Unsymmetrical azines via triisopropylsilylhydrazine

Article abstract of DOI:10.1016/S0040-4039(00)00398-1

Triisopropylsilylhydrazine, (1), easily prepared from anhydrous hydrazine and chlorotriisopropylsilane (TIPSCI), readily converts aldehydes and ketones to their triisopropylsilyl hydrazones (2 (61-85%)). Desilylation of 2 with TBAF in the presence of a se

Full text of DOI:10.1016/S0040-4039(00)00398-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3285–3289
Unsymmetrical azines via triisopropylsilylhydrazine
Jorge C. Justo de Pomar † and John A. Soderquist ∗
Department of Chemistry, University of Puerto Rico, Río Piedras, PR 00931-3346, Puerto Rico
Accepted 6 March 2000
Abstract
Triisopropylsilylhydrazine, (1), easily prepared from anhydrous hydrazine and chlorotriisopropylsilane
(TIPSCl), readily converts aldehydes and ketones to their triisopropylsilyl hydrazones (2 (61-85%)). Desilylation
of 2 with TBAF in the presence of a second aldehyde or ketone cleanly produces the desired unsymmetrical azines
(3 (74–92%)). © 2000 Elsevier Science Ltd. All rights reserved.
Azines exhibit unusual chemical and spectroscopic properties which have led to recent interest in their
stereochemical features both in solution and the gas phase as well as in the solid state.1a Undergoing
1,3-cycloadditions, they also provide an efficient route to 1,5-diazabicyclo[3.3.0]octanes by a criss-cross
addition.1b Unsymmetrical azines are particularly interesting because of the ability of this functionality
to link two dissimilar groups together in useful ways. For example, steroidal-opiate derivatives show
ultralong opioid antagonist activity, a finding which suggested to us that a new, general method for the
synthesis of unsymmetrical azines may greatly facilitate the development of other useful applications.1c,d
Although symmetrical systems are readily synthesized by the reaction of hydrazine with an excess of
an aldehyde or ketone,1e the preparation of their unsymmetrical counterparts is more challenging, with
the reported routes having in common, the initial formation of a derivatized hydrazone.2,3 However,
particularly harsh conditions are normally required in the second step, such as trifluoroacetic acid
catalysis combined with the azeotropic removal of water,2 or, alternatively, the formation of an amine
phosphonate ylide using strong bases.3 We envisaged a new reagent, triisopropylsilyl (TIPS) hydrazine
(1),4 which, with one side of the hydrazine effectively blocked, could be used to facilitate the clean
formation of the TIPS hydrazone 2 (Scheme 1). After the removal of the TIPS protection under mild
conditions in the presence of a second aldehyde or ketone would lead to unsymmetrical azines (3).
The new reagent 1 proved surprisingly easy to prepare from excess hydrazine (4 equiv.) and TIPSCl.5
The preparation of the novel TIPS hydrazones (2) is also a simple process through the reaction of 1 with
a ketone or aldehyde in the presence of pulverized 4 Å molecular sieves in anhydrous THF (Table 1).6
The formation of 2 is stereoselective, with the E isomer being favored with differences in the sizes of the
∗
†
Corresponding author.
Graduate student supported by DOE-EPSCoR (DE-FC02-91ER75674).
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00398-1
tetl 16678

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Scheme 1.
groups present in the starting carbonyl compound. Unfortunately, some hindered conjugated systems are
unreactive toward 1 (e.g. isophorone, 15% conversion in four days; benzophenone, NR, THF, reflux, 36
h).
Table 1
Triisopropylsilylhydrazones (2) from 1
The TIPS hydrazones 2 proved to be indefinitely stable to the open atmosphere, surprising behavior for
the normally very moisture-sensitive silylamines.8 However, rapid hydrolysis to PhCHO (87% by GC)
is observed for 2c in 3 M HCl (aq.) in THF. While not reduced by LiAlH4 in THF, 2c is deprotonated
by n-BuLi as evidenced by its conversion to the N-methylated hydrazone, 4 (anti:syn=83:17) with MeI
(Scheme 2).9,10
The conversion of 2 into the unsymmetrical azines, 3, is easily accomplished at 25°C with TBAF
in the presence of a slight excess of either a ketone or an aldehyde (Table 2).11 The better synthetic
sequence involves the initial formation of the bulkier 2 followed by the introduction of the less hindered

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Scheme 2.
Table 2
Representative unsymmetrical azines 3

