Conformation and Crystal Structure of Dipyrrinones with Oxindole Components

Article abstract of DOI:10.1007/s00706-002-0542-3

Pyrrole α-aldehydes (2-formyl-4,5-dimethyl- 1H-pyrrole and 2-formyl-N-methylpyrrole) condense readily at C(3) of indolin-2-ones to give dipyrrinone analogs, such as (3Z)-[(4,5-dimethylpyrrol-2-yl)-methylidenyl]- indolin-2-one and (3E)-[(1-methylpyrrol-2-y

Full text of DOI:10.1007/s00706-002-0542-3

Monatshefte f€ur Chemie 134, 489–499 (2003)
DOI 10.1007/s00706-002-0542-3
Conformation and Crystal Structure
of Dipyrrinones with Oxindole Components
ꢀ
Stefan E. Boiadjiev and David A. Lightner
Department of Chemistry, University of Nevada, Reno, Nevada 89557, USA
Received August 2, 2002; accepted August 30, 2002
Published online March 6, 2003 # Springer-Verlag 2003
Summary. Pyrrole ꢀ-aldehydes (2-formyl-4,5-dimethyl-1H-pyrrole and 2-formyl-N-methylpyrrole)
condense readily at C(3) of indolin-2-ones to give dipyrrinone analogs, such as (3Z)-[(4,5-dimethyl-
pyrrol-2-yl)-methylidenyl]-indolin-2-one and (3E)-[(1-methylpyrrol-2-yl)-methylidenyl]-indolin-2-
one. 1H-NMR NOE analyses and X-ray crystallography confirm the syn-(Z) configuration for the former
and the syn-(E) configuration for the latter. The former is stabilized by intramolecular hydrogen bonding.
Molecular mechanics calculations of the latter indicate no energy difference between the syn and anti
conformations.
Keywords. Pyrrole; X-ray structure; Hydrogen bonding.
Introduction
Our interest in synthetic bile pigments with aromatic substituents [1–3] and
annelated pyrrole rings led us to prepare and investigate potential dipyrrinone syn-
thons for the latter. Two types of potential precursors are oxisoindole and oxindole,
with the former leading to the conventional bile pigment types. The latter condenses
easily with pyrrole ꢀ-aldehydes, reactions that formed the basis for a study of
antiangiogenic agents targetting at receptor tyrosine kinases [4–6]. In the following
we describe the synthesis of a new potential antiangiogenic agent 1 (Fig. 1) from 2-
indolinone (3) and compare its conformation to that of a known analog 2 using NOE
NMR spectroscopy and X-ray crystallography.
Results and Discussion
Synthesis
3-[(Pyrrol-2-yl)-methylidenyl]-indolin-2-ones 1 and 2 were prepared in excellent
yields by piperidine-catalyzed condensation of 3 with 2-formyl-4,5-dimethylpyrrole
ꢀ
Corresponding author. E-mail: lightner@scs.unr.edu

490
S. E. Boiadjiev and D. A. Lightner
Fig. 1. 3-[(40,50-dimethylpyrrol-2-yl)-methylidenyl]-indolin-2-one (1) and 3-[(N-methylpyrrol-2-yl)-
methylidenyl]-indolin-2-one (2) and 2-oxindole (3), with numbering system consistent with Ref. [4]
(4) [7] and N-methylpyrrole-2-aldehyde (5), respectively, in refluxing methanol
(Scheme 1). The pyrrole aldehydes were prepared by Vilsmeier formylation of
2,3-dimethylpyrrole and N-methylpyrrole [8]. The former was synthesized from
benzyl 4,5-dimethylpyrrole-2-carboxylate.
Constitution and Conformation in Solution
The constitutional structures of 1 and 2 follow from the method of synthesis and
their NMR spectra (Table 1). The signal assignments of Table 1 were secured by
gHMQC and gHMBC NMR experiments. Compound 2 has been reported pre-
viously [4] to adopt an (E)-configuration of the exocyclic carbon–carbon double
bond to alleviate an unfavorable intramolecular steric buttressing between the
N–CH3 and the carbonyl group in the (Z)-configuration isomer. The (E)-configura-
tion of 2 is confirmed by NOEs seen between the aromatic ring 4-H and the pyrrole
30-H, and the syn-conformation is confirmed by an NOE between 60-H and the
N–CH3. In the anti-(Z) configuration, which is favored in 6 [9], one would expect
an NOE between 4-H and 60-H, which is not seen in 2.
The (Z)-configuration of 1 is confirmed by NOEs between 4-H and 60-H, and its
syn-conformation is confirmed by NOEs between the 60-H and 30-H. But very weak
NOEs between the 60-H and the pyrrole NH suggest the presence of some anti
diastereomer. Other NOEs are shown in Fig. 2 by double-headed curved arrows.
Scheme 1

