Generation of pyrrolo[2,1-a]isoquinoline derivatives from N-ylides: Synthetic control and structural characterization

Article abstract of DOI:10.1002/hc.20740

New pyrrolo[2,1-a]isoquinolines were obtained by two one-pot procedures via 1,3-dipolar cycloaddition between the isoquinolinium N-ylides and symmetrical acetylenic dipolarophiles, avoiding the formation of dihydro intermediates. For structural comparison

Full text of DOI:10.1002/hc.20740

Heteroatom Chemistry
Volume 22, Number 6, 2011
Generation of Pyrrolo[2,1-a]isoquinoline
Derivatives from N-ylides: Synthetic Control
and Structural Characterization
Florea Dumitrascu,1 Mino R. Caira,2 Emilian Georgescu,3
Florentina Georgescu,3 Constantin Draghici,1 and Marcel Mirel Popa1
1Centre of Organic Chemistry “C. D. Nenitzescu,” Roumanian Academy, Spl. Independent¸ei 202B,
Bucharest 060023, Romania
2Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
3Oltchim Research Center, St. Uzinei 1, 240050 Ramnicu Valcea, Romania
Received 8 April 2011; revised 31 May 2011
Shklyaev [1]. Subsequently, the interest in new
ABSTRACT: New pyrrolo[2,1-a]isoquinolines were
syntheses [2] of the pyrrolo[2,1-a]isoquinolines in-
obtained by two one-pot procedures via 1,3-dipolar
creased steadily owing to their significant biological
cycloaddition between the isoquinolinium N-ylides
activity, especially for natural products such as
and symmetrical acetylenic dipolarophiles, avoiding
lamellarins [3] and crispine [4] (Fig. 1).
the formation of dihydro intermediates. For struc-
One of the most versatile synthetic strategies
tural comparison, the dihydro derivatives obtained by
starting from isoquinoline is the 1,3-dipolar cy-
a classical two-stage reaction were characterized by
cloaddition of their corresponding ylides [1,2e,2f,5–
NMR and X-ray crystallography, allowing complete
9] with both acetylenic and olefinic dipolarophiles.
ꢀ
C
stereochemistry assignments. 2011 Wiley Periodicals,
Usually, the syntheses of pyrrolo[2,1-a]isoquinolines
involve two distinct steps: In the first step, the iso-
quinolinium salts are prepared and in the second
Inc. Heteroatom Chem 22:723–729, 2011; View this article
online at wileyonlinelibrary.com. DOI 10.1002/hc.20740
step these react with acetylenic or olefinic dipo-
larophiles in the presence of a base whose role is
INTRODUCTION
to generate the N-ylide in situ. By using acetylenic
dipolarophiles, dihydro derivative intermediates are
obtained along with the aromatic target products.
The stereochemistry of such derivatives is of interest
from the mechanistic point of view and thus received
some attention [6–10].
Herein is reported the synthesis of new
pyrrolo[2,1-a]isoquinoline derivatives by two one-
pot procedures that avoid the isolation of the dihydro
derivative intermediates. The one-pot reactions are
well known for their simplicity and efficiency [11].
Also, the structure of a representative dihydro inter-
mediate was studied by X-ray diffraction analysis in
order to assign its stereochemistry.
Pyrrolo[2,1-a]isoquinoline is an aromatic N-
heterocycle formally obtained by the condensation
of isoquinoline with pyrrole, the nitrogen atom
being at the junction. The synthesis, reactivity, and
biological properties of pyrrolo[2,1-a]isoquinoline
were reviewed in 1997 by Mikhailovskii and
Correspondence to: Florea Dumitrascu; e-mail: fdumitra@
yahoo.com.
Contract grant sponsor: POSDRU.
Contract grant number: 88/1.5/S/61178.
2011 Wiley Periodicals, Inc.
c
ꢀ
723

724 Dumitrascu et al.
R6
by the reaction of isoquinoline and substituted
2-bromoacetophenones, are mixed with the corre-
sponding acetylenic dipolarophile in the presence
of triethylamine and TPCD, leading directly to the
aromatic pyrrolo[2,1-a]isoquinolines 8. The oxidant
reagent TPCD was used in the cycloaddition reaction
between the N-heteroaromatic ylides and olefinic
dipolarophiles [14].
O
O
MeO
MeO
N
R5
N
R4
R3
R1
R2
The second synthetic procedure toward
a
b
pyrrolo[2,1-a]isoquinoline
derivatives
involves
the use of epoxides such as 1,2-epoxybutane, which
plays both the role of the reaction medium and
proton scavenger. Thus, the bromide ion from the
salt attacks the oxirane ring with formation of
an alkoxide, which extracts one of the methylene
protons in the isoquinolinium bromide generating
the corresponding N-ylide. The one-pot procedure
consists only in mixing the reactants under reflux
for 40 h. The fully aromatic compounds 8 are
obtained in good yields (Scheme 2, path B).
