Efficient synthesis of functionalized diazacyclopenta[c]pentalene with multiple intermolecular interactions in crystal

Article abstract of DOI:10.3987/COM-10-12102

Dedicated to Professor Nikolay S. Zefirov with recognition of his contributions to organic chemistry and on the occasion of 75th birthday Atom economic synthesis of functionalized polysubstituted racemic diazacyclopenta[c]pentalene 7 has been developed us

Full text of DOI:10.3987/COM-10-12102

HETEROCYCLES, Vol. 83, No. 2, 2011
323
HETEROCYCLES, Vol. 83, No. 2, 2011, pp. 323 - 330. © The Japan Institute of Heterocyclic Chemistry
Received, 10th November, 2010, Accepted, 13th December, 2010, Published online, 17th December, 2010
DOI: 10.3987/COM-10-12102
EFFICIENT
SYNTHESIS
OF
FUNCTIONALIZED
WITH MULTIPLE
DIAZACYCLOPENTA[C]PENTALENE
INTERMOLECULAR INTERACTIONS IN CRYSTAL
Konstantin V. Kudryavtsev
Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie
Gory 1/3, 119991, Moscow, Russian Federation; kudr@org.chem.msu.ru
Dedicated to Professor Nikolay S. Zefirov with recognition of his contributions to
organic chemistry and on the occasion of 75th birthday
Abstract – Atom economic synthesis of functionalized polysubstituted racemic
diazacyclopenta[c]pentalene
7
has been developed using sequential
organocatalytic 1,3-dipolar cycloaddition of azomethine ylide with maleic
anhydride and three successive amide bonds formation induced by interaction of
4-fluorobenzylamine with heterocyclic anhydride 5. Enantiomers of 7 are
connected by Cl-π, H···F and C=O···H intermolecular interactions in crystal.
INTRODUCTION
Different classes of natural compounds are characterized by polycyclic molecular skeletons. Attaching of
functional groups at definite positions of polycyclic scaffold could be responsible for specific biological
activities of natural products and their derivatives through formation of selected ligand-target
interactions.1 Non-aromatic complex carbon- and heteropolycyclic compounds are objects of
diversity-oriented synthesis (DOS) since the possibility to regulate scaffold appendages along the
spherical surface of ligand exists.2 Introduction of different functional groups and/or substituents in
three-dimensional space of polycyclic molecular skeleton allows to generate additional diversity and to
optimize discovered biological activity. The fusion of several non-aromatic rings provides geometrically
well-defined structures that are important for both receptor fitting and covering of pharmaceutically
relevant chemical space.3 Several synthetic strategies including cascade reactions1 and aza-annulations4
are utilized for effective construction of polycyclic skeleton of natural compounds. In this communication
we report a three-step synthetic procedure toward the well-defined functionalized diazatricyclic scaffold 1,
heterocyclic analog of angular triquinane 2,5 that is a constituent of a wide family of sesquiterpene natural

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HETEROCYCLES, Vol. 83, No. 2, 2011
products (Figure 1). The only published method of synthesis of heterocycles 3 possessing molecular
scaffold 1 is based on interaction of N-allyl-N-phenylprolinamides with benzaldehydes.6
R2
H
NH
N
N
N
O
R1
1
2
(±)-3
Figure 1. Structural formulae of octahydro-2,5a-diazacyclopenta[c]pentalene (1), decahydrocyclopenta-
[c]pentalene (2), and known compounds 3 with molecular skeleton 1.
RESULTS AND DISCUSSION
Our approach to functionalized diazacyclopenta[c]pentalene scaffold included three operational steps
(Scheme 1). At the first stage iminoester 4 was synthesized from 4-chlorobenzaldehyde and glutamate
dimethyl ester hydrochloride. Cycloaddition of azomethine ylides generated from iminoesters and
dipolarophiles is a widely used method of synthesis of functionalized pyrrolidines derivatives.7 Typically
interaction of 1,3-dipoles with olefins occurs under Lewis or Bronsted acids catalysis or requires elevated
temperatures.7
O
Cl
O
O
O
F
O
O
O
H2N
N-BocGly
Cl
Et3N, MgSO4
R
+
OMe
CH2Cl2, rt
+
CH2Cl2, rt
THF, rt
NH3
Cl
R
MeO
N
H
N
Cl
O
R
O
MeO
R = CH2CH2COOMe
O
4, quant
(±)-5, 85 %
O
O
additional
diversity points
O
O
3
2
HO
3a
HO
N
1
4
5
MeCN, reflux
N
9a
N
9
O
6
N
Cl
O
R
F
H
Cl
F
7
8
O
R = CH2CH2COOMe
(±)-6
(±)-7, 61 %
Scheme 1. Synthesis of functionalized diazacyclopenta[c]pentalene 7 by sequential 1,3-dipolar
cycloaddition – intramolecular amide bond formation.