Conformation and Crystal Structure
491
Table 1. Proton and carbon NMR assignments of 1 and 2 in CDCl3 at 25ꢁC
1
2
ꢁC=ppm
ꢁH=ppm
ꢁC=ppm
ꢁH=ppm
2-CO
169.50
113.02
126.32
117.57
121.62
125.76
109.22
137.05
127.93
122.67
120.28
135.44
126.16
–
–
171.15
121.35
122.49
122.40
121.66
128.65
109.91
140.73
128.49
116.02
109.67
127.72
124.23
34.61
–
–
3
–
–
4a
–
–
4
7.45
7.04
7.13
6.89
–
8.12
6.99
7.21
6.92
–
5
6
7
7a
20
30
40
50
–
–
6.56
–
7.15
6.34
6.89
7.63
3.81
–
–
60
7.30
–
N–CH3
40-CH3
50-CH3
CONH
pyr NH
10.83
12.19
–
2.08
2.34
7.84
13.06
–
–
–
8.48
–
–
–
Fig. 2. NOEs observed for 1 and 2 in CDCl3 solvent are shown by solid arrows. Weak NOEs are
shown by dashed arrows. The NOEs observed for 2 are consistent with the (E)-configuration
The unusually deshielded proton on the pyrrole nitrogen of 1 (Table 1) suggests
strong hydrogen bonding, presumably to the lactam carbonyl. In 2 the 4-H is
unusually deshielded (8.12 ppm) compared to 1 (7.45 ppm), but the remaining
aromatic hydrogens all have rather similar chemical shifts (6.89–7.21 ppm).
Interestingly, the aromatic ring carbons show an alternating effect of the (Z) or
(E) configuration, with carbons 5 (121.62, 121.66 ppm) and 7 (109.22, 109.91 ppm)
exhibiting similar chemical shifts, but carbons 4 (117.57, 122.40 ppm), 6 (125.76,
128.65 ppm), and 7a (137.05, 140.73 ppm) showing 3–5 ppm greater deshielding in
2 than in 1.

492
S. E. Boiadjiev and D. A. Lightner
Molecular Structure in the Crystal
Except for an X-ray crystal structure of 3-[(3-(2-carboxyethyl)-4-methylpyrrol-2-
yl)-methylidenyl]-2-indolinone located in the tyrosine kinase domain of fibroblast
growth factor receptor [6], crystal structures of 3-[(pyrrol-2-yl)-methylidenyl]-2-
indolinones appear to be absent. On the protein, the pigment is found to adopt a
syn-(Z) configuration [6].
Single crystals of 1 and 2 were grown from dichloromethane-methanol and from
diffusion of n-hexane vapor into dichloromethane-ethyl acetate, respectively. In
(yellow) crystals of 1, the C(1)–C(4)–C(5)–C(6) ¼ ꢂ 1.8ꢁ and C(4)–C(5)–C(6)–
N(2) ¼ ꢂ 1.5ꢁ torsion angles are both close to zero, which means the molecules
Fig. 3. (A) Crystal structure of 1, top view, with crystal structure numbering used. Top (B) and edge
(C) views of the dimer of 1 found in the crystal. The thermal ellipsoids represent 40% occupancy

Conformation and Crystal Structure
493
(Fig. 3) are planar and adopt the syn-(Z) configuration. The nonbonded distance
˚
between the pyrrole N–H and lactam carbonyl oxygen is only 1.919 A, suggesting
very strong intramolecular hydrogen bonding. Longer intermolecular hydrogen
Fig. 4. Crystal structure of 2, top view (A), with crystal numbering used, and (B) side view showing
nonplanarity of the molecule. (C) Top view of hydrogen-bonded dimer of 2 found in the crystal. The
thermal ellipsoids represent 40% occupancy (20% in (B)