Using these two one-pot procedures, a series of
12 variously substituted pyrrolo[2,1-a]isoquinoline
derivatives were obtained in good yields (Table 1). It
can be noticed that the yields obtained using path A
are generally slightly higher than the ones corre-
sponding to path B.
FIGURE 1 The structure of lamellarins (a) and crispine A
(b).
RESULTS AND DISCUSSION
One of the promising methods in the synthe-
sis of pyrroloazines is the 1,3-dipolar cycloaddi-
tion reaction of their corresponding N-ylides [5–
10, 11a,b]. Usually, the reaction of the N-ylides 1
(Scheme 1) with the acetylenic dipolarophiles 2
leads to formation of the primary cycloadducts 3,
which rearrange to the dihydro intermediates 4 or 5
[6–9,10d,12,13]. Such intermediates are susceptible
to further aromatization, under the reaction condi-
tions or by using oxidant reagents, leading to fully
aromatic pyrroloazines 6. Intermediates of type 4 or
5 could be of interest for stereochemical reasons but
their formation must be avoided in order to improve
the yield of the desired aromatic compounds.
Our interest in obtaining pyrroloazines [10d,e–
11c,d] by 1,3-dipolar cycloaddition reaction led
us to investigate the synthesis of pyrrolo[2,1-
a]isoquinolines by two simple one-pot procedures.
Thus, the first procedure involves the use of tetrak-
ispyridinecobalt(II) dichromate (TPCD) as oxidiz-
ing agent in order to direct the reaction toward
the fully aromatic target compounds (Scheme 2,
path A). The salts 7, obtained in a previous step
The structures of the new compounds 8a–l were
assigned by NMR spectroscopy. The spectra are in
good accordance with the proposed structures. The
1
main characteristic of the H NMR spectra are the
signals of the hydrogen atoms H-5 and H-6, which
appear as two doublets with the coupling constant
J = 7.4 Hz. The hydrogens H-5 and H-10 are the most
deshielded protons in the range 8.60–8.84 ppm. The
hydrogen H-6 appears shielded in the range 7.06–
7.26 ppm. An interesting observation could be made
for the compounds 8a, 8c, and 8l, which present
the signal of H-5 strongly deshielded at ∼9.50 ppm,
most probably due to the influence of the ortho sub-
stitution on the 2,4-dichlorobenzoyl substituent. H-
10 appears deshielded due to spatial vicinity of the
H
1
N
COR
N
COR
H
E-C C-E
Et3N/
+
–
E
E
TPCD
E
E
A
B
2
3
DMF
N
+
N
COR
COR
H
CH2COR
N
N
N
[O]
COR
COR
or
–
H
H
Br
E
E-C C-E
E
H
8
7
E
E
E
E
E
E
Et
O
4
5
6
SCHEME 1
SCHEME 2
Heteroatom Chemistry DOI 10.1002/hc

Generation of Pyrrolo[2,1-a]isoquinoline Derivatives from N-ylides 725
TABLE 1 New Pyrrolo[2,1-a]isoquinolines
7
6
5
8
Yield (%)
Method A/B)
Et N
10a
DMAD/
–
3
Compound
E
R
N
10b
3
9
Br
CN
N
+
CH2Cl2
H
10
CH2CN
8a
8b
8c
8d
8e
8f
8g
8h
8i
CO2Me
CO2Me
CO2Et
2,4-Cl2C6H3
3-MeOC6H4
2,4-Cl2C6H3
4-BrC6H4
71/64
61/49
68/61
58/60
75/72
85/67
81/78
80/73
77/70
72/66
87/75
75/68
2
MeO2C
1
H
CO2Me
CO2Et
9
10
CO2iPr
CO2iPr
CO2iPr
CO2iPr
CO2iPr
CO2iPr
CO2iPr
CO2iPr
C6H5
4-MeC6H4
4-C6H5C6H4
3-NO2C6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
SCHEME 3
data and details of the refinement appear in Table 2.
The stereochemistry of the two H atoms in ques-
tion is clearly trans. Although these H atoms were
located unequivocally in a difference Fourier synthe-
sis, they were added in idealized positions dependent
on the local geometries. Because the five-membered
ring adopts a twist conformation (twisted on C4–C5),
the final calculated dihedral angle H4-C4-C5-H5 is in
fact –145◦ for the S-, S- configurations at C4 and C5
shown in Fig. 1 and +145◦ for the inversion-related
molecule in the crystal. The bond lengths C4–C5 and
8j
8k
8l
2,4-Cl2C6H3
alkoxy carbonyl group. The 13C NMR spectra present
as main characteristics the signals of C-1 and C-6,
which appear strongly shielded at ∼110 ppm and
∼116 ppm, respectively.
