Azodicarhoxamides vs. azodicarboxylates in reactions against thioisomuenchnones: 1,3-dipolar cycloaddition or nucleophilic addition?

Article abstract of DOI:10.1002/ejoc.200901349

This communication presents the first study on the use of azodicarboxamides against mesoionic heterocycles as 1,3-dipoles. The reactions yield thioureido compounds. Their formation could be explained, on the basis of experimental results and preliminary theoretical calculations, by a nucleophilic addition followed by rearrangement; however, a formal 1,3-dipolar cycloaddition and subsequent fragmentation and rearrangement of the transient cycloadducts could not be ruled out. Reactions are carried out in refluxing toluene and are complete in 90-240 min. Structural elucidation of the products is based on single-crystal X-ray analysis, as well as other spectroscopic data and 2D-NMR correlations.

Full text of DOI:10.1002/ejoc.200901349

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901349
Azodicarboxamides vs. Azodicarboxylates in Reactions against
Thioisomünchnones: 1,3-Dipolar Cycloaddition or Nucleophilic Addition?
Bárbara Sánchez,[a] Ignacio López,[b] Mark E. Light,[c] Guadalupe Silvero,[b] and
José Luis Bravo*[a]
Keywords: Azo compounds / Thioisomünchnones / Mesoionic compounds / 1,3-Dipolar cycloadditions / Thioureas
This communication presents the first study on the use of
azodicarboxamides against mesoionic heterocycles as 1,3-di-
poles. The reactions yield thioureido compounds. Their for-
1,3-dipolar cycloaddition and subsequent fragmentation and
rearrangement of the transient cycloadducts could not be
ruled out. Reactions are carried out in refluxing toluene and
mation could be explained, on the basis of experimental re- are complete in 90–240 min. Structural elucidation of the
sults and preliminary theoretical calculations, by a nucleo-
philic addition followed by rearrangement; however, a formal
products is based on single-crystal X-ray analysis, as well as
other spectroscopic data and 2D-NMR correlations.
structure.[12–15] This ability makes them very valuable start-
ing materials in the synthesis of a vast array of heterocycles
by reaction with homo- and heterodipolarophiles.[2]
In our laboratory we have been studying the reactivity of
2-alkylthioisomünchnones and 2-aminothioisomünchnones.
The occurrence of a tautomeric equilibrium and a non-di-
polar behaviour of the former have been reported.[16–18] On
the other hand, 2-(dilakylamino) derivatives yield highly
functionalised, and often chiral, three-,[19–21] four-,[20–22]
five-,[23–27] and six-membered rings,[28,29] by appropriate
choice of the reactants.[30]
Introduction
1,3-Dipolar cycloaddition is a powerful and versatile meth-
odology to gain ready access to heterocycles in a stereo-
chemically controlled fashion.[1,2] Whether these reactions
proceed by a concerted mechanism, synchronous or not, as
first proposed by Huisgen et al.[3] or rather evolve stepwise
by means of diradicals or zwitterionic species is still a mat-
ter of controversy. Only in the last decade have several
sound computational studies been reported to help under-
standing the way this reaction occurs.[4–11]
Thioisomünchnones (1,3-thiazolium-4-olates or anhydro-
Regarding the use of azo compounds as dipolarophiles,
4-hydroxy-1,3-thiazolium hydroxides) constitute a group of pioneering work by Sheradsky and Itzhak described the
mesoionic heterocycles that behave as masked dipoles in formation of cycloadducts, hydrazinothiazols, and open-
1,3-dipolar cycloadditions due to their thiocarbonyl ylide chain thioxohydrazides by reaction of 2-phenylthioiso-
Scheme 1.
münchnones with azodicarboxylates.[31,32] In addition, we
[a] Departamento de Química Orgánica e Inorgánica, Universidad
de Extremadura,
have reported the formation of 1,2,4-triazines,[28] and 1,3,4-
thiadiazoles,[27] by reaction of 2-(dialkylamino)thioiso-
münchnones with dialkyl azodicarboxylates.
No examples on the use of azodicarboxamides as di-
polarophiles in reactions with any type of mesoionic hetero-
cycles were found.
Badajoz 06071, Spain
[b] Departamento de Química Orgánica e Inorgánica, Universidad
de Extremadura,
Cáceres 10071, Spain
[c] School of Chemistry, University of Southampton, Highfield,
Southampton SO17 1BJ, UK
E-mail: jlbravo@unex.es
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Azodicarboxamides vs. Azodicarboxylates in Reactions against Thioisomünchnones
We present herein our preliminary findings on the reac- could be obtained for compound 6 (Figure 1), thus proving
tion between mesoionic compounds and azodicarbox- unequivocally the acyclic structure formed.
amides. Interestingly, we came across an unprecedented re-
In order to corroborate these unexpected results,
sult, since these reactions produced open-chain thioureas, thioisomünchnones 1–3 were also allowed to react with
instead of any kind of heterocyclic compound. These pro- 1,1Ј-azobis(dimorpholide) (8) in refluxing toluene to afford
cesses take place with complete atom economy, giving rise compounds 9–11 as crystalline solids in moderate to good
to highly functionalised molecular structures (Scheme 1).
yields (40–75%) (Scheme 2).
To further extend the initial exploration on the scope of
this process, three asymmetric, carbohydrate-based
thioisomünchnones were studied. The tricyclic mesoionic
Results and Discussion
Reactions of thioisomünchnones 1–3 in refluxing toluene compounds 12–14, synthesised according to a previously
with N,N,NЈ,NЈ-tetramethylazodicarboxamide (4) resulted published protocol,[33] feature a rigid carbohydrate back-
in the formation of the crystalline solids 5–7 in 37–61% bone and a 2-[(alkyl)(aryl)amino] group on the 1,3-thiazol-
yields. Reactions were completed, as determined by tlc, in ium-4-olate moiety. When 12–14 were allowed to react with
90 min.
1,1Ј-azobisdimorpholide (8) in refluxing toluene, the thio-
IR and 13C NMR spectroscopic data reveal the existence ureido compounds 15–17 were isolated in modest yields
of one C=S group and several C=O functions in the three (15–35%) as the sole reaction products. Again, no interme-
compounds. Suitable crystals for X-ray diffractometry diate cycloadducts were detected (Scheme 3).
Figure 1. Crystal structure of 6.
Scheme 2.
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B. Sánchez, I. López, M. E. Light, G. Silvero, J. L. Bravo
SHORT COMMUNICATION
Scheme 3.
Table 1. Selected 13C NMR chemical shifts (δ [ppm]) for 5–7, 9–11 and 15–17.
5
6
7
9
10
11
15
16
17
C=S
NC=O
PhC=N
NCH2
NCH3
182.8
156.6
145.5
58.7, 57.7
37.3, 37.2
184.3
156.7
145.4
58.6, 57.7
37.4, 37.2
184.4
156.6
145.7
58.5, 57.6
37.3, 37.2
182.9
155.4
145.8
58.7, 57.5
42.3, 38.7
184.7
154.9
150.2
58.8, 58.2
41.1, 39.4
184.0
154.8
150.2
58.8, 58.2
41.1, 39.4
174.7, 176.4
155.1, 155.0
144.0, 147.1
175.5, 176.9
155.1, 155.2
144.8, 147.4
175.8, 176.8
155.1, 155.2
144.9, 147.5
Once the structure of 6 was unequivocally determined by
X-ray analysis, the molecular structures of 5, 7, 9–11, and
15–17 were assigned to open-chain thioureas on the basis
of analogous IR and, essentially, 1H and 13C NMR spectro-
scopic data, including 2D NOE experiments and heteronuc-
lear multiple-bond correlation techniques (HMBC). Char-
acteristic 13C chemical shifts are gathered in Table 1.
1
Duplicate signals, both in the 13C and H NMR spectra,
have been attributed to conformational s-cis/s-trans isomers
at the thiourea unit of 5–7, and 9–11, as shown in Figure 2.
In contrast, peak splitting for 15–17 corresponds to hin-
dered rotation around the N–C=O group.
Figure 2. s-cis/s-trans isomerism in 5–7 and 9–11.
The unexpected formation of thioureido compounds 5–
7, 9–11, and 15–17, can be explained by a 1,3-dipolar cyclo- N-aryl group (4-nitrophenyl, phenyl or 4-methoxyphenyl)
addition followed by cleavage and rearrangement of the exerts no influence on the way that cycloadducts cleave.
transient cycloadducts, in agreement to previous re- This fact opens the prospect for a noncycloadditive mecha-
ports.[27,28] In the present study, however, the endocyclic nism, in which the first step would be a nucleophilic ad-
Scheme 4.
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Eur. J. Org. Chem. 2010, 1648–1652

