Tandem [3+2] cycloaddition reaction of azo-alkenes and thiocyanic acid: Extending the scope of the classical "criss-cross" cycloaddition reaction

Article abstract of DOI:10.1055/s-1998-1759

Phenylazoalkenes 4 with full substitution at the terminal carbon atom react with thiocyanic acid affording 2,3,5,6,7,7a-hexahydro-3-phenyl-1H-imidazo[1,5-b][1,2,4]triazole-2,5-dithiones 8. The bicyclic compounds 8 result from two consecutive [3+2] cycloaddition steps, thus adding a novel facet to the classical "Criss-cross" reaction.

Full text of DOI:10.1055/s-1998-1759

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Tandem [3+2] Cycloaddition Reaction of Azo-alkenes and Thiocyanic Acid: Extending the
Scope of the Classical “Criss-Cross” Cycloaddition Reaction
Joachim G. Schantl* and Peter Nádeník
Institut für Organische Chemie, Universität Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria
Fax: +43 (0)512 507 2855; E-mail: Joachim.Schantl@uibk.ac.at
Received 25 March 1998
Abstract: Phenylazoalkenes 4 with full substitution at the terminal
carbon atom react with thiocyanic acid affording 2,3,5,6,7,7a-
hexahydro-3-phenyl-1H-imidazo[1,5-b][1,2,4]triazole-2,5-dithiones 8.
5 undergoes a further [3+2] cycloaddition reaction with thiocyanic acid
at the azomethine imine function giving rise to the bicyclic product
16
imidazo[1,5-b][1,2,4]triazole-2,5-dithione 8.
The bicyclic compounds
8
result from two consecutive [3+2]
cycloaddition steps, thus adding a novel facet to the classical “Criss-
cross” reaction.
An alternative one-pot procedure also providing bicyclic products 8
involves the treatment of an α,α-disubstituted α-bromo carbonyl
2
3
compound 1 (X = Br; R , R ≠ H) with excess of potassium thiocyanate
in acetic acid and one equivalent of phenylhydrazine (Scheme 1). The
presumed initial substitution of 1 with potassium thiocyanate is
followed by conversion of the resultant α-thiocyanato carbonyl
compound 2 into phenylhydrazone 3. The subsequent conjugate
elimination reaction provides phenylazoalkene 4 and thiocyanic acid,
both intermediates reacting further in the fashion outlined above and
furnishing 8.
The heterodiene system of conjugated azoalkenes (1,2-diaza-1,3-
butadienes) is capable of participating in various cycloaddition
1,2
reactions. Azoalkenes can react as the dipolarophile (olefinic moiety)
3-5
in [3 + 2] cycloaddition reactions or as the three-center component
(olefinic π-bond and the nonbonding electron pair at the adjacent
nitrogen atom), thus resembling an isoelectronic hetero equivalent of the
6-11
allyl anion.
Following this procedure 2-bromo-2-methylpropanal 1a gave (7aRS)-
8a, 2-bromo-2-phenylpropanal 1b provided
diastereomers 8b, which were separated by column chromatography
a 4:1 mixture of
Recently, we reported the reaction of conjugated phenylazoalkenes 4
3
12
(R = H) and thiocyanic acid giving rise to the formation of 1-anilino-
13,14
(silica gel, ether) into colorless crystals of (7R*,7aS*)-8b and
2,3-dihydro-1H-imidazole-2-thiones 7 (Scheme 1).
This reaction is
17
(7S*,7aS*)-8b;
similarly, 3-bromo-3-methylbutan-2-one 1c was
considered to be initiated by a [3+2] cycloaddition step forming
18
converted into (7aRS)-8c.
cycloadduct 5. Protonation at the exocyclic nitrogen atom of
3
intermediate 5 followed by deprotonation of 6 (R = H) at C-4 yields the
The dithione structure of compounds 8 (as opposed to a conceivable
thiazole structure) is supported (a) by the solubility in alkaline solution
and (b) by the transformation of e.g. (7aRS)-8c into the base insoluble
final heteroaromatic product 7. Compounds 7 can be obtained also in the
course of a one-pot reaction; the two reagents undergoing the
cycloaddition reaction are generated in situ from α-halo carbonyl
19
2,6-bis(methylsulfanyl) derivative (7aRS)-9c (Scheme 1). Hydrogen
compounds
1
(X
15
=
Br, Cl), potassium thiocyanate, and
peroxide in sodium hydroxide solution transformed both thione
functions of (7aRS)-8c into carbonyl groups of (7aRS)-10c (this
20
phenylhydrazine.
compound (7aRS)-10c was not available by the analogous reaction of 1c
with potassium cyanate).