Both one-pot procedures avoid the formation
of the dihydro intermediates leading to the desired
aromatic compounds. By comparison, if no oxidiz-
ing agents were used, it was observed that in dif-
ferent solvents (CH2Cl2, benzene, DMF, MeCN) the
reaction between the corresponding N-ylides and
symmetrical acetylenic dipolarophiles leads to the
formation of dihydro derivatives together with the
aromatic compounds. These dihydro derivatives can
be assigned as pyrrolo[2,1-a]phtalazines (type 4) [12]
and pyrrolo[1,2-a][1,10]phenanthrolines (type 5)
[13] (Scheme 1), which are important synthetic in-
termediates.
˚
C2–C3 are 1.551(2) and 1.357(2) A, respectively, in
accordance with the formal bond orders indicated
for 10 in Scheme 3.
The stereochemistry of the compound 10 was
thus unambiguously assigned to be in reality trans,
which is consistent with another structure discussed
in the literature [9]. On the basis of the results
highlighted in this paper and the reported litera-
ture [9,12,13], we can conclude that the primary cy-
cloadducts of type 3 (Scheme 1) rearrange to the
trans isomer of type 4 or 5.
In the case of the dihydro derivatives obtained
previously [6,7] from isoquinolinium N-ylides, some
investigations were carried out in order to estab-
lish their stereochemistry [6,7]. Thus, the stereo-
chemistry of the dihydro derivative 10 obtained by
the reaction of isoquinolinium salt 9 with DMAD
(dimethyl acetylenedicarboxylate) in the presence
of triethylamine in methylene chloride as solvent
(Scheme 3) was assigned on the basis of NMR spec-
troscopy [7].
The high coupling constant between protons
from the pyrroline moiety H1 and H-10b, of mag-
nitude 13–14 Hz was considered sufficiently large to
ascertain a cis stereochemistry of the two hydrogen
atoms under discussion. However, with the unex-
pected trans configuration observed for the dihydro
pyrrolo[2,1-a]phthalazines [12] in mind, we reinves-
tigated the structure of the dihydro derivative 10 by
single crystal X-ray analysis.
Figure 2 shows the molecular structure of 10
and the crystallographic numbering scheme. Crystal
FIGURE 2 X-ray structure of 10 with thermal ellipsoids
drawn at the 50% probability level.
.
Heteroatom Chemistry DOI 10.1002/hc

726 Dumitrascu et al.
TABLE 2 Crystal Data and Refinement Data for 10a
Molecular Formula
C17H14N2O4
M
310.30
Triclinic
P(-1)
Crystal system
Space group
˚
a(A)
8.5014(6)
8.8217(6)
˚
b(A)
˚
c(A)
10.3998(9)
104.960(5)
95.532(5)
101.455(4)
α(◦)
β(◦)
γ(◦)
3
˚
Vcell (A )
729.47(10)
Z
T(K)
2
173(2)
0.102
324
2.72–27.48
Absorption coefficient (mm−1
F(000)
)
θ-range (◦)
Index ranges
Reflections collected
Unique reflections
−11 ≤ h ≤ 11, −11 ≤ k ≤ 11, −13 ≤ l ≤ 13
21152
3317
Observed reflections [I > 2σ(I )]
Data/restraints/parameters
Goodness-of-fit on F2
2794
3317/0/210
1.033
Final R indices [I > −2σ3(I )]
R1 = 0.0409, wR2 = 0.0906
˚
ꢀρ(max., min.)/(e A
)
0.226, –0.216
aFull crystallographic data (CCDC 820337).
CONCLUSIONS
General Procedure for Synthesis of
Pyrrolo[2,1-a]isoquinolines 8
New pyrrolo[2,1-a]isoquinolines were obtained by
two one-pot procedures via 1,3-dipolar cycload-
dition between the isoquinolinium N-ylides and
symmetrical acetylenic dipolarophiles, avoiding the
formation of mixtures of dihydro derivatives. The
compounds were fully characterized by standard
techniques. The structure of the dihydro deriva-
tives, of interest from a stereochemical viewpoint,
was confirmed by the single crystal X-ray diffraction
analysis of the representative dihydro derivative 10.
Furthermore, on the basis of the X-ray analysis, it
can be concluded that the dihydro derivatives ob-
tained together with the aromatic pyrroloazines pos-
sess a trans stereochemistry, no presence of the cis
isomer being observed.
Method A. Isoquinolinium bromide 7 (5 mmol)
was suspended in dimethylformamide (25 mL)
and then dimethyl (diethyl or diisopropyl)
acetylenedicarboxylate (5.5 mmol) was added.