494
S. E. Boiadjiev and D. A. Lightner
bonds between the lactam groups are suggested by the nonbonded distances, but the
two molecules of the hydrogen-bonded pair are not co-planar (Fig. 3B and C). The
dominant factor in stabilizing the syn-conformation in the crystal and in solution
appears to be the strong intramolecular hydrogen bond between the pyrrole NH and
lactam C¼O.
Unlike 1, the crystal structure (Fig. 4) of 2 (yellow plates) confirms the syn-(E)
configuration and shows the molecule to be twisted about the middle, mainly in the
C(5)–C(6) single bond, with torsion angle C(4)–C(5)–C(6)–C(7) ¼ ꢂ 25.3ꢁ. Very
little twisting is observed in the exocyclic carbon–carbon double bond: C(3)–
C(4)–C(5)–C(6) ¼ ꢂ 9.3ꢁ. Like 1, dipyrrinone 2 forms lactam to lactam hydro-
gen-bonded dimers in the crystal, where enantiomeric conformations pair up.
Intramolecular hydrogen bonding may account for the slightly longer C¼O bond
˚
˚
length in 1 (1.249 A) vs. that of 2 (1.229 A) and a wider N(2)–C(6)–C(5) bond angle
in 1 (125.1ꢁ) vs. that of 2 (121.9ꢁ). However, the choice of (Z) or (E) configuration at
C(4)–C(5) does not result in much change in this bond length, nor in the C(5)–C(6)
bond length, and most bond lengths and angles in 1 and 2 are comparable.
Conformational Analysis by Molecular Mechanics Calculations
Computations using PCModel [10a] and Sybyl [10b] show that the syn-Z config-
uration of 1 is planar and favored over the anti rotamer by 13.8–32.2 kJ molꢂ 1
(Table 2). The larger relative total energy found in Sybyl is probably due to an
overestimation of stabilization by hydrogen bonding. In 2, the syn and anti (E)-
isomers are nearly isoenergetic; yet, the NOE data and X-ray crystallographic
study clearly indicates a preference for the syn conformation in solution and in
the solid state. Also, the torsion angle from X-ray crystallography of 2 is less (25ꢁ)
than that found by molecular mechanics (80ꢁ). Possibly, crystal packing forces
come into play to stabilize the more planar conformation of the syn conformation
and shrink the torsion angle.
UV-Visible Spectral Characteristics
The long-wavelength UV-visible maximum absorbance of 1 is significantly shifted
to longer wavelengths than that of 2 in all solvents studied. For the former, solvent
Table 2. Computeda torsion angles ꢁ and relative energies for the syn and anti conformations of 1 and 2
1
2
3-60-20-10
Relative
total Eb=kJ molꢂ 1
3-60-20-10
Relative
total Eb=kJ molꢂ 1
(4-5-6-N)=deg
(4-5-6-N)=deg
syn-(Z)
0.1ꢁ
ꢂ 0.2ꢁ
108.0ꢁ
0.0
syn-(E)
anti-(E)
80.4ꢁ
80.4ꢁ
0.4
0.0
0.0
anti-(Z)
13.8
ꢂ 81.8ꢁ
0.0
108.2ꢁ
32.2
ꢂ 58.2ꢁ
0.0
a
Values using the MMX force field of PCModel v7.5 [10a] and in italics from Tripos’ Sybyl [10b];
relative E ¼ total E (anti) ꢂ total E (syn)
b