These findings prompted the investigation of this reaction with
21
phenylazoalkenes 4 being fully substituted at the terminal carbon atom
2
3
(R , R ≠ H;) and an excess of potassium thiocyanate in acetic acid
The NMR spectra are consistent with the structures; diastereotopic
methyl groups at C-7 of 8a, 8c, 9c and 10c reflect the chirality at fusion
2
3
(Scheme 1). Cycloadduct 5 (R , R ≠ H) is envisaged to be the first
formed intermediate; however, lacking a hydrogen atom at 4-C, adduct
Scheme 1

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atom C-7a. NOE experiments led to the assignment of structure
(7R*,7aS*)-8b for the major diastereomer.
(5) Schultz, A. G.; Hagmann, W. K.; Shen, M. Tetrahedron Lett.
1979, 2965.
2
3
The conversion of phenylazoalkenes 4 (R , R ≠ H) into 8 is reminiscent
(6) Schultz, A. G.; Shen, M. Tetrahedron Lett. 1979, 2969.
22-25
of a reaction so far mainly confined to azines I
heterodiene system of azines I adds two molecules of a dipolarophile
and furnishes bicyclic products III. For this tandem [3+2] cycloaddition
(Scheme 2). The
(7) Sommer, S. Angew. Chem. 1979, 91, 756; Angew. Chem., Int. Ed.
Engl. 1979, 18, 695.
(8) Schultz, A. G.; Shen, M. Tetrahedron Lett. 1981, 22, 1775.
(9) Brodka, S.; Simon, H. Liebigs Ann. Chem. 1971, 745, 193.
23
reaction the name “Criss-cross” reaction has been coined. The
conversion of phenylazoalkenes 4 into the bicyclic products 8 as
reported herein is an analogous reaction extending the scope of the
classical “Criss-cross” reaction. Apparently, only a single example of a
similar cycloaddition sequence of an azoalkene with two different
(10) Attanasi, O. A.; Ballini, R.; Liao, Z.; Santeusanio, S.; Serra-
Zanetti, F. Tetrahedron 1993, 49, 7027.
(11) Burger, K.; Rottegger, S. Tetrahedron Lett. 1984, 24, 4091.
7
dipolarophiles has been reported.
(12) This term is used for the mixture of both tautomers, thiocyanic
acid and isothiocyanic acid: Beard, C. I.; Dailey, B. P. J. Chem.
Phys. 1950, 18, 1437.
(13) Schantl, J. G.; Prean, M. Monatsh. Chem. 1993, 124, 299.
(14) Schantl, J. G.; Kählig, H.; Prean, M. Heterocycles 1994, 37, 1873.
(15) Schantl, J. G.; Lagoja, I. M. Heterocycles 1997, 45, 691.
(16) Typical procedure:
2,3,5,6,7,7a-Hexahydro-7,7-dimethyl-3-phenyl-1H-imidazo[1,5-
27
b][1,2,4]triazole-2,5-dithione (7aRS)-8a: A solution of 4a (0.5 g,
3.1 mmol) in absol. THF (3 mL) was added dropwise to a solution
of KNCS (0.9 g, 9.3 mmol) in AcOH (10 mL) under N . After
2
stirring at room temperature for 2 h the solvent was evaporated,
water (5 mL) was added to the residue, and the mixture was
extracted with AcOEt (4 x 20 mL); the combined extracts were
washed with H O and dried over MgSO . Upon removal of the
2
4
solvent the residue was recrystallized from ethanol: Colorless
crystals (7aRS)-8a (0.6 g, 70%), mp 200-202 °C (EtOH). IR
-1
1
Azines I (2,3-diaza-1,3-butadienes) and azoalkenes 4 (1,2-diaza-1,3-
butadienes) formally differ in the position of the two heterodienic
nitrogen atoms (Scheme 2). Involving N-2 and C-4, the first
cycloaddition step is analogous for both substrates I and 4. The resulting
primary adducts II and 5, respectively, are characterized by different
positions of the terminal nitrogen atom of the azomethine imine
function: endocyclic (N-3) in II, and exocyclic (N-1) in 5. The
orientation of the azomethine imine function affects the regiochemistry
of the second cycloaddition step providing the bicyclic products III and
8, respectively. The overall tandem [3+2] cycloaddition reaction of
unsymmetrical dipolarophiles like thiocyanic acid with azines I results
in an antiparallel orientation of the added C–N bonds in III (pointing to
(KBr): ν 3225 (NH), 3115 (NH), 1453 cm (N-CS-NH); H-
NMR (300 MHz, DMSO-d ): δ 1.30 (s, 7-CH ), 1.36 (s, 7-CH ),
6
3
3
5.48 (s, 7a-H), 7.15 (t, J = 7.5 Hz, 4-H 3-C H ), 7.34 (dd, J = 7.5
6
5
Hz, 3,5-H 3-C H ), 7.86 (d, J = 7.5 Hz, 2,6-H 3-C H ), 9.87 (s, 1-
6
5
6 5
13
H), 10.36 (s, 6-H); C-NMR (75 MHz, DMSO-d ): δ 25.3 (7-
6
CH ), 26.4 (7-CH ), 60.8 (7-C), 83.9 (7a-C), 123.1, 125.0, 127.4,
3
3
141.2 (2,6-, 4-, 3,5-, 1-C 3-C H ), 179.5 (2-C), 188.1 (5-C).
