Reaction of Fischer alkynylcarbene complexes with 1-azadiene derivatives: unexpected formation of 3,4-dihydropyridines

Abstract

4-Amino-1-azabutadienes 2 underwent [3 + 3] cyclization with Fischer alkynylcarbene complexes of chromium and tungsten 1 to furnish high yields of substituted 3,4-dihydropyridines 3. The expected pyridine ring formation, which would result from cyclization/aromatization, does not take place. The process is thought to involve a 1,2-imidoyl group shift triggered by a 1,2-metal pentacarbonyl shift as the more characteristic steps. An X-ray diffraction experiment supports the proposed structure for the dihydropyridines.

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Since their discovery in 1964 by Fischer,¹ stabilized Fischer carbene complexes of Group 6 have been recognized to play an important role in the construction of a variety of 3- to 7-membered rings and acyclic compounds. The reaction can occur either on the carbene ligand wherein the metal acts as reactivity and selectivity auxiliary, or at the metal center allowing a great number of cycloadditions in the coordination sphere.² Owing to their great potential, these complexes have frequently become also useful reagents in heterocyclic synthesis.

Particularly alkynylcarbene complexes³ are appropriate precursors of heterocycles through a sequence involving addition and cyclization. In this field, several [3 + 2],⁴ [4 + 2]⁵ and [4 + 3]⁶N-heterocyclizations using alkynyl Fischer carbene complexes have been accomplished. On the contrary, [3 + 3] N-heterocyclizations are much less common and only a few examples are known.^7–9

On the other hand, we recently discovered a novel reaction pathway for alkenyl- and alkynyl-carbene complexes towards unsaturated substrates.⁶ This mechanism is exemplified in Scheme 1 for the [4 + 3] cycloaddition of alkenylcarbene complexes with 4-amino-1-azabutadienes giving azepines^6a and consists in (i) 1,2 addition of the imine nitrogen to the carbene carbon (step 1) and 1,2-(OC)₅M migration-promoted cyclization (step 2).

Scheme 1 Mechanism for the synthesis of azepines from 4-amino-1-azadienes and alkenyl Fischer carbene complexes.

Continuing our interest in the chemistry of azabutadiene derivatives and Fischer carbene complexes, we report herein the reaction of 4-amino-1-azadienes 2 with pentacarbonyl(1-methoxy-3-phenyl-2-propynylidene)-chromium and -tungsten complexes 1 leading to dihydropyridines 3, wherein the imidoyl fragment of the azadiene is transferred to the metal-ligand fragment. Thus, azadiene derivatives 2 were mixed with chromium carbene complex 1a (molar ratio 1:1) in THF at −20 °C and the mixture allowed to reach 0 (for R¹ = Bu^t) or 25 °C (for R¹ = c-C₆H₁₁). Column chromatography purification allowed us to isolate a single adduct. Surprisingly, the expected pyridine ring 4¹⁰ was not formed at all, but substituted 3,4-dihydropyridines 3 were obtained in high yields (Scheme 2, Table 1). Replacement of chromium complex 1a with tungsten complex 1b resulted neither in change of the reaction course nor in noticeable change of reaction yields.

Scheme 2 Synthesis of the 3,4-dihydropyridines 3 from alkynyl Fisher carbene complexes.

Table 1 Dihydropyridines 3 synthesized

Compound^a	R^1	R^2	Yield (%)
a Isolated yields for M = Cr.
3a	Bu^t	Ph	87
3b	Bu^t	c-C3H5	84
3c	Bu^t	i-C3H5	92
3d	c-C6H11	4-MeC6H4	58

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The spectroscopic data found are in concordance with structure 3. Thus, the diastereotopic hydrogen atoms attached to the ring C3 appear as two doublets (J = 16 Hz) around δ 2.5 and 3.2 in the ¹H NMR spectra. Moreover, the more characteristic resonances in the ¹³C NMR spectra are found at δ 166–167 (C2), 35–36 (C3), 48–49 (C4), 104–107 (C5), 145–153 (C6) and 154–159 (CH[double bond, length half m-dash]N).

The structure of compounds 3 was unambiguously confirmed by an X-ray¹¹ diffraction experiment performed on 3d (Fig. 1).

Fig. 1 Crystal structure of the 3,4-dihydropyridine 3d.