Conformation and Crystal Structure
495
Fig. 5. UV-Vis spectra of 10ꢂ 5 M 1 ( — ) and 2 (– – – –) in chloroform (left) and methanol
(right) at 23ꢁC
influence on ꢂmax and "max is relatively small (Fig. 5). Thus, 1 exhibits ꢂmax at
445 nm (" ¼ 34,200) in CHCl3 solvent and ꢂmax at 444 nm (" ¼ 31,600) in DMSO.
In contrast, 2 exhibits ꢂmax 404 (" ¼ 19,100) in CHCl3 and ꢂmax at 381 (" ¼ 19,400)
in DMSO. The ꢃ50 nm longer ꢂmax of 1 (relative to 2) is presumably due to the
more extended and flattened chromophore of the former.
Experimental
1
All NMR spectra were obtained on a Varian Unit Plus spectrometer operating at H frequency of
500 MHz in CDCl3 solvent. Chemical shifts are reported in ꢁ (ppm) referenced to the residual CHCl3
1H signal at 7.26 ppm, and CDCl3 13C signal at 77.00ppm. A J-modulated spin-echo experiment
(Attached Proton Test) as well as 2D HETCOR, gHMQC and gHMBC spectra were used to assign
1
the H and 13C-NMR spectra. UV-visible spectra were measured on a Perkin-Elmer lambda-12 spec-
trophotometer. Melting points were taken on a Mel-Temp capillary apparatus and are uncorrected. Gas
chromatography-mass spectrometry analyses were carried out on a Hewlett-Packard 5890A capillary
gas chromatograph (30 m DB-1 column) equipped with Hewlett-Packard 5970 mass selective detector.
Radial chromatography was carried out on Merck silica gel PF254 with CaSO4 binder, preparative layer
grade, using a chromatotron (Harrison Research, Inc., Palo Alto, CA). Combustion analyses were
carried out by Desert Analytics, Tucson, AZ. The experimental values were within ꢄ 0.3% of the
calculated values. Commercial reagents and HPLC grade solvents were dried and purified following
standard procedures [11]. Oxindole and piperidine were from ACROS. Benzyl 4,5-dimethyl-1H-pyr-
role-2-carboxylate [12], 2,3-dimethyl-1H-pyrrole [7c]. 4,5-dimethyl-2-formyl-1H-pyrrole (4) ([7a, b]
adapted from [13]) and 2-formyl-N-methylpyrrole (5) [8] were synthesized according to literature
procedures.
(3Z)-[(4,5-Dimethylpyrrol-2-yl)-methylidenyl]-indolin-2-one (1, C15H14N2O)
A mixture of 616 mg (5.00 mmol) of 4,5-dimethyl-2-formyl-1H-pyrrole (4) [7, 13], 533mg
(4.00 mmol) of oxindole, 0.21 cm3 (2.00 mmol) of piperidine, and 25cm3 of anh. methanol was heated
at reflux for 8.5 h. After cooling the mixture was chilled overnight at ꢂ 15ꢁ. Then the precipitated
product was collected by filtration and washed with cold CH3OH. Purification by radial chromatog-
raphy (eluting with CH2Cl2–CH3OH ¼ 100:2 to 100:4) and recrystallization from CH2Cl2–CH3OH
afforded pure bright yellow-orange 1. Yield 829mg (87%); mp 271–272ꢁC; 1H-NMR and 13C-NMR