Under stirring, triethylamine (5.5 mmol) and
tetrakispyridinecobalt(II) dichromate (TPCD) (2 g,
3.2 mmol) were added to the reaction mixture.
The reaction mixture was stirred at 80–90◦C for
4 h and then cooled at room temperature and
poured into a 5% aqueous HCl solution (100 mL).
The solid product was filtered, washed with water,
and purified either by crystallization or column
chromatography on neutral Al2O3, using CH2Cl2 as
eluent.
EXPERIMENTAL
Method B. To a suspension of 2.5 mmol of iso-
quinolinium bromide 7 in 25 mL 1,2-epoxybutane
3.5 mmol of acetylenic dipolarophile was added. The
mixture was heated at reflux temperature for 40 h.
A part of solvent was removed in vacuum, 5 mL
of methanol was added, and the mixture was left
overnight at room temperature. The solid was fil-
tered, washed with a MeOH-Et2O 1:1 mixture, and
recrystallized from CHCl3/MeOH.
Melting points were determined on a Boe¨tius hot
plate microscope and are uncorrected. The elemen-
tal analysis was carried out on a COSTECH Instru-
ments EAS32 apparatus. The NMR spectra were
recorded on a Varian Gemini 300 BB instrument, op-
erating at 300 MHz for 1H NMR and 75 MHz for 13
C
NMR. Supplementary evidence was given by HET-
COR and COSY experiments.
Heteroatom Chemistry DOI 10.1002/hc

Generation of Pyrrolo[2,1-a]isoquinoline Derivatives from N-ylides 727
1
Dimethyl 3-(2,4-dichlorobenzoyl)pyrrolo[2,1-a]
isoquinoline-1,2-dicarboxylate (8a). Light yellow
crystals; mp 212–214◦C; Anal. Calcd. C23H15Cl2NO5:
C 60.54; H 3.31; Cl 15.54; N 3.07. Found: C 60.89; H
16.31, N 3.01; H NMR (300 MHz, CDCl3) δ: 1.01,
1.37 (2t, 6H, J = 7.1 Hz, 2Me); 3.75, 4.44 (2q, 4H,
J = 7.1 Hz, 2CH2); 7.16 (d, 1H, J = 7.4 Hz, H-6);
7.58–7.66 (m, 4H, H-8, H-9, H-3ꢁ, H-5ꢁ); 7.68 (d, 2H,
J = 8.2 Hz, H-2ꢁ, H-6ꢁ); 7.69–7.73 (m, 1H, H-7); 8.84
(d, 1H, J = 7.4 Hz, H-5); 8.85–8.88 (m, 1H, H-10);
13C NMR (75 MHz, CDCl3) δ: 13.6, 13.9 (2Me); 61.5,
61.6 (CH2); 110.2 (C-1); 115.9 (C-6); 122.2, 124.3,
127.2, 129.5, 132.4 (C-2, C-3, C-6a, C-10a, C-10b);
123.5, 127.1, 129.0 (C-7, C-8, C-9); 125.7 (C-5); 127.6
(C-4ꢁ); 128.3 (C-10); 130.5, 131.8 (C-2ꢁ, C-3ꢁ, C-5ꢁ,
C-6ꢁ); 138.5 (C-4ꢁ); 164.1, 165.4 (COO); 185.9 (COAr).
1
3.08; Cl 15.74; N 3.21; H NMR (300 MHz, CDCl3)
δ: 3.30, 3.83 (2s, 6H, 2MeO); 7.20–7.31 (m, 3H, H-6,
H-5ꢁ, H-6ꢁ); 7.41 (d, 1H, J = 1.9, H-3ꢁ); 7.56–7.62 (m,
2H, H-8, H-9); 7.69–7.72 (m, 1H, H-7); 9.06–9.10
(m, 1H, H-10); 9.45 (d, 1H, J = 7.4 Hz, H-5); 13C
NMR (75 MHz, CDCl3) δ: 13.8, 14.1 (2Me); 61.6, 62.0
(CH2); 110.3 (C-1); 116.9 (C-6); 121.1, 124.1, 130.6,
131.7, 133.7 (C-2, C-3, C-6a, C-10a, C-10b) 134.8,
137.1, 137.4 (C-1ꢁ, C-2ꢁ, C-4ꢁ); 124.4 (C-5); 126.7,
127.0, 127.2, 129.8, 130.0, 131.0 (C-7, C-8, C-9, C-3ꢁ,
C-5ꢁ, C-6ꢁ); 128.4 (C-10); 164.5, 164.7 (COO); 183.4
(COAr).