From a mechanistic point of view it is not easy to rationalize the formation of compounds 3, specifically the observed 1,2-imidoyl rearrangement. The present proposal is based primarily on the mechanism shown in Scheme 1 along with the assumption that a cyclopropane intermediate participates (Scheme 3). The reaction must be initiated by Michael-type addition of the C_β–H enamine to form intermediate I. The second step would involve formation of the dihydropyridine intermediate II by intramolecular nitrogen addition to the metal carbene carbon. The key step is the formation of the cyclopropane species III by intramolecular 1,2-M(CO)₅ migration-promoted anti nucleophilic attack at the imine function. Finally, cyclopropane ring opening of III followed by hydrogen transfer and reductive metal elimination transforms III into the dihydropyridine ring 3.

Scheme 3 Proposed mechanism in the synthesis of the 3,4-dihydropyridines 3.

In summary, we have shown that 4-amino-1-azabutadienes readily react with alkynylcarbene complexes under very mild reaction conditions affording high yields of 3,4-dihydropyri dines, whose structure is certainly unusual.¹² This reaction features the following aspects: (i) a [3 + 3] N-heterocycloaddition that is rather uncommon in the field of carbene complexes, (ii) a 1,2-imidoyl shift which results in the formation of a quaternary center in preference to the expected cyclization to the pyridine ring and (iii) 1,2-metal migration.

Experimental

General methods

All reactions were carried out under a N₂ atmosphere. All common reagents and solvents were obtained from commercial suppliers and used without further purification unless otherwise indicated. THF was distilled from sodium–benzophenone under a N₂ atmosphere prior to use. Flash column chromatography was carried out on silica gel 60, 230–240 mesh. NMR spectra were run on a Bruker AC-300 spectrometer.

Synthesis of 3,4-dihydropyridines 3a–3d

Over a 50 mL THF solution of the 4-amino-1-azabutadiene 2 (1.5 mmol) at −80 °C, 1.5 mmol of the alkynyl Fischer carbene complex 1 were added. The stirred solution was allowed to reach 0 °C for 3a–3c and two additional days at room temperature for 3d. Solvents were removed under vacuum and the residue was purified by chromatographic column over silica gel (hexane–triethylamine (10:1)).

4-tert-Butyliminomethyl-2-methoxy-4,6-diphenyl-3,4-dihydropyridine 3a. Yield 87%. Oil. ¹H NMR (300 MHz, CDCl₃): δ 0.3 (s, 9H); 2.5 (d, 1H, J  = 15.9); 3.4 (d, 1H, J  = 15.9 Hz); 4.0 (s, 3H); 6.1 (s, 1H); 7.3–7.6 (m, 8H); 7.6 (s, 1H); 8.0 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 167.2 (s); 154.4 (d); 145.0 (s); 143.3 (s); 138.5 (s); 128.6 (d); 128.1 (d); 127.8 (d); 126.9 (d); 126.8 (d); 125.5 (d); 107.5 (d); 56.6 (s); 53.1 (q); 48.6 (s); 35.4 (t); 29.4 (q). HRMS (C₂₃H₂₆N₂O): calculated m/z 346.20451, found 346.20379.

4-tert-Butyliminomethyl-6-cyclopropyl-2-methoxy-4-phenyl-3,4-dihydropyridine 3b. Yield 84%. Oil. ¹H NMR (300 MHz, CDCl₃): δ 0.7 (m, 2H); 0.9 (m, 2H); 1.2 (s, 9H); 1.7 (m, 1H); 2.3 (d, 1H, J  = 16.0); 3.2 (d, 1H, J  = 16.0 Hz); 3.7 (s, 3H); 5.3 (s, 1H); 7.3 (m, 6H). ¹³C NMR (75 MHz, CDCl₃): δ 167.2 (s); 155.1 (d); 148.0 (s), 143.8 (s); 128.5 (d); 128.0 (d); 126.7 (d); 104.5 (d); 56.4 (s); 52.7 (q); 48.1 (s); 36.0 (t); 29.4 (q); 16.0 (d); 4.6 (t); 4.3 (t). HRMS (C₂₀H₂₆N₂O): calculated m/z 310.20451, found 310.20322.

4-tert-Butyliminomethyl-6-isopropyl-2-methoxy-4-phenyl-3,4-dihydropyridine 3c. Yield 92%. Oil. ¹H NMR (300 MHz, CDCl₃): δ 1.15 (d, 6H, J  = 6.6); 1.2 (s, 9H); 2.3 (d, 1H, J  = 16.2); 2.5 (sp, 1H, J  = 6.6); 3.15 (d, 1H, J  = 16.2 Hz); 3.8 (s, 3H); 5.2 (s, 1H); 7.2–7.4 (m, 5H); 7.45 (s, 1H). ¹³C NMR (75 MHz, CDCl₃): δ 166.6 (s); 155.0 (d); 153.9 (s); 143.8 (s); 128.5 (d); 126.8 (d); 126.7 (d); 103.7 (d); 56.3 (s); 52.7 (q); 47.7 (d); 35.8 (t); 34.5 (d); 29.4 (q); 20.9 (q).

