles was evidenced by isolation and characterization
O
O
N
O
Et
Me
E1
N
E2
Me
H
O
Et3N, CDCl3
30 min, r.t.
H
H
N
+
Me
H
N
3
E1
E1
N
N
–
CHCOAr
ArOC
ArOC
H
E2
E2
5
6
4
Scheme 3 One-pot synthesis of pyrroles 4
Synlett 2009, No. 20, 3336–3340 © Thieme Stuttgart · New York

LETTER
A New Synthesis of N-Arylpyrroles
3339
1-(2-Phenyl-2-oxoethyl)-3-methyl-4(3H)-quinazolinon-
1-ium Bromide
by NMR spectroscopy. Hindered rotation about the N–Ar
bond in pyrroles 4 was deduced from H NMR spectrosco-
py and its probable origin was inferred from observations
based on the X-ray crystal data for representative com-
pounds.
Colorless crystals with mp 287–289 °C were obtained by
recrystallization from MeOH; yield 81%. Anal. Calcd
C17H15BrN2O2: N, 7.80. Found: N, 8.04. FT-IR: 1687, 1709,
2927 cm–1. 1H NMR (300 MHz, CDCl3): d = 3.87 (s, 3 H,
MeN), 6.34 (s, 2 H, CH2), 7.43 (d, 1 H, J = 8.5 Hz, H-8),
7.57–7.62 (m, 2 H, H-3¢,H-5¢), 7.74–7.97 (m, 1 H, H-4¢),
7.83 (t, 1 H, J = 7.8 Hz, H-6), 7.98 (dt, 1 H, J = 8.5, 1.65 Hz,
H-7), 8.09–8.12 (m, 2 H, H-2¢, H-6¢), 8.53 (dd, 1 H, J = 7.8,
1.65 Hz, H-5), 9.88 (s, 1 H, H-2). 13C NMR (75 MHz,
CDCl3): d = 36.9 (MeN), 58.7 (CH2), 117.4 (C-8), 128.9,
129.7 (C-5, C-2¢, C-3¢, C-5¢, C-6¢), 131.0 (C-6), 119.6,
132.6, 137.8 (C-4a, C-8a, C-1¢), 136.3 (C-4¢), 137.7 (C-7),
154.4 (C-2), 157.9 (CON), 190.4 (COAr).
Acknowledgment
M.R.C. thanks the University of Cape Town and the NRF (Pretoria)
for financial support.
References and Notes
(1) Shaban, M. A. E.; Mamdouh Tahaa, M. A. M.; Sharshira,
E. M. Adv. Heterocycl. Chem. 1991, 52, 7.
(5) General Procedure for Obtaining the Pyrroles 4
Quaternary salt (5 mmol) and dipolarophile (7.5 mmol) are
heated under reflux in 30 mL 1,2-epoxybutane for 60 h. The
obtained precipitate is filtered and then recrystallized from
MeOH.
(2) (a) Iminov, R. T.; Tverdokhlebov, A. V.; Tolmachev, A. A.;
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Ethyl 2-(4-Fluorobenzoyl)-1-(2-methylaminocarbonyl-
phenyl)pyrrole-4-carboxylate (4h)
Colorless crystals with mp 158–160 °C were obtained by
recrystallization from MeOH; yield 61%. Anal. Calcd
C22H19FN2O4: N, 7.10. Found: N, 7.28. FT-IR: 1635, 1660,
1708, 3389 cm–1. 1H NMR (300 MHz, CDCl3): d = 1.33 (t, 3
H, J = 7.1 Hz, MeCH2), 2.67 (d, 1 H, J = 4.9 Hz, MeNH),
4.30 (sext, 2 H, J = 9.5, 7.1 Hz, CH2), 6.66 (q, 1 H, J = 4.9
Hz, NH), 7.15–7.22 (m, 3 H, H-6¢¢, H-3¢, H-5¢), 7.26 (d, 1 H,
J = 1.6 Hz, H-5), 7.41–7.52 (m, 2 H, H-4¢¢, H-5¢¢), 7.61 (d, 1
H, J = 1.6 Hz, H-3), 7.65–7.68 (m, 1 H, H-3¢¢), 7.98 (dd, 2 H,
J = 8.8, 5.5 Hz, H-2¢, H-6¢).13C NMR (75 MHz, CDCl3):
d = 14.4 (MeCH2), 26.6 (MeNH), 60.6 (CH2O), 115.7 (d,
J = 21.9 Hz, C-3¢, C-5¢), 117.3 (C-4), 122.1 (C-5), 127.1 (C-
6¢¢), 128.9 (C-3¢¢), 129.4, 130.7 (C-4¢¢, C-5¢¢), 132.5, 133.5,
136.7 (C-2, C-1¢¢, C-2¢¢), 132.6 (d, J = 9.0 Hz, C-2¢, C-6¢),
133.4 (d, J = 3.0 Hz, C-1¢), 135.0 (C-3), 163.5 (COO), 167.7
(CONH), 166.0 (d, J = 245.9 Hz, C-4¢), 184.8 (COAr).
Dimethyl 2-Benzoyl-1-(2-methylaminocarbonylphenyl)-
pyrrole-3,4-dicarboxylate (4m)
Heterocycles 1998, 48, 529. (o) Cobb, J.; Demetropoulos,
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Colorless crystals with mp 163–165 °C were obtained by
recrystallization from MeOH; yield 53%. Anal. Calcd
C23H20N2O6: C, 65.71; H, 4.79; N, 6.66. Found: C, 65.97; H,
5.03; N, 6.51. FT-IR: 1649, 1651, 1724, 3285 cm–1. 1H NMR
(300 MHz, CDCl3): d = 2.72 (1 H, d, J = 4.9 Hz, MeNH),
3.29, 3.81 (6 H, 2 s, 2 MeO), 7.03 (1 H, q, J = 4.9 Hz, NH),
7.05–7.08 (1 H, m, H-6¢¢), 7.34–7.40, 7.45–7.52 (4 H, 2 m,
H-3¢, H-5¢, H-4¢¢, H-5¢¢), 7.50 (1 H, s, H-5), 7.59–7.65 (1 H,
m, H-4¢), 7.66–7.69 (1 H, m, H-3¢¢), 7.83–7.87 (2 H, m, H-
2¢,H-6¢).13C NMR (75 MHz, CDCl3): d = 26.7 (MeNH),
51.9, 52.0 (2 MeO), 115.4, 123.0, 132.9, 135.2, 135.4, 137.4
(C-2, C-3, C-4, C-1¢, C-1¢¢, C-2¢¢), 127.0, 129.1, 129.3,
130.8, 132.7 (C-5, C-3¢¢, C-4¢¢, C-5¢¢, C-6¢¢), 128.8, 129.5
(C-2¢, C-3¢, C-5¢, C-6¢), 134.1 (C-4¢), 162.8, 163.8, 167.2 (2
COO, CONH), 188.2 (COAr).
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(4) General Procedure for Obtaining the Bromide Salts 3
3-Methyl-4(3H)-quinazolin-4-one (1, 10 mmol) and
2-bromoacetophenone 2 (10 mmol) in EtOH (30 mL) was
stirred under reflux for 20 h. The obtained precipitate was
filtered and then recrystallized from MeOH.
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Synlett 2009, No. 20, 3336–3340 © Thieme Stuttgart · New York