Diisopropyl 3-benzoylpyrrolo[2,1-a]isoquinoline-
1,2-dicarboxylate (8e). Light yellow crystals; mp
179–180◦C; Anal. Calcd. C27H25NO5: C 73.12; H 5.68;
1
N 3.16. Found: C 73.44; H 5.29; N 3.40; H NMR
Dimethyl 3-(3-methoxybenzoyl)pyrrolo[2,1-a]iso-
quinoline-1,2-dicarboxylate (8b). Light yellow crys-
tals; mp 193–194◦C; Anal. Calcd. C24H19NO6: C 69.06;
(300 MHz, CDCl3) δ: 0.86, 1.42 (2d, 12H, J = 6.3
Hz, 4Me-isopropyl); 4.67, 5.40 (2 sept, 2H, J = 6.3
Hz, 2CH-isopropyl); 7.10 (d, 1H, J = 7.4 Hz, H-6);
7.43–7.49 (m, 2H, H-3ꢁ, H-5ꢁ); 7.55–7.61 (m, 3H, H-
8, H-9, H-4ꢁ); 7.66–7.71 (m, 1H, H-7); 7.87–7.91 (m,
2H, H-2ꢁ, H-6ꢁ); 8.68 (d, 1H, J = 7.4 Hz, H-5); 8.71–
8.75 (m, 1H, H-10); 13C NMR (75 MHz, CDCl3) δ:
21.2, 21.8 (4Me); 69.6 (2CHMe2); 111.0 (C-1); 115.6
(C-6); 122.8, 124.6, 125.9, 129.4, 131.4 (C-2, C-3, C-
6a, C-10a, C-10b); 125.4 (C-5); 123.6, 127.3, 128.8
(C-7, C-8, C-9); 128.3 (C-10); 128.7, 129.9 (C-2ꢁ, C-
3ꢁ, C-5ꢁ, C-6ꢁ); 133.3 (C-4ꢁ); 139.6 (C-1ꢁ); 163.7, 165.6
(COO); 187.3 (COAr).
1
H 4.59; N 3.36. Found: C 69.21; H 4.27; N 3.52; H
NMR (300 MHz, CDCl3) δ: 3.30, 3.85, 3.94 (3s, 9H,
3MeO); 7.10–7.14 (m, 1H, H-4ꢁ); 7.17 (d, 1H, J = 7.4
Hz, H-6); 7.31–7.39 (m, 2H, H-2ꢁ, H-6ꢁ); 7.57–7.63 (m,
4H, H-8, H-9); 7.68–7.73 (m, 1H, H-7); 8.87–8.90 (m,
1H, H-10); 8.91 (d, 1H, J = 7.4 Hz, H-5); 13C NMR
(75 MHz, CDCl3) δ: 51.8, 52.4, 55.4 (4MeO); 109.6
(C-1); 112.9, 119.6, 121.7, 129.4 (C-2ꢁ, C-4ꢁ, C-5ꢁ, C-
6ꢁ); 115.8 (C-6); 122.9, 124.4, 127.4, 129.5, 132.4 (C-
2, C-3, C-6a, C-10a, C-10b); 125.7 (C-5); 127.1, 127.4,
129.0 (C-7, C-8, C-9); 128.3 (C-10); 142.0 (C-1ꢁ); 159.6
(C-4ꢁ); 164.6, 165.8 (2COO); 185.8 (COAr).
Diisopropyl
3-(4-methylbenzoyl)pyrrolo[2,1-a]
isoquinoline-1,2-dicarboxylate (8f). Light yellow
crystals; mp 147–148◦C; Anal. Calcd. C28H27NO5: C
73.51; H 5.95; N 3.06. Found: C 73.88; H 5.71; N
Diethyl 3-(2,4-dichlorobenzoyl)pyrrolo[2,1-a]iso-
quinoline-1,2-dicarboxylate (8c). Light yellow crys-
tals; mp 160–162◦C; Anal. Calcd. C25H19Cl2NO5: C
62.00; H 3.95; Cl 14.64; N 2.89. Found: C 62.32; H
1
3.31; H NMR (300 MHz, CDCl3) δ: 0.87, 1.41 (2d,
12H, J = 6.3 Hz, 4Me-isopropyl); 2.42 (s, 3H, 4ꢁ-Me);
4.70, 5.39 (2 sept, 2H, J = 6.3 Hz, 2CH-isopropyl);
7.06 (d, 1H, J = 7.4 Hz, H-6); 7.26 (d, 2H, J =
8.2 Hz, H-3ꢁ, H-5ꢁ); 7.54–7.60 (m, 2H, H-8, H-9);
7.65–7.71 (m, 1H, H-7); 7.78 (d, 2H, J = 8.2 Hz,
H-2ꢁ, H-6ꢁ); 8.60 (d, 1H, J = 7.4 Hz, H-5); 8.70–8.75
(m, 1H, H-10); 13C NMR (75 MHz, CDCl3) δ: 21.2,
21.7 (4Me); 69.4, 69.5 (2CHMe2); 110.7 (C-1); 115.4
(C-6); 123.2, 124.7, 125.4, 129.3, 131.1 (C-2, C-3,
C-6a, C-10a, C-10b); 125.3 (C-5); 123.6, 127.3, 128.6
(C-7, C-8, C-9); 128.2 (C-10); 129.3, 130.0 (C-2ꢁ, C-3ꢁ,
C-5ꢁ, C-6ꢁ); 136.9 (C-1ꢁ); 144.3 (C-4ꢁ); 163.7, 165.6
(COO); 187.0 (COAr).