HETEROCYCLES, Vol. 83, No. 2, 2011
325
Recently we reported an amino acid catalyzed cycloaddition of activated dipolarophiles (maleimides,
maleic anhydride) to azomethine ylides under mild conditions.8 Cycloadditions of 1,3-azadipoles with
maleic anhydride are insufficiently studied because of the last reagent reactivity towards nucleophilic
species and reagents. Our method8 overcomes these limitations and provides approach to heterocyclic
anhydrides but in case of iminoester 4 leads to pyrrolidine tricarboxylic acid anhydride 5 contaminated
with an amino acid catalyst. To perform reaction homogeneously we have used soluble in non-polar
solvents N-tert-butoxycarbonyl glycine (N-BocGly) as a Bronsted acid catalyst of cycloaddition process9
and succeeded in good yield of functionalized pyrrolidine 5 (Scheme 1). Presumably N-BocGly
protonates iminoester 4 at the first step and subsequent deprotonation of α-position leads to ylide A
formation (Scheme 2). endo-Cycloaddition of maleic anhydride to the reactive species A gives rise to the
stereoselective formation of four stereogenic centers in molecule 5. Relative cis-stereochemistry of
protons at 6-, 6a- and 3a-positions of pyrrolidine ring of heterocyclic anhydride 5 is deduced from the 9.1
3
1
Hz value of J(H6-H6a) constant in compound 5 H NMR spectrum10 and corresponds to our previous
results on cycloaddition of maleic anhydride to other types of azomethines catalyzed by amino acids.8
a
O
O
H
O
O
O
O
b
COOMe
COOMe
3a
6a
6
5
-
N+
Ar
COOMe
4
N
H
OMe
Cl
c
O
A
(±)-5
Scheme 2. endo-Transition state for heterocyclic anhydride 5 formation and possible nucleophilic attack
directions in 5.
Polyfunctional nature of bicyclic anhydride 5 prompted us to study it’s reactivity toward nitrogen
nucleophiles. There are four possible positions for nucleophilic attack in 5 according to number of
carbonyl functions (Scheme 2). The most reactive functionalities should be anhydride carbonyls (Scheme
2, routes a and b) and in case b primary nucleophilic interaction with anhydride could be followed by
cyclization at 4-carboxymethyl group leading to annulation at 3a,4-bond of starting heterocycle 5.
Inramolecular interaction of 5-nitrogen and distal carboxymethyl group (Scheme 2, route c) could provide
annulation at 4,5-bond of starting heterocycle 5. Considered lactamization may take place
spontaneously11a or under elevated temperatures11b and has been used by us for construction of
pyrrolizidin-3-one scaffold.11

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Treatment of THF solution of anhydride 5 with equimolar amount of 4-fluorobenzylamine led to expected
consumption of starting materials (Scheme 1). The progress of the reaction was monitored by 1H NMR of
concentrated at room temperature probes. After the changes in the reaction mixture ceased we observed a
predominant product in 1H NMR. Thorough analysis of obtained 1H NMR data let us to assign structural
formula 6 to the major product (Scheme 1). Formation of substituted octahydropyrrolo[3,4-b]pyrrole 6
corresponds to the discussed above tandem 3a,4-annulation of anhydride 5 induced by
4-fluorobenzylamine (Scheme 2, route b). The second step of this process occurred spontaneously at
remarkably mild conditions: formation of the imide bridge in our recent approach towards
3,6-diazabicyclo[3.2.1]octane scaffold took place at elevated temperatures and in the presence of copper
salt catalyst.12 Subsequent heating of the mixture contained predominantly compound 6 in acetonitrile led
to the isolation after purification of a major component – functionalized diazacyclopenta[c]pentalene 7
(Scheme 1).
Figure 3. Fragment of crystalline structure of 7
along the c crystallographic axis. Intermolecular
contacts Cl(1)-π and F(1)···H(16AB) are shown.
Figure 2. General view of molecule 7 (only
3aS,4S,5S,9aR-enantiomer is shown).
Structure of the novel polysubstituted diazatricycle 7 was unambiguously determined by X-ray analysis
(Figure 2).13 Epimerization of β-carboxylic function took place apparently during the lactamization step at
elevated temperature, all other stereochemical outcomes accord with considered reactions pathways.
Detailed examination of solid state structure of 7 revealed two types of interesting intermolecular
interactions in crystal (Figures 3, 4). The first type of intermolecular contacts comprises rarely observed
CAr–F···H–Cα–N contact14 and more frequent Cl–π interaction15 with both halogen atoms belonging to
one enantiomeric molecule 7 and connecting to the benzylic part of another (Figure 3). The distance
between F(1) and H(16AB) atoms is significantly below the sum of the van der Waals radii (2.67Å) and