4-Cyclohexyliminomethyl-2-methoxy-6-(4-methylphenyl)-4-phenyl-3,4-dihydropyridine 3d. Yield 58%. Solid. mp 77–79 °C. ¹H NMR (300 MHz, CDCl₃): δ 1.2–1.9 (m, 10H); 2.4 (s, 3H); 2.5 (d, 1H, J  = 15.9); 3.1 (m, 1H); 3.25 (d, 1H, J  = 15.9 Hz); 3.9 (s, 3H); 6.0 (s, 1H); 7.2–7.9 (m, 6H). ¹³C NMR (75 MHz, CDCl₃): δ 167.0 (s); 158.7 (d); 145.1 (s); 143.0 (s); 137.6 (s); 135.7 (s); 128.8 (d); 128.6 (d); 127.0 (d); 126.9 (d); 125.4 (d); 106.5 (d); 68.7 (d); 53.1 (q); 48.6 (s); 35.6 (t); 34.2 (t); 34.0 (t); 25.6 (t); 24.5 (t); 24.3 (t); 21.1 (q). HRMS (C₂₆H₃₀N₂O): calculated m/z 386.23581, found 386.23558.

Notes and References

1. E. O. Fischer and A. Maasböl, Angew. Chem., 1964, 3, 580.
2. Recent reviews: W. D. Wulff, in Comprehensi[italic v]e Organometallic Chemistry II, eds. E. W. Abel, F. G. A. Stone and G. Wilkinson, Pergamon, New York, 1995, vol. 12, p. 469; W. D. Wulff, Organometallics, 1998, 17, 3116; J. Barluenga, Pure Appl. Chem., 1999, 71, 1385.
3. R. Aumann and H. Nienabar, Ad[italic v]. Organomet. Chem., 1997, 41, 163.
4. W. Chan, K. S. Chan, M. L. Yeung, R. J. Wang and T. C. W. Mak, J. Org. Chem., 1995, 60, 1741; T. N. Danks and D. Velo-Rego, Tetrahedron Lett., 1994, 35, 9443; J. Barluenga, M. Tomás, J. A. López-Pelegrín and E. Rubio, J. Chem. Soc., Chem. Commun., 1995, 665.
5. J. Barluenga, M. Tomás, J. A. López-Pelegrín and E. Rubio, Tetrahedron Lett., 1997, 38, 3981; R. Aumann, Z. Yu and R. Frölich, J. Organomet. Chem., 1997, 549, 311.
6. (a) J. Barluenga, M. Tomás, A. Ballesteros, J. Santamaría, R. J. Carbajo, F. López-Ortíz, S. García-Granda and P. Pertierra, Chem. Eur. J., 1996, 2, 88; (b) J. Barluenga, M. Tomás, E. Rubio, J. A. López-Pelegrín, S. García-Granda and P. Pertierra, J. Am. Chem. Soc., 1996, 118, 695.
7. R. Aumann, K. Roths and M. Grehl, Synlett, 1993, 669.
8. R. Polo, J. M. Moretó, U. Schick and S. Ricart, Organometallics, 1998, 17, 2135.
9. J. Barluenga, M. Tomás, E. Rubio, J. A. López-Pelegrín, S. García-Granda and M. Pérez, J. Am. Chem. Soc., 1999, 121, 3065.
10. The formation of this adduct would result from Michael-type addition followed by cyclization and aromatization.⁷.
11. Crystal data for 3d: C₂₆H₃₀N₂O, M_r  = 386.52, orthorhombic, space group Pbc2₁, a  = 6.632(2), b  = 19.859(2), c  = 34.049(4) Å, V  = 4484(2) ų, Z  = 8, Mo-Kα radiation (graphite crystal monochromator), λ  = 0.71073 Å, μ  = 0.069 mm⁻¹, T  = 293(2) K. Final conventional R  = 0.0591 (for 1368 F_O>4σ(F_O)), and wR2  = 0.2829 (for all reflections). CCDC reference number 440/215. See http://www.rsc.org/suppdata/nj/b0/b005648k/ for crystallographic files in .cif format..
12. A. R. Katritzky and C. W. Rees, Comprehensi[italic v]e Heterocyclic Chemistry, eds. A. J. Boulton and A. McKillop, Pergamon, New York, 1984..

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