3340
F. Dumitrascu et al.
LETTER
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Greene, L.; Thompson, A. Synlett 2009, 112. (e) Ullah, F.;
Dang, T. T.; Heinicke, J.; Villinger, A.; Langer, P. Synlett
2009, 838. (f) Trost, B. M.; Muller, C. J. Am. Chem. Soc.
2008, 130, 2438. (g) Aureggi, V.; Davoust, M.; Gericke,
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Crystal Data for 4m
C23H20N2O6; colorless prism; M = 420.41, monoclinic,
P21/c, a = 13.874 (3) Å, b = 9.111 (2) Å, c = 17.175 (3) Å,
b = 105.53 (3)°, V = 2087.7 (8) Å3, Z = 4, T = 173 (2) K,
F000 = 880, R1 = 0.0401, wR2 = 0.1072. The CCDC
deposition number is 750005.
(9) (a) Meth-Cohn, O. Tetrahedron Lett. 1975, 31, 413.
(b) Zhang, X.-C.; Huang, W.-Y. Tetrahedron 1998, 54,
12465.
(10) Dimethyl 1-Benzoyl-4-methyl-1,3a-dihydro-5(4H)-
pyrrolo[1,2-a]quinazoline-5-one-2,3-dicarboxylate (6m)
Colorless crystals with mp 156–158 °C were obtained by
recrystallization from MeOH; yield 51%. Anal. Calcd
C23H20N2O6: C, 65.71; H, 4.79; N, 6.66. Found: C, 66.01; H,
5.68; N, 6.89. FT-IR: 1632, 1659, 1705, 3387 cm–1. 1H NMR
(300 MHz, CDCl3): d = 3.10 (s, 3 H, MeN), 3.54, 3.90 (s, 6
H, 2 CO2Me), 6.32 (d, 1 H, J = 6.0 Hz, H-1), 6.34 (d, 1 H,
J = 8.0 Hz, H-9), 6.45 (d, 1 H, J = 6.0 Hz, H-3a), 6.93 (t, 1
H, J = 7.5 Hz, H-7), 7.22 (ddd, 1 H, J = 7.5, 1.6 Hz, H-8),
7.54–7.59 (m, 2 H, H-3¢, H-5¢), 7.67–7.72 (m, 1 H, H-4¢),
8.02 (dd, 1 H, J = 7.5, 1.6 Hz, H-6), 7.09–7.12 (m, 2 H, H-
2¢, H-6¢). 13C NMR (75 MHz, CDCl3): d = 29.4 (MeN), 52.7,
53.0 (CO2Me), 71.7 (C-3a), 79.6 (C-1), 114.5 (C-9), 120.9
(C-7), 129.1 (C-2¢, C-6¢), 129.2 (C-3¢, C-5¢), 129.5 (C-6),
133.8 (C-8), 134.6 (C-4¢), 117.6, 135.2, 137.7, 139.7, 143.11
(C-2, C-3, C-5, C-5a, C-1¢), 161.8, 163.3, 163.4 (3 CO),
195.2 (CO).
(8) Crystal Data for 4h
C22H19FN2O4; colorless prism; M = 394.39, monoclinic,
C2/c, a = 32.702 (1) Å, b = 7.6703 (3) Å, c = 18.6347 (6) Å,
b = 123.376 (1)°, V = 3903.3 (2) Å3, Z = 8, T = 100 (2) K,
F000 = 1648, R1 = 0.0374, wR2 = 0.1028. CCDC 750004
contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
Synlett 2009, No. 20, 3336–3340 © Thieme Stuttgart · New York

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