Synthesis and photochemical cyclization of a novel enyne-carbodiimide

Article abstract of DOI:10.3390/51201372

The triplet sensitized cyclization of enyne-carbodiimide 4 leads to efficient formation of indoloquinoline 5 with concomittant loss of a methyl group. The efficient loss of the methyl group was explained using AM1 semiempirical calculations.

Full text of DOI:10.3390/51201372

Molecules 2000, 5, 1372-1378
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis and Photochemical Cyclization of a Novel Enyne-
Carbodiimide
Michael Schmittel,* David Rodríguez 1 and Jens-Peter Steffen
FB 8 - OC1 (Chemie und Biologie), Universität Siegen, Adolf-Reichwein-Strasse, D-57068 Siegen,
Germany. Tel. (+49)-271-4356, Fax (+49) 271-3270. E-mail: schmittel@chemie.uni-siegen.de.
1 Present address: Facultad de Química, Universidad de Santiago de Compostela, Spain.
Received: 21 July 2000 / Accepted: 19 October 2000 / Published: 20 December 2000
Abstract: The triplet sensitized cyclization of enyne-carbodiimide 4 leads to efficient formation
of indoloquinoline 5 with concomittant loss of a methyl group. The efficient loss of the methyl
group was explained using AM1 semiempirical calculations.
Keywords: Carbodiimides; diradicals; enynes; photocyclization; triplet.
Introduction
Thermal diradical cyclizations of enediynes (Bergman) [1] and enyne-allenes (Myers-Saito) [2] have
attracted a lot of attention due to their key role in the mode of action of natural enediyne antitumor
antibiotics [3]. Over many years, however, other cyclization pathways in these systems have been
neglected, until we [4] and others [5] were able to control deliberately the regioselectivity of the thermal
cyclization of enyne-allenes towards fulvene diradicals (cf. C2-C6 cyclization).
C1-C5
Bergman
cycl.
cycl.
C2-C6
cycl.
Myers-Saito
cycl.
© 2000 MDPI. All rights reserved.

Molecules 2000, 5
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Recently, it was demonstrated that the thermal C2-C6 cyclization of enyne-carbodiimides and enyne-
ketenimines [6] can be complemented by a very efficient triplet sensitized photochemical route [7]. As the
latter reaction has important consequences with regards to the development of photoactive prodrugs, e.g.
in approaches to the ellipticine family [8], we have now investigated the photocyclization of enyne-
carbodiimide 4 whose N-phenyl terminus is sterically blocked using methyl groups. The present results
indicate that the efficient photoreaction of this compound is composed of a cascade of three individual
steps: diradical cyclization, ring closure on the stage of the diradical, and methyl group loss.
Results and Discussion
Enyne-carbodiimide 4 was synthesized as usual via the corresponding thiourea 3. However, preparation
of 3 was found to be much more problematic than expected. First, the reactivity of 2,6-dimethylphenyl
isothiocyanate (2) was reduced as compared to other aryl substituted isothiocyanates, presumably because
of steric hindrance caused by the ortho-methyl substituents, so that under usual reaction conditions
(ethanol, room temperature) only small amounts of 3 were produced (≤28%) from 1 and 2. On the other
hand, at elevated temperature (e.g. at the boiling point of ethanol) an undesired intramolecular cyclization
product resulted. Optimization of the reaction conditions and use of acetone as solvent [9] finally led to
isolation of 3 in 68% yield. Carbodiimide 4 was synthesized from 3 in 86% yield according to a method
described by Fell and Coppola [10] which allows for a fast and highly efficient preparation under mild
conditions using methanesulfonyl chloride and triethylamine (Scheme 1).
Ph
Ph
Me
DMAP
acetone
Me
Me
Me
S
+
50 °C, 4.5 d
68%
NH2
SCN
N
H
N
H
Me
Me
1
2
3
Ph
MeSO2Cl, NEt3
DMAP, CH2Cl2
Me
Me
0 °C, 10 min
86%
N
N
Me
4
Scheme 1.
Irradiation of 4 led to formation of indoloquinoline 5 in high yield (83%) when it was carried out using
triplet sensitization (toluene as triplet sensitizer at λ = 254 nm with ET = 83 kcal mol-1) [11] for 60 min. In
contrast, when 4 was irradiated without triplet sensitization (toluene, λ = 300 nm) no reaction was
observed after 90 minutes.