HETEROCYCLES, Vol. 83, No. 2, 2011
327
amounts to 2.20 Å (Figure 3). The chlorine atom Cl(1) is located 3.50 Å from aromatic carbon C(19A)
(Figure 3). This distance practically coincides with 3.45 Å sum of chlorine-carbon van der Waals radii
and appropriate interaction could provide up to 2 kcal/mol energetic benefit.15a Both types of observed in
7 non-covalent bonding exampled in complexes of thrombin with small-molecule inhibitors.
CAr–F···H–Cα–C=O contact has been observed in inhibitor-enzyme complex for 4-fluorobenzyl fragment
of an inhibitor and Asn98 in the S3-pocket of the thrombin active site.14 Chlorine–π contacts are
characteristic for chloroaryl fragments of small-molecule inhibitors interacting with Tyr228 in the
S1-pocket of the thrombin active site.15 We have tested diazacyclopenta[c]pentalene 7 on thrombin
inhibition activity and unfortunately found only poor enzyme inactivation.16 Another type of
intermolecular interactions in crystal of 7 represents canonical hydrogen bonds between carbonyl oxygen
atoms and carboxylic protons (Figure 4). Two mirror enantiomers of fused diazatricycle 7 are connected
by two practically linear O···H–O interactions forming 16-membered circular chain (Figure 4).
F
O
O
HO
Ar
O
O
N
N
Ar
N
N
O
O
OH
O
O
F
16-membered cycle
Figure 4. H-bonded dimer of 7: O2-HO2 0.82, HO2-O1A 1.85, O2-O1A 2.667(3) Å; angle O2-HO2-O1A 173°.
In conclusion we have developed short and convenient synthetic approach towards functionalized
octahydro-2,5a-diazacyclopenta[c]pentalene (1) scaffold. It was demonstrated the effectiveness of
application of N-tert-butoxycarbonyl α-amino acid as a homogeneous organocatalyst of 1,3-dipolar
cycloaddition of activated dipolarophile to azomethine. The method is characterized by good atom
economy with only one molecule of water and two molecules of methanol excreted during the whole
synthetic cycle. Different intermolecular interactions in functionalized diazacyclopenta[c]pentalene 7
monocrystal could be used in crystal engineering and structure-based design of enzymes inhibitors.
EXPERIMENTAL
Reagents were obtained from Alfa Aesar and used without further purification unless otherwise stated.

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Solvents were dried using standard procedures. Reactions were monitored by thin layer chromatography
(TLC) on precoated silica gel plates (Sorbfil) with a UV indicator. Melting points were determined in
13
open capillary and are uncorrected. 1H NMR and C NMR spectra were recorded with a Bruker Avance
400 MHz spectrometer. The chemical shifts (δ) are reported in parts per million upfield using residual
signals of solvents as internal standards. Coupling constants (J values) were measured in hertz (Hz).
Combustion analyses were performed with a Carlo Erba CHN analyzer.
Dimethyl 2-(4-chlorobenzylideneamino)pentanedioate (4)
Under argon atmosphere 5.02 ml (3.643 g, 36 mmol) of NEt3 were added to a suspension of 7.620 g (36
mmol) of glutamic acid dimethyl ester hydrochloride and 7.222 g (60 mmol) of MgSO4 in 100 mL of
CH2Cl2. After 1 h stirring at rt 4-chlorobenzaldehyde (4.217 g, 30 mmol) was added and the resulted
mixture was stirred at rt overnight. The solid was removed by filtration and the filtrate was washed once
with H2O. The aqueous phase was extracted once with 30 mL of CH2Cl2 and the combined organic layers
were washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated. The
product was isolated as yellowish oil, 8.900 g (100%), and used in the next step without additional
purification. 1H NMR (400 MHz; CDCl3):  8.26 (s, 1H, CH=), 7.72 (d, J = 8.4, 2H, Ar), 7.40 (d, J = 8.4,
2H, Ar), 4.06 (dd, J = 8.0, 5.0, 1H, CHN), 3.76 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 2.43-2.21 (m, 4H,
CH2CH2).
Methyl (3aR*,4S*,6R*,6aS*)-6-(4-chlorophenyl)-4-(3-methoxy-3-oxopropyl)-1,3-dioxohexahydro-
1H-furo[3,4-c]pyrrole-4-carboxylate (5)
Iminoester 4 (4.500 g, 15.1 mmol) was dissolved in 20 mL of CH2Cl2 under air atmosphere and CH2Cl2
solutions of 1.480 g of maleic anhydride (15.1 mmol) and 0.264 g N-BocGly (1.5 mmol) were added
sequentially. The mixture was stirred for 24 h at rt. The solution was concentrated under reduced pressure,
and the residue was recrystallized from hexane/CH2Cl2. 5.083 g (85%), colorless crystals, mp 96-99 °C.
1H NMR (400 MHz; DMSO-d6):  7.42-7.37 (m, 4H, Ar), 4.70 (d, J = 9.1, 1H, H6), 3.98 (dd, J = 9.1, 7.8,
1H, H6a), 3.75 (d, J = 7.8, 1H, H3a), 3.72 (s, 3H, OCH3), 3.58 (s, 3H, OCH3), 2.58-2.52 (m, 1H, CH2),
13
2.18-2.14 (m, 2H, CH2), 2.10-2.02 (m, 1H, CH2). C NMR (100 MHz; DMSO-d6):  173.07, 171.89,
171.23, 170.31, 137.99, 132.61, 129.44 (2C), 128.54 (2C), 70.40, 59.87, 55.64, 52.61, 51.92, 50.38, 29.60,
28.54. Anal. Calcd for C18H18ClNO7: С, 54.62; Н, 4.58; N, 3.54. Found: С, 54.79; Н, 4.55; N, 3.81.
(3aR*,4R*,5R*,9aS*)-5-(4-Chlorophenyl)-2-(4-fluorobenzyl)-1,3,7-trioxooctahydro-7H-pyrrolo[3,4-
g]pyrrolizine-4-carboxylic acid (7)
Anhydride 5 (1.000 g, 2.53 mmol) was dissolved in 25 mL of dry THF and 0.300 mL (0.320 g, 2.53
mmol) of 4-fluorobenzylamine were added to the solution. The mixture was stirred for 72 h at rt,
concentrated under reduced pressure, and the residue was redissolved in 25 mL of MeCN. The solution