1
4.11; Cl 14.97; N 2.99; H NMR (300 MHz, CDCl3)
δ: 1.20, 1.34 (2t, 6H, J = 7.1 Hz, 2Me); 3.70, 4.38
(2q, 4H, J = 7.1 Hz, 2CH2); 7.26–7.32 (m, 2H,
H-6, H-5ꢁ); 7.38 (d, 1H, J = 8.2, H-6ꢁ); 7.48 (d, 1H,
J = 1.9, H-3ꢁ); 7.59–7.67 (m, 2H, H-8, H-9); 7.72–
7.75 (m, 1H, H-7); 9.11–9.15 (m, 1H, H-10); 9.49 (d,
1H, J = 7.4 Hz, H-5); 13C NMR (75 MHz, CDCl3) δ:
13.8, 14.1 (2Me); 61.6, 62.0 (CH2); 110.3 (C-1); 116.9
(C-6); 121.1, 124.1, 130.6, 131.7, 133.7 (C-2, C-3, C-
6a, C-10a, C-10b) 134.7, 137.1, 137.7 (C-1ꢁ, C-2ꢁ, C-4ꢁ);
124.5 (C-5); 126.7, 126.9, 127.2, 129.8, 130.0, 131.0
(C-7, C-8, C-9, C-3ꢁ, C-5ꢁ, C-6ꢁ); 128.4 (C-10); 164.5,
164.7 (COO); 183.4 (COAr).
Diisopropyl 3-(4-phenylbenzoyl)pyrrolo[2,1-a]iso-
quinoline-1,2-dicarboxylate (8g). Colorless crystals;
mp 130–132◦C; Anal. Calcd. C33H29NO5: C 76.28;
H 5.63; N 2.70. Found: C 76.56; H 5.71; N 3.04;
1H NMR (300 MHz, CDCl3) δ: 0.88, 1.42 (2d, 12H,
Diethyl
3-(4-bromobenzoyl)pyrrolo[2,1-a]iso-
quinoline-1,2-dicarboxylate (8d). Colorless crystals;
mp 160–162◦C; Anal. Calcd. C25H20BrNO5: C 60.74;
H 4.08; Br 16.16, N 2.83. Found: C 61.08; H 4.29; Br
Heteroatom Chemistry DOI 10.1002/hc

728 Dumitrascu et al.
J = 6.3 Hz, 4Me-isopropyl); 4.73, 5.40 (2 sept, 2H, J
= 6.3 Hz, 2CH-isopropyl); 7.11 (d, 1H, J = 7.4 Hz,
H-6); 7.38–7.51 (m, 3H, H-3ꢁ, H-4ꢁ, H-5ꢁ); 7.57–7.64
(m, 3H, H-8, H-9, H-2ꢁ, H-6ꢁ); 7.67–7.71 (m, 3H, H-7,
H-3”, H-5”); 7.96 (d, 2H, J = 8.6 Hz, H-2”, H-6”);
8.69 (d, 1H, J = 7.4 Hz, H-5); 8.71–8.73 (m, 1H, H-
10); 13C NMR (75 MHz, CDCl3) δ: 21.3, 21.8 (4Me);
69.6 (2CHMe2); 111.0 (C-1); 115.6 (C-6); 123.0, 124.7,
125.8, 129.4, 131.4 (C-2, C-3, C-6a, C-10a, C-10b);
125.4 (C-5); 123.6, 127.4, 128.8 (C-7, C-8, C-9); 128.2
(C-10); 127.1, 129.1, 130.5 (9C, C-2ꢁ, C-3ꢁ, C-5ꢁ, C-6ꢁ,
Ph); 138.3, 140.0, 146.1 (C-1ꢁ, C-4ꢁ, Cq-Ph); 163.8,
165.7 (COO); 186.8 (COAr).