6
5
(17) Physical data of (7R*,7aS*)-8b: Colorless crystals (64%), mp
165-167 °C (EtOH). Rf = 0.51 (silica gel, Et O); IR (KBr): ν 3365
2
-1
1
(NH), 3130 (NH), 1444 cm (N-C(=S)-NH); H-NMR (300
MHz, DMSO-d ): δ 1.66 (s, 7-CH ), 5.73 (s, 7a-H), 7.13 (t, J =
6
3
7.5 Hz, 4-H 3-C H ), 7.27-7.47 (m, 7-C H , 3,5-H 3-C H ), 7.79
26
6
5
6
5
6 5
opposite directions). By contrast, the cycloaddition sequence of
13
(d, J = 7.5 Hz, 2,6-H 3-C H ), 9.93 (s, 1-H), 11.01 (s, 6-H); C-
6
5
phenylazoalkenes 4 giving rise to 8 occurs in the sense of a parallel
“Criss-cross” reaction (the added C–N bonds pointing to the same
direction).
NMR (75 MHz, DMSO-d ): δ 23.4 (7-CH ), 66.6 (7-C), 85.1 (7a-
6
3
C), 124.8-142.4 (7-C H , 2,3,4,5,6-C 3-C H ), 141.0 (1-C 3-
6
5
6 5
C H ), 179.4 (2-C), 189.3 (5-C).
6
5
(7S*,7aS*)-8b: Colorless crystals (16%), mp 183-185 °C (EtOH).
Rf = 0.54 (silica gel, Et O); IR (KBr): ν 3371 (NH), 3134 (NH),
Acknowledgement: This research has received financial support by the
Fonds zur Förderung der Wissenschaftlichen Forschung (FWF), Vienna
(Project Nr. P8544).
2
-1
1
1444 cm (N-C(=S)-NH); H-NMR (300 MHz, DMSO-d ): δ
6
1.76 (s, 7-CH ), 5.82 (s, 7a-H), 7.13 (t, J = 7.5 Hz, 4-H 3-C H ),
3
6 5
7.27-7.47 (m, 7-C H , 3,5-H 3-C H ), 7.87 (d, J = 7.5 Hz, 2,6-H
6
5
6 5
13
3-C H ), 9.14 (s, 1-H), 10.85 (s, 6-H); C-NMR (75 MHz,
6
5
References and Notes
DMSO-d ): δ 26.4 (7-CH ), 68.4 (7-C), 84.9 (7a-C), 123.3-138.2
6
3
(1) Attanasi, O. A.; Caglioti, L. Org. Prep. Proc. Int. 1986, 18, 299.
(7-C H , 2,3,4,5,6-C 3-C H ), 141.3 (1-C 3-C H ), 180.1 (2-C),
6
5
6
5
6 5
(2) Schantl, J. G. in Houben-Weyl, Methoden der Organischen
Chemie, Vol. E15. Kropf, H.; Schaumann, E., Eds.; Thieme;
Stuttgart, 1993; p 909.
189.1 (5-C).
(18) Physical data of (7aRS)-8c: Colorless crystals (91%), mp 216-217
-1
°C (EtOH). IR (KBr): ν 3360 (NH), 3130 (NH), 1430 cm (N-
C(=S)-NH); H-NMR (300 MHz, DMSO-d ): δ 1.30, (s, 7-CH ),
1.33 (s, 7-CH ), 1.43 (s, 7a-CH ), 7.16 (t, J = 7.5 Hz, 4-H 3-
1
(3) Collins, P. M.; Hurford, J.R.; Overend, W. G. J. Chem. Soc. Perkin
Trans. I. 1975, 2178.
6
3
3
3
(4) Vasil'eva, L. P.; Akimova, G. S.; Chistokletov, V. N.; Zelenin, K.