HETEROCYCLES, Vol. 83, No. 2, 2011
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was heated at 82 °C for 24 h, concentrated and the residue was recrystallized from CH2Cl2/MeOH. 0.703
g (61%), colorless crystals, mp 282-283 °C. 1H NMR (400 MHz; DMSO-d6):  13.36 (br.s, 1H, COOH),
7.15 (d, J = 8.6, 2H, Ar), 7.04-7.02 (m, 2H, Ar), 7.01-6.94 (m, 4H, Ar), 5.42 (s, 1H, H5), 4.27-4.16 (m,
2H, CH2Ar), 3.76 (s, 1H, H4), 3.67 (s, 1H, H3a), 2.99 (ddd, J = 16.4, 11.2, 9.2, 1H, H8), 2.58 (dd, J = 12.8,
9.2, 1H, H8), 2.45-2.39 (m, 1H, H9), 2.30 (dd, J = 12.8, 11.2, 1H, H9). 13C NMR (100 MHz; DMSO-d6): 
178.06, 177.69, 175.66, 173.24, 161.94 (J 243.7), 137.34, 132.90, 131.23, 130.72, 130.64, 128.94 (2C),
127.04 (2C), 115.68, 115.47, 73.10, 61.57, 53.93, 52.41, 41.88, 32.89, 29.73. Anal. Calcd for
C23H18ClFN2O5: С, 60.47; Н, 3.97; N, 6.13. Found: С, 60.69; Н, 4.05; N, 6.01.
Crystal structure determination of compound 7.
The single crystal of 7 of approximate dimensions 0.40 x 0.20 x 0.20 mm was mounted in inert oil on the
top of glass fibre and transferred on the Bruker SMART APEX II diffractometer. Crystal data:
C23H18ClFN2O5, M = 456.84, monoclinic, a = 13.6113(18), b = 12.5729(18), c = 12.4174(16) Å, β =
108.234(4)°, V = 2018.3(5) Å3, space group P21/c, Z = 4, Dc = 1.503 g/cm3, F(000) = 944, µ(Mo-K) =
0.239 mm-1. Total of 18287 reflections (4187 unique, Rint = 0.0457) were measured using graphite
monochromatized Mo-K radiation (λ = 0.71073 Å) at 100 K. Data were collected in the range 1.58 < θ
< 26.54 (-17 ≤ h ≤ 17, -15 ≤ k ≤ 15, -15 ≤ 1 ≤ 15). The structure was solved by direct methods17 and
refined by full matrix least-squares on F2. All H atoms (except HO2) were placed in calculated positions
and refined using a riding model. The final residuals were: R1 = 0.0527, wR2 = 0.0981 for 3076
reflections with I > 2σ(I) and 0.0784, 0.1079 for all data and 289 parameters. Goof = 1.108, maximum Δρ
= 0.487 e/Å3.
ACKNOWLEDGEMENTS
This research was kindly supported by Russian Foundation for Basic Research (grants 08-04-01800-a and
09-03-92011-HHC_a) to K.V.K. Ms. Alexandra O. Borissova is acknowledged for X-ray investigation of
compound 7.
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