496
S. E. Boiadjiev and D. A. Lightner
data in Table 1; UV=vis (C6H6): ꢂsh ¼ 468 (24700), ꢂmax ¼ 444 (34100), ꢂsh ¼ 423 (26600); (CH3OH):
ꢂsh ¼ 465 (22100), ꢂmax ¼ 439 (32500), ꢂsh ¼ 420 (27900), ꢂmax ¼ 276 (9700)nm (").
(3E)-[(1-Methylpyrrol-2-yl)-methylidenyl]-indolin-2-one (2, C14H12N2O)
Following the procedure above, 2 was synthesized from 533mg (4.00 mmol) of oxindole and 655 mg
(6.00 mmol) of 2-formyl-N-methylpyrrole (5) [8]. After chromatography, the material was recrystal-
lized from CH2Cl2–CH3OH to afford bright yellow 2 [4]. Yield 834 mg (93%); mp 216–217ꢁC;
1H-NMR and 13C-NMR data in Table 1; UV=vis (C6H6): ꢂmax ¼ 404 (18200), ꢂmax ¼ 379 (17700);
(CH3OH): ꢂsh ¼ 403 (20200), ꢂmax ¼ 389 (20800)nm (").
Table 3. Crystal data and structure refinement for 1 and 2
1
2
Formula weight
Crystallized from
Temperature
Formula
238.28
224.26
CH2Cl2=CH3OH
298(2) K
CH2Cl2=ethyl acetate, n-hexane diffusion
298(2) K
C14H12N2O
0.45ꢅ0.22ꢅ0.08
orthorhombic
Pbca
C15H14N2O
0.40ꢅ0.40ꢅ0.08
monoclinic
P2(1)=n
Crystal size [mm]
Crystal system
Space group
Z
4
8
ꢁ
ꢁ
˚
˚
Unit cell dimensions
a ¼ 12.1011(16) A ꢀ ¼ 90
a ¼ 14.231(3) A ꢀ ¼ 90
ꢁ
ꢁ
˚
˚
b ¼ 6.3689(18) A ꢃ ¼ 102.374(16)
b ¼ 7.5238(19) A ꢃ ¼ 90
ꢁ
ꢁ
˚
˚
c ¼ 16.333(4) A ꢄ ¼ 90
c ¼ 21.770(4) A ꢄ ¼ 90
3
˚
3
˚
Volume
1229.6(5) A
2330.9(8) A
Density (calculated)
Absorption coefficient
F(000)
1.287 Mg=m3
0.082 mmꢂ 1
504
1.278 Mg=m3
0.082 mmꢂ 1
944
Crystal habit and color
Theta range for data
collection
plate, yellow
1.91ꢁ to 29.79ꢁ
plate, yellow
1.87 to 22.51ꢁ
Index ranges
ꢂ 1ꢆhꢆ14, ꢂ 8ꢆkꢆ1, ꢂ 19ꢆlꢆ19
ꢂ 15ꢆhꢆ15, ꢂ 8ꢆkꢆ1, ꢂ 23ꢆlꢆ23
Reflections collected
Independent reflections
Completeness to theta ¼
29.79ꢁ (1); 22.51ꢁ (2)
Absorption correction
Max. and min.
2985
6882
2174 [R(int) ¼ 0.0313]
1523 [R(int) ¼ 0.1498]
52.4%
82.0%
empirical
empirical
0.9102 and 0.8771
0.9670 and 0.8741
transmission
Refinement method
Data=restraints=
parameters
full-matrix least-squares on F2
2174=0=164
full-matrix least-squares on F2
1523=0=155
Goodness-of-fit on F2
1.020
1.024
Final R indices
R1 ¼ 0.0596, wR2 ¼ 0.1250
R1 ¼ 0.0642, wR2 ¼ 0.1073
[I>2sigma(I)]
R indices (all data)
Largest diff. peak and
hole
R1 ¼ 0.1288, wR2 ¼ 0.1539
R1 ¼ 0.1743, wR2 ¼ 0.1420
ꢂ 3
ꢂ 3
˚
˚
0.239 and ꢂ 0.159 e A
0.219 and ꢂ 0.196 e A