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carbonyl species. The products are stable to vacuum distillation, with only 3c and 3e exhibiting significant
decomposition upon standing. The azines 3 do not retain the original anti/syn configuration present in 2,
with 3 being formed with a clear preference for the anti or anti, anti configuration, consistent with the
known isomerization behavior of azines.1c
In summary, 1 is an efficient hydrazine equivalent which is easily converted to stable hydrazones 2
which are easily deprotected to permit the clean formation of unsymmetrical azines 3 under very mild
conditions.
Acknowledgements
The support of the DOE-EPSCoR Program (DE-FC02-91ER75674) is gratefully acknowledged. We
also thank Professor Rainer Glaser (U of Missouri) for providing us with leading references and Ms.
Marcelina Santiago-Salinas for her help with the experimental work.
References
1. (a) Glaser, R.; Chen, G. S.; Barnes, C. L. J. Org. Chem. 1993, 58, 7446. (b) Grashey, R. Azomethine Imines in Padwa, A.
1,3-Dipolar Cycloaddition Chemistry; Taylort, D. C.; Weissberger, A., Eds.; General Heterocyclic Chemistry Series; John
Wiley & Sons: New York, 1984; Vol. 1, p. 733 ff. (c) Kolb, V. M.; Hua, D. H. J. Org. Chem. 1984, 49, 3824. (d) Kolb,
V. M.; Hua, D. H.; Duax, W. L. J. Org. Chem. 1987, 52, 3003 and references cited therein. (e) Kobach, D.; Koruncev, D.
Methoden der Organischen Chemie; Thieme-Verlag: Stuttgart, 1967; Vol. X/2, 89.
2. Barluenga, J.; Fustero, S.; Gómez, N.; Gotor, V. Synth. 1982, 966.
3. Zwierzak, A.; Turski, K.; Koziara, A. Synth. 1986, 298.
4. Hydrazinotriisopropylsilane (1): Safety precautions: Hydrazine is highly flammable and toxic. Avoid exposure to skin, eyes
or mucous membranes. Keep away from peroxides, heat and flames. Hydrazine has been reported to detonate if exposed to
trace amounts of oxygen when distilled anhydrous. Compound 1 is a moisture-sensitive (producing hydrazine and TIPSOH)
and flammable and should be handled as hydrazine. To reduce the risk of exposure, all operations were carried out under
a nitrogen atmosphere using Schlenk-type handling techniques. To anhydrous hydrazine (12.8 g, 0.40 mol) under a N2
atmosphere, TIPSCl (19.3 g, 100 mmol) was added dropwise (Caution! Exothermic!), and after stirring at 25°C for 12 h,
hexane (25 mL) was added and the upper layer decanted. Repeating this process three times, concentration and distillation
of the residual oil affords 18.5 g (98%) of 1 (b.p. 52–55°C at 15 torr). 1H NMR (CDCl3, 500 MHz) 2.86 (s, 3H); 1.05 (m,
21H). 13C NMR (CDCl3, 125.8 MHz) 11.1, 18.4. MS m/z (relative intensity) 188 (20), calcd for C9H24N2: H, 57.4; C, 12.8.
Found: C, 57.7; H, 13.0.
5. For polysilylated hydrazines, see: Wiberg, N.; Veith, M. Chem. Ber. 1971, 104, 3176.
6. Representative procedure for 2a. To a suspension of molecular sieves (1.46 g, 4, activated overnight at 315°C, 15 torr) in
anhydrous THF (10 mL) under nitrogen atmosphere and 1 (1.88 g, 10 mmol), was added valeraldehyde (0.86 g, 10 mmol).
The mixture was vigorously stirred for 3 h at rt. The volume was doubled with hexane and the suspension filtered. The
filtrate was washed with hexane (3×10 mL), concentrated, and distilled in vacuo to yield 2.16 g (85%) of 2a (b.p. 77–79°C,
1
15 torr) whose isomer ratio was measured by H NMR, 13C NMR and confirmed by GC analysis. This and all products
were fully characterized by 1H and 13C NMR, IR, MS and gave satisfactory elemental analyses and/or HRMS data.
7. The quantitative determination of anti/syn ratios in hydrazones using NMR techniques is described by Bunnell, C. A.;
Fuchs, P. L. J. Org. Chem. 1977, 42, 2614.
8. Colvin, E. Silicon in Organic Synthesis; Butterworths: London, 1981.
9. Reaction of 2c with n-BuLi: To 2c (0.83 g, 3.0 mmol) in anhydrous THF (6 mL) under nitrogen atmosphere at −78°C,
n-BuLi (1.5 mL of 2.3 M solution in hexanes) was added dropwise. After 30 min, the reaction temperature was increased
to −30°C and MeI (0.47 g, 3.3 mmol) was added slowly. The mixture was allowed to reach rt and its volume was doubled
with hexane and washed with water (6×50 mL), dried (Na2SO4), filtered and concentrated to produce 0.83 g (95%) of 4
which was characterized by 1H, 13C NMR, MS and elemental analysis.
10. Attempted reaction of 2c with LiAlH4: To 2c (0.83 g, 3 mmol) in anhydrous THF (6 mL) at 0°C, LiAlH4 (1.5 mL of a
1.0 M THF solution, 6 mmol of hydride) was added and the mixture was stirred for 3 h. After carefully adding D2O (3

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mL of a 50% THF solution, 80 mmol), the mixture was extracted with hexane (2×15 mL), dried (K2CO3,), filtered and
concentrated to produce 0.83 g of crude 2c (100% recovery) which gave identical MS, 1H and 13C NMR characteristics to
the starting material.
11. Representative procedure for azine formation: To 2e (2.41 g, 7.4 mmol) under nitrogen atmosphere was added TBAF (11
mL of 1.0 M solution in THF, 11 mmol) followed by PhCHO (0.86 g, 8.1 mmol, freshly distilled). After 12 h, the reaction
mixture was filtered through silica gel (15 g, 70–230), eluting with hexane/ethyl acetate mixture (4:1, 150 mL). The filtrate
was concentrated and distilled to afford 1.69 g (90%) of 3d (b.p. 145–149°C, 0.03 torr). Satisfactory spectroscopic data
(1H and 13C NMR, MS, IR) and analytical data were obtained for all products 3 with the exception of the unstable 3c and
3e.
12. Compound 3f was prepared to confirm the presence of the anti/syn isomerism in azines, a phenomenon described by Kolb
et al.1c This isomerization can explain the change in the anti/syn ratios observed in azines 3a, 3d and 3f compared to
those in the starting hydrazones 2c and 2d. Pure anti, anti 3f was synthesized from benzaldehyde and hydrazine hydrate in
refluxing ethanol as described by Glaser, R.; Chen, G. S.; Anthamatten, M.; Barnes, C. L. J. Chem. Soc., Perkin Trans. 2
1995, 1449.