δ: 0.92, 1.42 (2d, 12H, J = 6.3 Hz, 4Me-isopropyl);
4.73, 5.40 (2 sept, 2H, J = 6.3 Hz, 2CH-isopropyl);
7.11 (d, 1H, J = 7.4 Hz, H-6); 7.44 (d, 2H, J = 8.4
Hz, H-3ꢁ, H-5ꢁ); 7.53–7.59 (m, 2H, H-8, H-9); 7.67–
7.71 (m, 1H, H-7); 7.82 (d, 2H, J = 8.4 Hz, H-2ꢁ,
H-6ꢁ); 8.68 (d, 1H, J = 7.4 Hz, H-5); 8.69–8.74 (m,
1H, H-10); 13C NMR (75 MHz, CDCl3) δ: 21.2, 21.7
(4Me); 69.6, 69.7 (2CHMe2); 111.1 (C-1); 115.7 (C-
6); 122.3, 124.5, 126.0, 129.4, 131.6 (C-2, C-3, C-6a,
C-10a, C-10b); 125.4 (C-5); 123.5, 127.3, 128.9 (C-7,
C-8, C-9); 128.3 (C-10); 128.9, 131.1 (C-2ꢁ, C-3ꢁ, C-
5ꢁ, C-6ꢁ); 138.0, 139.7 (C-1ꢁ, C-4ꢁ); 144.3 (C-4ꢁ); 163.6,
165.4 (COO); 185.9 (COAr).
Diisopropyl 3-(3-nitrobenzoyl)pyrrolo[2,1-a]iso-
quinoline-1,2-dicarboxylate (8h). Colorless crystals;
mp 170–172◦C; Anal. Calcd. C27H24N2O7: C 66.39; H
Diisopropyl 3-(4-bromobenzoyl)pyrrolo[2,1-a]iso-
quinoline-1,2-dicarboxylate (8k). Colorless crystals;
mp 146–147◦C; Anal. Calcd. C27H24BrNO5: C 62.08;
H 4.63; Br 15.30, N 2.68. Found: C 62.29; H 4.82; Br
1
4.95; N 5.73. Found: C 66.70; H 4.70; N 5.65; H
1
NMR (300 MHz, CDCl3) δ: 0.90, 1.42 (2d, 12H, J =
6.3 Hz, 4Me-isopropyl); 4.65, 5.47 (2 sept, 2H, J =
6.3 Hz, 2CH-isopropyl); 7.16 (d, 1H, J = 7.4 Hz, H-6);
7.54–7.62 (m, 2H, H-8, H-9); 7.63 (t, 1H, J = 8.0 Hz,
H-5ꢁ); 7.66–7.72 (m, 1H, H-7); 8.10–8.14, 8.37–8.41
(2m, 2H, H-4ꢁ, H-6ꢁ); 8.65–8.70 (m, 2H, H-10, H-2ꢁ);
8.81 (d, 1H, J = 7.4 Hz, H-5); 13C NMR (75 MHz,
CDCl3) δ: 21.3, 21.8 (4Me); 69.8, 69.9 (2CHMe2);
111.6 (C-1); 116.2 (C-6); 121.6, 124.3, 127.0, 129.6,
132.2 (C-2, C-3, C-6a, C-10a, C-10b); 124.1 (C-4ꢁ);
125.4 (C-5); 123.5, 127.4, 129.2 (C-7, C-8, C-9); 126.2,
130.3 (C-2ꢁ, C-5ꢁ); 128.4 (C-10); 135.2 (C-6ꢁ) 141.3 (C-
1ꢁ); 148.4 (C-3ꢁ); 163.4, 165.1 (COO); 184.5 (COAr).
15.67, N 2.82; H NMR (300 MHz, CDCl3) δ: 0.92,
1.42 (2d, 12H, J = 6.3 Hz, 4Me-isopropyl); 4.73, 5.39
(2 sept, 2H, J = 6.3 Hz, 2CH-isopropyl); 7.11 (d, 1H,
J = 7.4 Hz, H-6); 7.56–7.63 (m, 4H, H-8, H-9, H-3ꢁ,
H-5ꢁ); 7.67–7.71 (m, 1H, H-7); 7.74 (d, 2H, J = 8.2
Hz, H-2ꢁ, H-6ꢁ); 8.68 (d, 1H, J = 7.4 Hz, H-5); 8.69–
8.74 (m, 1H, H-10); 13C NMR (75 MHz, CDCl3) δ:
21.2, 21.7 (4Me); 69.6, 69.7 (2CHMe2); 111.1 (C-1);
115.7 (C-6); 122.3, 124.4, 126.1, 129.4, 131.6 (C-2,
C-3, C-6a, C-10a, C-10b); 123.5, 127.3, 128.9 (C-7, C-
8, C-9); 125.4 (C-5); 126.6 (C-4ꢁ); 128.3 (C-10); 131.2,
131.9 (C-2ꢁ, C-3ꢁ, C-5ꢁ, C-6ꢁ); 138.4 (C-4ꢁ); 163.6, 165.4
(COO); 186.0 (COAr).
Diisopropyl 3-(4-fluorobenzoyl)pyrrolo[2,1-a]iso-
quinoline-1,2-dicarboxylate (8i). Colorless crystals;
mp 156–158◦C; Anal. Calcd. C27H24FNO5: N 3.04.