Conformation and Crystal Structure
497
X-Ray Structure and Solution
Yellow-orange crystals of 1 were grown in CH2Cl2–CH3OH. A suitable crystal (0.40ꢅ0.40ꢅ0.08 mm)
was mounted on a glass fiber, coated with epoxy and placed on the goniometer of a Siemens P4
diffractometer.ꢁUnit cell parameters were determined by least squares analysis of 28 reflections with
ꢁ
˚
5.1 <ꢅ<11.7 using graphite monochromatized MoKꢀ radiation (ꢂ ¼ 0.71073A). A total of 2985
reflections were collected between 3.8ꢁ <2ꢅ<59.7ꢁ yielding 2174 unique reflections (Rint ¼ 0.0313).
The data were corrected for Lorentz, polarization effects and absorption using an empirical model
derived from psi scans. Crystal data are presented in Table 3. Scattering factors and corrections for
anomalous dispersion were taken from a standard source [14]. Calculations were performed with
Siemens SHELXTL Plus (v 5.1) software package [15]. The structure was solved by direct methods
in space group P2(1)=n.
Long yellow plates of 2 were grown by n-hexane vapor diffusion into CH2Cl2-ethyl acetate solu-
tion. A crystal, after cutting to size 0.45ꢅ0.22ꢅ0.08mm, was manipulated as above. Unit cell was
determined by least squares analysis of 24 reflections with 4.7ꢁ <ꢅ<9.9ꢁ and data collection and
analysis proceeded as described above for 1. Crystal data for 2 are given in Table 3. The structure was
solved by direct methods in Pbca space group.
All non-hydrogen atoms were refined with anisotropic thermal parameters. Hydrogen atoms were
˚
placed at ideal positions calculated using a riding model with a C–H distance fixed at 0.96 A and a
thermal parameter 1.2 times the host atoms. The structures were refined by the full-matrix least squares
method on F2. The final refinement converged to R1¼ 0.0596, wR2 ¼ 0.1250 for 1; R1¼ 0.0642,
wR2 ¼ 0.1073 for 2 and goodness-of-fit: 1.020 and 1.024, respectively. Tables 4 and 5 provide atomic
coordinates for 1 and 2, respectively.
Tables of anisotropic displacement parameters, isotropic displacement parameters, atomic coordi-
nates, bond angles and lengths for 1 and 2 have been deposited at the Cambridge Crystallographic Data
Center (CCDC No. 190066 for 1 and 190067 for 2).
4
2
3
˚
Table 4. Atomic coordinates (ꢅ10 ) and equivalent isotropic displacement parameters (A ꢅ10 )
for 1. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor
x
y
z
U(eq)
N(1)
N(2)
O(1)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
956(2)
766(2)
516(2)
916(2)
2953(4)
1299(4)
3641(3)
2446(5)
1355(5)
ꢂ 275(5)
335(5)
ꢂ 293(2)
2379(2)
985(1)
54(1)
53(1)
57(1)
47(1)
49(1)
46(1)
45(1)
50(1)
47(1)
52(1)
50(1)
50(1)
62(1)
72(1)
72(1)
57(1)
65(1)
73(1)
515(2)
1441(2)
1740(2)
1420(2)
1525(2)
1234(2)
1326(2)
898(3)
ꢂ 680(2)
ꢂ 106(2)
673(2)
ꢂ 873(5)
ꢂ 515(5)
1380(2)
2157(2)
2837(2)
3458(2)
3151(2)
ꢂ 1870(5)
ꢂ 869(5)
1105(5)
543(3)
1615(3)
2133(3)
2447(3)
2250(3)
806(3)
1259(6)
ꢂ 1484(2)
ꢂ 1705(2)
ꢂ 1146(2)
ꢂ 342(2)
4302(2)
ꢂ 525(7)
ꢂ 2170(7)
ꢂ 2048(6)
ꢂ 1720(6)
2837(6)
8(3)
3544(2)

498
S. E. Boiadjiev and D. A. Lightner
4
2
3
˚
Table 5. Atomic coordinates (ꢅ10 ) and equivalent isotropic displacement parameters (A ꢅ10 ) for
2. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor
x
y
z
U(eq)
N(1)
N(2)
O(1)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
4335(3)
4062(3)
4814(3)
4447(4)
3952(3)
3780(4)
4071(4)
4100(4)
3735(4)
2986(4)
2870(4)
3558(4)
4859(4)
3764(4)
3401(4)
3261(4)
3444(4)
2086(6)
3931(6)
263(6)
4964(2)
2297(2)
4173(2)
4356(3)
5030(3)
4436(3)
3992(2)
3368(2)
2898(2)
2867(2)
2269(2)
1927(2)
2106(2)
5562(3)
5502(3)
4928(3)
4398(3)
48(1)
47(1)
63(1)
50(2)
45(1)
44(2)
43(2)
54(2)
40(1)
63(2)
62(2)
60(2)
65(2)
60(2)
71(2)
67(2)
61(2)
1644(9)
3791(7)
4460(8)
3131(8)
2982(8)
4045(7)
5229(8)
5805(8)
4975(8)
2851(8)
4688(9)
6418(9)
7122(8)
6156(9)
Acknowledgments
We thank the U.S. National Institutes of Health (HD 17779) for generous support of this research.
Dr. S.E.B. is on leave from the Institute of Organic Chemistry, Sofia, Bulgaria. We thank Dr. G.B.
Quistad for preparing the N-methyl-2-pyrrole aldehyde used in this work. Special thanks are accorded
to Profs. J. Nelson and V.J. Catalano for helpful discussions on the X-ray crystallographic
determinations.
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