Intramolecular heteroconjugate addition of heterocumulenes to α,β- unsaturated carbonyl compounds promoted by the CS2/TBAF system

Article abstract of DOI:10.1016/S0040-4039(00)00756-5

We describe a new method for the preparation of dihydroquinazoline-2- thione and 4H-3,1-benzothiazine-2-thione derivatives by intramolecular heteroconjugate addition of carbodiimides or isothiocyanates bearing one o- substituted α,β-unsaturated carbonyl f

Full text of DOI:10.1016/S0040-4039(00)00756-5

Tetrahedron Letters 41 (2000) 4895±4899
Intramolecular heteroconjugate addition of heterocumulenes
to a,b-unsaturated carbonyl compounds promoted by the
CS2/TBAF system
Alberto Tarraga,* Pedro Molina* and Juan Luis Lopez
Â
Departamento de Quõmica Organica, Facultad de Quõmica, Universidad de Murcia, Campus de Espinardo,
Â
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E-30071 Murcia, Spain
Received 14 March 2000; accepted 10 May 2000
Abstract
We describe a new method for the preparation of dihydroquinazoline-2-thione and 4H-3,1-benzothiazine-
2-thione derivatives by intramolecular heteroconjugate addition of carbodiimides or isothiocyanates bearing
one o-substituted a,b-unsaturated carbonyl fragment promoted by the CS2/TBAF system. # 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: Aza-Wittig reaction; azaheterocycles; intramolecular hetero-Michael addition; carbodiimide; isothiocyanate.
The conjugate addition of heteronucleophiles to activated alkenes has often been used in
organic synthesis to prepare compounds with heteroatoms b to various activating functional
groups.1 In particular, the aza-Michael addition is noteworthy as a widely used method for
the C±N bond formation.2 Several procedures exist for the intramolecular and intermolecular
aza-Michael addition of amides,3 urea,4 carbamates,5 thiolactam6, guanidines7 and hydrazine
derivatives8 to electron de®cient alkenes. However, the use of heterocumulenes as nitrogen
nucleophiles is very rare.
It is known that N,N0-diarylcarbodiimides bearing one o-vinyl substituent undergo a thermally
induced 6p-electrocyclization to give quinoline derivatives.9 In this context, we have reported the
®rst example of an intramolecular heteroconjugate addition of carbodiimides to a,b-unsaturated
esters promoted by tetrabutylammonium ¯uoride (TBAF) to give rise to dihydroquinazolinone
derivatives, which represents a formal ureidocyclization process.10
We now address the potentiality of this approach to elaborate new dihydroquinazoline
derivatives which are of immense importance in the quinazoline series, mainly because their
diverse reactions make them convenient intermediates11 as well as in the pharmaceutical
discovery research ®eld. While we were preparing this manuscript, a paper reporting the synthesis
* Corresponding author. Fax: +34 968 364149.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00756-5

4896
of dihydroquinazoline derivatives via intramolecular hetero-Michael addition of ureas to o-
substituted a,b-unsaturated esters appeared.12 This prompts us to report our own results on the
TBAF-promoted cyclization of heterocumulenes as a preliminary communication.
In this work we wish to report the peculiar reactivity of carbodiimides 2 and the isothiocyanate
4 toward the CS2/TBAF system.13 The aza-Wittig reaction of iminophosphorane 114 with
isocyanates in dry dichloromethane gave the corresponding carbodiimides 2, which were used for
the next step without puri®cation. When compounds 2 were treated with the CS2:TBAF system
(4:1 molar ratio) at room temperature for 3 h, the dihydroquinazolinethione derivatives 3 were
obtained in yields ranging from 45 to 50%15 along with a small amount of its oxo-analog.
Iminophosphorane 1 also reacted with CS2 at 40ꢀC to give the expected isothiocyanate 4, which
by treatment with the CS2/TBAF system under the same reaction conditions a€orded the 4H-3,1-
benzothiazine-2-thione 5 in 60% yield (Scheme 1). When a 1:1 molar ratio was used, the yields
were somewhat lower and the conversion required longer reaction times.
Scheme 1. Reagents and conditions: (a) R-NCO, CH2Cl2, rt; (b) CS2/TBAF, rt; (c) CS2/40ꢀC
In spite of the moderate yields for the conversions 1!3 and 1!5, and considering the number
of steps: aza-Wittig reaction, activation of heterocumulene moiety and ®nally cyclization, the
yields may be considered as good. The reaction also works with N-aryliminophosphoranes
bearing an a,b-unsaturated ester moiety in the ortho position. Thus, the iminophosphorane 616
was converted into the dihydroquinazoline-2-thione 7 in 45% yield by sequential treatment with
p-tolylisocyanate and the CS2:TBAF system (4:1 molar ratio) under the same conditions.
Likewise, formation of 8 was achieved in 35% yield by initial conversion into the corresponding
isothiocyanate by aza-Wittig reaction with CS2 followed by TBAF-promoted cyclization17
(Scheme 2).
A double annelation process took place when a bis(iminophosphorane) was used as starting
material. Bis(iminophosphorane) 9 was prepared in high yield by a two-step sequence: (a)
condensation of o-azidobenzaldehyde with acetone under basic conditions (58%); and (b)
Staudinger reaction of the resulting bis(azide) with triphenylphosphine (70%). Conversion of the
bis(iminophosphorane) 9 into the bis(dihydroquinazoline-2-thione) derivative 10 was achieved in
40% yield by using the above-mentioned protocol (Scheme 2).
In these transformations one stereogenic center is formed and the NMR spectra data of
compounds 3, 5, 7, 8 and 10 therefore deserve some comment.18