Azodicarboxamides vs. Azodicarboxylates in Reactions against Thioisomünchnones
dition. Both possibilities are shown in Scheme 4, along with
those reported for azodicarboxylates for the sake of com-
parison.
Acknowledgments
B. S. thanks the Spanish Ministerio de Educación y Ciencia for a
Ph. D. scholarship. Financial support from the same Ministry
(Grant CTQ2007-66641) and the Universidad de Extremadura
(Grant A7-11/9) is gratefully acknowledged. We are thankful to
Profs. Pedro Cintas and José Luis Jiménez for fruitful discussions
and to Dr. José Luis Barneto for helpful work on theoretical calcu-
lations.
In order to clarify the mechanism, initial DFT calcula-
tions were carried out with the Gaussian03 program pack-
age.[34] Two reactions were studied, those of 1 and 2 with 4.
Optimisation of reactants and location of the first transi-
tion structure (TS1) of the process and the corresponding
zwitterionic intermediates (ZI) were computed at the
B3LYP/6-31G* level.[35,36] Transition structures and sta-
tionary points were characterised by frequency calculations.
These calculations rendered a stepwise mechanistic path-
way.
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Conclusion
We have shown that highly functionalised thioureido
compounds can be readily obtained by reaction of 2-amino-
thioisomünchnones with azodicarboxamides. Although the
reaction can be envisaged as a nucleophilic addition/re-
arrangement process, a formal 1,3-cycloaddition followed
by fragmentation of the cycloadducts cannot be ruled out.
Preliminary DFT calculations support a stepwise process.
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B. Sánchez, I. López, M. E. Light, G. Silvero, J. L. Bravo
SHORT COMMUNICATION
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Received: November 23, 2009
Published Online: February 16, 2010
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Eur. J. Org. Chem. 2010, 1648–1652