Molecules 2000, 5
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Previous mechanistic results [7] exclude a singlet reaction and suggest a pathway via the triplet excited
state of the carbodiimide unit [12] which then triggers ring closure to the biradical 6, formally by an 5-exo-
dig cyclization. 6 can be understood as a triplet analogue of the biradical that is formed in the thermal C2-
C6 cyclization of enyne-(hetero)allenes [4,6]. Direct combination of the two radical sites could lead to the
strained tricycle 8 with an azet ring but this is not observed. Instead, intramolecular cyclization takes place
at the 2,6-dimethylphenyl ring yielding the cross-conjugated tetracycle 7. A concerted Diels-Alder
cyclization 4 → 7 under these conditions can be excluded both on theoretical arguments (it would violate
the Woodward-Hoffmann rules [13]), and on steric grounds (the steric shielding of the methyl groups at
the N-phenyl terminus should prevent C-C bond formation).
Ph
Ph
Me
hν (254 nm)
Me
toluene
Me
N
N
60 min
83%
N
H
N
Me
Me
4
5
hν
Ph
*
Me
Me
Ph
N
N
Me
Me
Me
Me
N
N
Me
7
Ph
Ph
N
Me
Me
Me
N
N
N
Me
Me
6
8
Scheme 2.
Importantly, we have not been able to detect any trace of compound 7 in the product mixture [14],
which indicates that the final rearomatization step 7 → 5 involving methyl group loss should be a very
facile step in the overall reaction. To understand the mechanistic situation, we have calculated part of the
energy hypersurface of the triplet reaction using the semiempirical AM1 method.[15]

Molecules 2000, 5
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∆Hf
[kcal mol-1]
34
219
37
9 + 10
191
191
reaction coordinate
Ph
Me
Me
N
N
Me
9
10
Figure 1. Heat of formation ∆Hf (see italic numbers, calculated by AM1 without C.I.) of
the triplet excited key intermediates in the photochemical transformation 4 → 9 + 10.
Interestingly, the calculations indicate clearly that starting from the triplet excited 7 (∆Hf = 191 kcal mol-1)
a roughly thermoneutral homolytic bond cleavage reaction to radical 9 (∆Hf = 160 kcal mol-1) and the
methyl radical (10) is possible (∆Hf = 31 kcal mol-1). The energy to populate the triplet excited 7 could in
principle be derived from the initial photochemical excitation of 4, as the reaction of 34 to the triplet
3
excited 7 is overall exothermic by 28 kcal mol-1. Hydrogen abstraction from toluene will then allow for
the reaction 9 → 5 thus completing the reaction sequence.
Conclusions
An unusual photocyclization was presented incorporating a diradical cyclization, ring closure of the
diradical and methyl loss which occurs at good yield (83%). Semiempirical calculations indicate that all
steps take place on the stage of triplet excited species.
Experimental
General
All melting points are uncorrected. 1H- and 13C-NMR spectra were obtained using a Bruker AC200 or
AM250 and were recorded at 200/250 and 50/63 MHz respectively. IR spectra were recorded on a Perkin-
Elmer 1605 FT-IR spectrometer. Elemental analyses were carried out on a Bruker Elemental Analyzer
1106. 4-Methyl-2-phenylethynyl aniline was synthesized according to literature procedure [16] and