N. Zh. Org. Khim. 1982, 18, 1853; Chem. Abstr. 1983, 98, 53746;
Zh. Org. Khim. 1985, 21, 2013; Chem. Abstr. 1986, 104, 68788.
C H ), 7.34 (dd, J = 7.5 Hz, 3,5-H 3-C H ), 7.87 (d, J = 7.5 Hz,
6 5 6 5
13
2,6-H 3-C H ), 9.77 (s, 1-H), 10.40 (s, 6-H); C-NMR (75 MHz,
6
5
DMSO-d ): δ 19.2 (7a-CH ), 25.3, 26.4 (7-CH ), 62.9 (7-C), 89.2
6
3
3

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(7a-C), 122.5, 124.9, 127.9, 141.1 (2,6-, 4-, 3,5-, 1-C 3-C H ),
(21) All new compounds 8, 9c and 10c gave satisfactory elemental
6
5
178.1 (2-C), 187.4 (5-C).
analyses.
(19) Physical data of (7aRS)-9c: Colorless crystals (82%), mp 135-136
(22) Bailey, J. R.; Moore, N. H. J. Am. Chem. Soc. 1917, 39, 279.
(23) Bailey, J. R.; McPherson, A. T. J. Am. Chem. Soc. 1917, 39, 1322.
-1
1
°C (EtOH). IR (KBr): ν 1600 (C=N), 1593 cm (C=N); H-NMR
(300 MHz, DMSO-d ): δ 1.27 (s, 7-CH ), 1.29 (s, 7-CH ), 1.41 (s,
6
3
3
(24) Reviews of “Criss-cross” cycloaddition reactions: (a) Wagner-
Jauregg, T. Synthesis 1976, 349. (b) Rádl, S. in Comprehensive
Heterocyclic Chemistry II, Vol 8. Katritzky, A. R.; Rees, C. W.;
Scriven, E. F. V., Eds.; Pergamon; Oxford, 1996; p 747.
(c) Rádl, S. Aldrichimica Acta 1997, 30, 97.
7a-CH ), 2.41 (s, 2-SCH ), 2.46 (s, 5-SCH ), 7.10 (t, J = 7.5 Hz,
3
3
3
4-H 3-C H ), 7.30 (dd, J = 7.5 Hz, 3,5-H 3-C H ), 7.38 (d, J = 7.5
6
5
6 5
13
Hz, 2,6-H 3-C H ); C-NMR (75 MHz, DMSO-d ): δ 13.7 (5-
6
5
6
SCH ), 15.7 (2-SCH ), 21.8 (7a-CH ), 25.8 (7-CH ), 26.8 (7-
3
3
3
3
CH ), 72.7 (5-C), 100.9 (6-C), 121.6, 125.0 128.9 143.7 (2,6-, 4-,
3
3,5-, 1-C 3-C H ), 158.2 (2-C), 167.3 (5-C).
6
5
(25) Schantl, J. G.; Gstach, H.; Hebeisen, P.; Lanznaster, N.
Tetrahedron 1985, 41, 5525.
(20) Physical data of (7aRS)-10c: Colorless crystals (84%), mp 254-
-1
255 °C (EtOH). IR (KBr): ν 3261 (NH), 1736 (C=O), 1720 cm
(26) The reaction of hexafluoroacetone azine with alkyl acrolates has
been reported to furnish some parallel cycloadducts beside the
typical antiparallel regioisomers: Burger, K.; Schickaneder, H.;
Hein, G.; Gieren, A.; Lamm, V.; Engelhardt, H. Liebigs Ann.
Chem. 1982, 845.
1
(C=O); H-NMR (300 MHz, DMSO-d ): δ 1.23 (s, 7a-CH ), 1.29
6
3
(s, 7-CH ), 1.33 (s, 7-CH ), 6.89 (t, J = 7.5 Hz, 4-C 3-C H ), 7.27
3
3
6 5
(dd, J = 7.5 Hz, 3,5-H 3-C H ), 7.60 (d, J = 7.5 Hz, 2,6-H 3-
6
5
13
C H ), 7.93 (s, 1-H), 8.04 (s, 6-H); C-NMR (75 MHz, DMSO-
6
5
d ): δ 19.6 (7a-CH ), 23.2, 26.2 (7-CH ), 56.6 (7-C), 83.0 (7a-C),
6
3
3
(27) Schantl, J. G.; Hebeisen, P. Tetrahedron 1990, 46, 395.
116.1, 122.0, 128.1, 141.3 (2,6-, 4-, 3,5-, 1-C 3-C H ), 156.5 (2-
6
5
C), 161.2 (5-C).