Diisopropyl 3-(2,4-dichlorobenzoyl)pyrrolo[2,1-a]
isoquinoline-1,2-dicarboxylate (8l). Light yellow
crystals; mp 146–147◦C; Anal. Calcd. C27H23Cl2NO5:
C 63.29; H 4.52; Cl 13.84, N 2.73. Found: C 63.41; H
4.49; Cl 14.17, N 2.94; 1H NMR (300 MHz, CDCl3) δ:
1.09, 1.40 (2d, 12H, J = 6.3 Hz, 4Me-isopropyl); 4.60,
5.35 (2 sept, 2H, J = 6.3 Hz, 2CH-isopropyl); 7.25–
7.31 (m, 2H, H-6, H-5ꢁ); 7.43 (d, 1H, J = 8.2, H-6ꢁ);
7.48 (d, 1H, J = 1.9, H-3ꢁ); 7.58–7.68 (m, 2H, H-8, H-
9); 7.75–7.78 (m, 1H, H-7); 8.80–8.84 (m, 1H, H-10);
9.36 (d, 1H, J = 7.4 Hz, H-5); 13C NMR (75 MHz,
CDCl3) δ: 21.5, 21.8 (4Me); 69.7, 70.5 (2CHMe2);
111.5 (C-1); 116.5 (C-6); 121.3, 124.1, 130.0, 130.2,
133.3 (C-2, C-3, C-6a, C-10a, C-10b); 134.0, 137.3,
137.4 (C-1ꢁ, C-2ꢁ, C-4ꢁ); 124.3 (C-5); 126.1, 126.8,
127.3, 129.4, 130.5, 131.5 (C-7, C-8, C-9, C-3ꢁ, C-5ꢁ, C-
6ꢁ); 128.1 (C-10); 163.8, 164.7 (COO); 183.4 (COAr).
1
Found: N 3.26; H NMR (300 MHz, CDCl3) δ: 0.92,
1.42 (2d, 12H, J = 6.3 Hz, 4Me-isopropyl); 4.73, 5.40
(2 sept, 2H, J = 6.3 Hz, 2CH-isopropyl); 7.09 (d, 1H,
J = 7.4 Hz, H-6); 7.14 (t, 2H, J = 8.5 Hz, H-3ꢁ, H-5ꢁ);
7.54–7.60 (m, 2H, H-8, H-9); 7.66–7.71 (m, 1H, H-7);
7.91 (dd, 2H, J = 8.5, 5.5 Hz, H-2ꢁ, H-6ꢁ); 8.63 (d, 1H,
J = 7.4 Hz, H-5); 8.70–8.74 (m, 1H, H-10); 13C NMR
(75 MHz, CDCl3) δ: 21.3, 21.7 (4Me); 69.6 (2CHMe2);
110.9 (C-1); 115.6 (C-6); 115.8 (d, J = 21.8 Hz, C-
3ꢁ, C-5ꢁ); 122.5, 124.5, 125.7, 129.3, 131.4 (C-2, C-3,
C-6a, C-10a, C-10b); 125.3 (C-5); 123.4, 127.3, 128.8
(C-7, C-8, C-9); 128.3 (C-10); 132.3 (d, J = 9.2 Hz,
C-2ꢁ, C-6ꢁ); 136.2 (d, J = 2.9 Hz, C-1ꢁ); 163.6, 165.5
(COO); 165.1 (d, J = 252.2 Hz, C-4ꢁ); 185.6 (COAr).
Diisopropyl 3-(4-chlorobenzoyl)pyrrolo[2,1-a]iso-
quinoline-1,2-dicarboxylate (8j). Light yellow crys-
tals; mp 147–148◦C; Anal. Calcd. C27H24ClNO5: C
67.85; H 5.06; Cl 7.42, N 2.93. Found: C 68.01; H
X-Ray Analysis of Compound 10
Intensity data from a specimen of 10 with dimen-
sions 0.10 × 0.22 × 0.24 mm were collected on
a Nonius Kappa CCD diffractometer. The crystal
1
5.35; Cl 7.78, N 3.03; H NMR (300 MHz, CDCl3)
Heteroatom Chemistry DOI 10.1002/hc

Generation of Pyrrolo[2,1-a]isoquinoline Derivatives from N-ylides 729
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+ (aP)2 + bP]−1 with P = [max(Fo2, 0) + 2Fc2]/3 were
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F.; Draghici, B.; Popa, M. M.; Dumitrascu, F.
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ACKNOWLEDGMENTS
MRC acknowledges research support from the Uni-
versity of Cape Town and the National Research
Foundation (Pretoria).
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Heteroatom Chemistry DOI 10.1002/hc