Molecules 2000, 5
1376
characterized by comparison to literature [17]. All other reagents and chemicals were commercially
available and used as received.
N-(2,6-Dimethylphenyl)-N'-(4-methyl-2-phenylethynyl) thiourea (3)
4-Methyl-2-phenylethynylaniline (500 mg, 2.41 mmol), 2,6-dimethylphenyl isothiocyanate (377 mg,
2.31 mmol) and catalytic amounts of N,N-dimethylamino pyridine (DMAP) were dissolved in acetone (5
mL) and stirred at 50 °C until reaction control by TLC showed complete disappearance of the
isothiocyanate (4.5 d). Column chromatography on silica gel (Rf 0.25, petroleum ether/CH2Cl2/ethyl
1
acetate 20/7/2) yielded 3 as a pale yellow solid (580 mg, 1.57 mmol, 68%): m.p. 169-170 °C; H-NMR
(CDCl3) δ: 2.28 (br s, 9H, CH3), 6.87-7.25 (m, 7H), 7.29-7.38 (m, 3H), 7.59 (br s, 1H, NH), 7.97 (br s, 1H,
NH), 8.41 (d, 1H, J = 9.1); most signals are broadened because of coalescence; 13C-NMR (CDCl3) δ:
18.11, 20.66, 84.00, 95.07, 115.63, 122.24, 123.63 (br), 128.09, 128.70, 128.88 (br), 129.43 (br), 131.76,
132.28 (br), 132.70, 134.55, 136.82, 137.25, 179.18; several signals are broadened because of coalescence,
two signals coincide; IR (neat) cm-1: 3336, 3155, 2923, 2214, 1585, 1535, 1346, 1266; elemental analysis
for C24H22N2S: Calcd C 77.80, H 5.98, N 7.56, S 8.65; Found C 77.31, H 5.92, N 7.48, S 8.44.
N-(2,6-Dimethylphenyl)-N'-[4-methyl-2-(phenylethynyl)phenyl] carbodiimide (4)
Thiourea 3 (56.8 mg, 153 µmol) was dissolved in anhydrous CH2Cl2 under an atmosphere of nitrogen
and, after addition of triethylamine (70 µL, 51.1 mg, 505 µmol) and catalytic amounts of DMAP,
methanesulfonyl chloride (35 µL, 51.5 mg, 356 µmol) was added dropwise via syringe under vigorous
stirring and cooling in an ice bath. The mixture was stirred for 10 more minutes. Then the solvent was
removed in vacuo and 4 was isolated from the crude mixture by column chromatography (Rf 0.64,
conditions see 3) as a yellow oil (44.4 mg, 132 µmol, 86%) that crystallized on standing at -30 °C and that
is not stable in CDCl3 for longer times: m.p. 47 °C (DSC); 1H-NMR (CDCl3) δ: 2.34 (s, 3H, CH3), 2.36 (s,
6H, CH3), 6.88-7.00 (m, 3H), 7.05 (d, 1H, J = 8.1), 7.08-7.29 (m, 6H), 7.35 (s, 1H); 13C-NMR (CDCl3) δ:
19.01, 20.63, 86.20, 95.78, 118.75, 122.77, 123.85, 124.89, 127.97, 128.05, 130.18, 131.29, 132.20,
133.16, 133.55, 134.11, 134.84, 135.01, 137.46; IR (neat) cm-1: 3054, 3025, 2979, 2948, 2150 (N=C=N),
1593, 1477, 1202; elemental analysis for C24H20N2: Calcd C 85.68, H 5.99, N 8.33; Found C 85.33, H
6.08, N 8.13.
Photolysis
Photolysis of a degassed solution of 4 (20.0 mg, 59.4 µmol) in toluene (14 mL, c = 4.2 mM) was carried
out in a Rayonet RPR-100 Photochemical Reactor, fitted with 16 RPR 253.7 nm lamps. The solution was
placed in a quartz flask under a nitrogen atmosphere and irradiated for 60 minutes (internal water cooling
to 20 ± 5 °C). When reaction control by TLC showed complete disappearance of 4 the solvent was

Molecules 2000, 5
1377
removed in vacuo and 5 was isolated by column chromatography on neutral alumina (Rf 0.38,
n-hexane/ethyl acetate 6/1) as a yellow solid (16.0 mg, 49.6 µmol, 83%).
4,9-Dimethyl-11-phenyl-6H-indolo[2,3-b]quinoline (5)
m.p. 236.5-238 °C; 1H-NMR (CDCl3) δ: 2.27 (s, 3H, CH3), 2.94 (s, 3H, CH3), 6.80 (s, 1H), 7.22 (d, 1H,
J = 8.3), 7.28 (d, 1H, J = 8.3), 7.28 (dd, 1H, J = 8.2, 6.7), 7.52-7.56 (m, 2H), 7.59-7.68 (m, 5H), 9.54 (br s,
1H, NH); 13C-NMR (CDCl3) δ: 18.88, 21.38, 110.16, 115.88, 121.38, 122.47, 123.25, 123.70, 124.55,
128.43, 128.80, 128.87, 129.08, 129.21, 129.34, 134.65, 136.91, 138.92, 142.67, 145.63, 152.33; IR (KBr)
cm-1: 3166, 3055, 2967, 2944, 1614, 1599, 1487, 1382, 1220; elemental analysis for C23H18N2: Calcd C
85.68, H 5.63, N 8.69; Found C 85.19, H 5.97, N 8.51.
Calculations
Calculations were performed using the semiempirical AM1 method as implemented on a PC. The
following results were obtained (without C.I.): 34 (∆Hf = 218.6 kcal mol-1), 37 (∆Hf = 191.4 kcal mol-1), 9
3
(∆Hf = 159.7 kcal mol-1), 10 (∆Hf = 31.2 kcal mol-1). Inclusion of C.I. (3,3) leads to similar results: 4
(∆Hf =215.5 kcal mol-1), 37 (∆Hf =186.8 kcal mol-1), 9 (∆Hf =153.6 kcal mol-1), 10 (∆Hf =28.5 kcal mol-1).
The C.I. (3,3) results were not used as the experimental ∆Hf (10) = 35 kcal mol-1 was reproduced better
without C.I. [18].
Acknowledgements
We would like to express our gratitude to the Deutsche Forschungsgemeinschaft, the Volkswagen-
Stiftung, the Fonds der Chemischen Industrie, and the Ministerio de Educación y Ciencia (Spain) for
generous support of this research.
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Samples Availability: Not available.
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