4897
Scheme 2. Reagents and conditions: (a) R-NCO, CH2Cl2, rt; (b) CS2/TBAF, rt; (c) CS2/40ꢀC
As far as the mechanism for this kind of cyclization is concerned, we think that the interaction
of the TBAF with CS2 must give rise to a highly reactive S-nucleophile like 11, with more
nucleophilic character than the water present in the reaction medium, which by nucleophilic
attack on the central atom of the heterocumulene portion strongly increases the nucleophilic
character of the heteroatom (S or N) promoting an intramolecular N- or S-conjugate addition to the
o-unsaturated side chain in a Michael-type fashion followed by cleavage of the 2-thiosubstituent
of the resulting cyclized product either by the water present in the TBAF/THF solution or during
the work-up. This mechanism shown in Scheme 3 remains highly speculative. However, we feel it
best explains the available experimental results.
Scheme 3.
The work described herein is noteworthy in the following three points. Firstly, the behavior of
the carbodiimide moiety as a synthetic equivalent of the thiourea as speci®c N-nucleophile; this
fact is quite important as thiourea is known as a typical ambident nucleophile and generally
serves as the S-nucleophile towards electrophile centers. Secondly, the action of the TBAF on the

4898
CS2 generates a highly reactive S-nucleophile able to react under mild conditions with the central
carbon atom of the heterocumulene promoting a new class of thioureido cyclization, being the
CS2 the only source of sulfur. In this context, we have also found that alkyl halides are converted
in almost quantitative yield into the corresponding trithiocarbonates by the action of the CS2/
TBAF system. Thirdly, regardless of the mechanistic aspects, this kind of cyclization constitutes a
direct access to sulfur-functionalized azaheterocycles, since the described reactions are carried
out directly with the starting iminophosphorane without the isolation of the heterocumulene
intermediates.
Acknowledgements
We gratefully acknowledge the ®nancial support of DGES (MEC) (project number PB95-
1019). J.L.L. also thanks the Fundacion Seneca (CARM) for a studentship.
References
1. Jung, M. E. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 4, p. 1.
2. Perlmutter, P. In Conjugate Addition Reactions in Organic Synthesis, Tetrahedron Organic Chemistry Series;
Baldwin, J. E.; Magnus, P. D., Eds.; Pergamon Press: Oxford, 1992; Vol. 9.
3. Ahn, K. H.; Lee, S. J. Tetrahedron Lett. 1994, 35, 1875±1878.
4. Kumar, S.; Saini, R.; Singh, H. Tetrahedron Lett. 1992, 33, 7937±7940.
5. Hirama, M.; Shigemoto, T.; Yamazaki, Y.; Ito, S. J. Am. Chem. Soc. 1985, 107, 1797±1798.
6. (a) Fang, F. G.; Prato, M.; Kim, G.; Danishefsky, S. J.; Tetrahedron Lett. 1989, 30, 3625±3628. (b) Maggini, M.;
Prato, M.; Ranelli, M.; Scorrano, G. Tetrahedron Lett. 1992, 33, 6537±6540.
7. (a) Murphy, P. J.; Williams, H. L.; Hursthouse, M. B.; Malik, K. M. A. Chem. Commun. 1994, 119±120. (b)
Murphy, P. J.; Williams, H. L. Chem. Commun. 1994, 819±820. (c) Saito, T.; Tsuda, K.; Saito, Y. Tetrahedron
Lett. 1996, 37, 209±212.
8. Enders, D.; Muller, S. F.; Raabe, G.; Runsink, J. Eur. J. Org. Chem. 2000, 879±892.
9. Molina, P.; Vilaplana, M. J. Synthesis 1994, 1197±1218.
10. (a) Molina, P.; Aller, E.; Lorenzo, A. Synthesis 1998, 283±287. (b) Tarraga, A.; Molina, P.; Curiel, D.; Lopez, J. L.;
Velasco, M. D. Tetrahedron, 1999, 55, 14701±14718.
11. Brow, D. J. In Comprehensive Heterocyclic Chemistry; Katrizky, A. R.; Rees, C. W., Eds.; Pergamon Press:
Oxford, 1984; Vol. 3, p. 57.
12. Xin, Z.; Pei, Z.; von Geldem, T.; Jirousek, M. Tetrahedron Lett. 2000, 1147±1150.
13. The blood red CS2/TBAF system was prepared by slow addition of the appropriate amount of 1 M TBAF in THF
to an excess of CS2 and vigorous stirring of the resulting mixture for 10 min at room temperature.
14. Molina, P.; Tarraga, A.; Lopez, J. L.; Martõnez, J. C. J. Organomet. Chem. 1999, 584, 147±158.
15. General procedure for the preparation of 3, 7 and 10: To a solution of the appropriate iminophosphorane (0.84
mmol) in ahydrous CH2Cl2 (15 ml) a solution of an equimolar amount of the adequate isocyanate, in the same
solvent (5 ml) was added under nitrogen; the resultant mixture was stirred at room temperature for 8 h and then
the preformed CS2/TBAF system [1 M TBAF/THF (water content 5 wt.%): 3.52 ml and CS2: 0.85 ml] was added
and stirring was continued until the carbodiimide band had completely dissappeared from the IR spectra. The
crude was poured into Na2HPO4 bu€er (pH 7, 20 ml), extracted with CH2Cl2 (3Â50 ml) and dried (MgSO4). After
®ltration, the solution was concentrated to dryness and chromatographed on a silica gel column, using ethyl
acetate:n-hexane (1:1) as eluent to give 3, 7 and 10.
16. Molina, P.; Alajarõn, M.; Vidal, A.; Sanchez-Andrada, P. J. Org. Chem. 1992, 57, 929±939.
17. General procedure for the preparation of 5 and 8: A solution of the corresponding iminophosphorane (0.084 mmol)
in CS2 (30 ml) was heated at 40ꢀC under nitrogen, overnight. When the formation of the isothiocyanate was

4899
complete, the solution was allowed to cool at room temperature and then the preformed CS2/TBAF system was
added. From this step, the work-up followed was the same as that described above.
18. The Fc-CO-CH2 protons were diastereotopic, appearing in compounds 3 as two double doublets in the region
2.91±3.24 ppm (J=15.5±17.0 and 10.0±10.6 Hz) and 3.24±3.52 ppm (J=15.5±17.0 and 3.0±4.0 Hz). Similar
chemical shifts and pattern were found for these protons in compound 5 at ꢀ=3.12 ppm (J=17.5 and J=7.5 Hz)
and ꢀ=3.40 ppm (J=17.5 and J=7.0 Hz); the methine proton in compounds 3 appeared as a double doublet in
the region 5.26±5.50 ppm (J=10.0±10.6 and 3.0±4.0 Hz), while in compound 5 it appears as a multiplet at ꢀ=4.74±
4.78 ppm. Similarly, the protons of the methylene group in 7 also appeared as two double doublets at ꢀ=2.76 ppm
(J=15.0 and J=8.4 Hz) and ꢀ=2.87 ppm (J=15.0 and J=5.1 Hz) and the same pattern was observed for
compound 8 at ꢀ=2.80 (J=16.5 and J=6.9 Hz) and ꢀ=2.97 (J=16.5 and J=6.9 Hz). On the other hand, the
methine proton in compound 7 appeared as a double doublet at ꢀ=5.22 (J=8.4 and J=5.1 Hz), while in
compound 8 appeared as a triplet at ꢀ=4.5 (J=6.9 Hz). With reference to compound 10 it is worth noting that
two di€erent methyl groups appeared at ꢀ=2.35 and 2.37 ppm while the protons of the methylene and methine
groups appeared as two di€erent multiplets at ꢀ=2.47±2.91 and 5.12±5.68 ppm, respectively.