Unsubstituted pyrido[3,4-d ]pyridazine as an electron-deficient azadiene in [4+2] cycloaddition reactions: a short route to g -fused isoquinolines

Pyrido[3,4-d ]pyridazine was shown to undergo thermally induced Diels–Alder reactions (inverse electron-demand) with enamines as electron-rich dienophiles, yielding isoquinoline derivatives. The regiochemistry of the cycloaddition was investigated


Introduction
In many cases, ring transformation reactions can offer an elegant and efficient access to monoand polycyclic systems, which would be available by conventional assembly only via multi-step procedures.In this context, the inverse-electron-demand Diels-Alder reaction of π-deficient hetarenes with electron-rich dienophiles has been proven to be of particular value.Whereas the behavior of monocyclic tetrazines, triazines, and diazines in this reaction type has been extensively studied, [1][2][3][4][5] condensed π-deficient heteroaromatic compounds have been employed less frequently as starting materials in such cyclo-addition reactions.][8][9][10][11][12][13][14] It could be demonstrated that the annulation of a π-electron-poor ring onto the 1,2-diazine system leads to an activation of this azadiene structure towards electron-rich dienophiles (such as enamines or ketene aminals) in a similar fashion as it can be effected by introduction of one or more electronwithdrawing substituents.So far, however, only two examples of fused pyridazines without any substituents, participating in "inverse" Diels-Alder reactions, are known: Gruseck and Heuschmann 15 succeeded in the conversion of phthalazine into naphthalene derivatives, using extremely reactive dienophiles with a 2-methyleneimidazolidine structure and more recently, the ring transformation of unsubstituted pyrido [2,3-d]pyridazine ("5-azaphthalazine") into various quinoline derivatives was reported by us. 11In the course of our studies in this field, we now investigated also the behavior of the isomeric parent system, pyrido [3,4-d]pyridazine (1) ("6azaphthalazine"), towards simple enamines derived from cyclic ketones as dienophilic reagents, and the utility of such cycloaddition reactions for the synthesis of a new type of cycloalkenefused isoquinolines.

Results and Discussion
The experimental conditions for the reaction of compound 1 with cyclic enamines of different ring size were chosen in analogy to the previously reported cycloaddition reactions of pyrido [2,3-d]pyridazine with the same reagents, 11 i.e. heating of the hetarene with an excess of enamine in 1,4-dioxane under an argon atmosphere.Not surprisingly, the slightly lower LUMO energy of 1, compared to that of its isomer (-1.215 eV for 1, -1.122 eV for pyrido [2,3d]pyridazine, calculated with the AM1 method 16 ) is reflected by a noticeably shorter time required for complete consumption of the starting material.
Thus, when 1-pyrrolidino-1-cyclopentene was used as the dienophile, compound 1 was completely consumed after 4 hours of refluxing, compared to 20 hours in the case of pyrido [2,3d]pyridazine. 11According to 1 H-NMR, the product obtained after evaporation of all volatile components consisted of a 7:1 mixture of two isomeric cyclopentane-fused dihydroisoquinolines, still bearing the pyrrolidinyl moiety, together with a small amount of the corresponding aromatic isoquinoline 2. In order to complete the rearomatization step, the crude mixture was refluxed in toluene in the presence of trifluoroacetic acid (conditions which had been used previously for similar reactions 6,7,11 ), which smoothly effected the elimination of pyrrolidine from either isomeric dihydro intermediate and afforded compound 2 as a single product in 47% overall yield (Scheme 1).

Scheme 1
In contrast to this two-step ring transformation 1 → A/B → 2, employment of six-, seven-, and eight-membered cyclic enamines directly leads to the cycloalkene-fused aromatic isoquinolines 3-5 by spontaneous elimination of pyrrolidine from the presumable primary reaction products of type A/B.In accordance with previous findings, 11,14,17,18 the enamines derived from cyclohexanone and cyclooctanone turned out to be significantly less reactive, requiring longer reaction times (7 days) than the seven-membered analog which effected completion of the cycloaddition in even shorter time (0.5 hours) than the five-membered reagent (4 hours, see above).After chromatography, the novel g-fused isoquinolines were isolated as solids (3, 4) or as an oil (5) in yields between 33 and 56%.Taking into account the convenient availability of the starting material 1, [19][20][21] this method offers a short and easy access to these hitherto unknown isoquinolines 22 bearing a cycloalkene scaffold of variable ring size.

Scheme 2
In order to gain some insight into the regiochemistry of the cycloaddition reaction of the pyridopyridazine 1 with enamines, the initial reaction mixture obtained after refluxing of 1 with 1-pyrrolidino-1-cyclopentene was examined more closely, as in this case the two isomeric cycloadducts A and B are still present (see above).We succeeded in the isolation of the major isomer A by means of medium-pressure liquid chromatography, and the structure of this compound could be established unambiguously by NOE difference spectroscopy.Saturation of the 4-H resonance leads to difference signals for the adjacent 3-H (8.32 ppm) as well as the olefinic proton at lower field (singlet at 6.18 ppm, 5-H) and not for its counterpart at higher field (4.01 ppm, 9-H).The latter signal, however, appears as a doublet because of coupling (3J = 14.1 Hz) with the adjacent angular 8a-H.Thus, the position of the pyrrolidinyl substituent in compound A must be at 5a-C.Consequently, the structure of the 8a-pyrrolidino isomer has to be assigned to the minor cycloadduct B. This result indicates the preferred regioselectivity of the cycloaddition reaction: the major cycloadduct A emerged from the interaction of the 1-positions of both pyrido [3,4-d]pyridazine (1) and 1-pyrrolidino-1cyclopentene as shown in Figure 2.

Figure 2
For the observed regioselectivity (ratio A : B = 7 : 1, see above), steric factors can be safely excluded because of the symmetrical shape of the azadiene substructure with respect to the approaching dienophile.Thus, the regiochemistry must be primarily governed by the electronic properties of the reactants.In general, the isomer distribution of such [4+2] cycloaddition processes can be understood, based on the magnitudes of frontier orbital coefficients at the atoms involved in the reaction: the preferred orientation is characterized by a combination of "large/large" and "small/small" coefficients at the terminal diene and dienophile atoms. 24oreover, some contribution of the corresponding partial charges at the reacting centers has to be considered.In the case of an enamine-type 1-pyrrolidino-1-cyclopentene, the two sp 2hybridized carbon atoms are clearly distinct from each other, with 2-C showing a significantly larger HOMO pz orbital coefficient and a more negative partial charge than 1-C.For the azadiene 1 however, the electronic differences between the involved atoms 1-C and 4-C are less striking, as semiempirical calculations revealed: all methods used by us (MNDO, 25 AM1, 16 PM3, 26 and SAM1 27 ) indicated a slightly larger LUMO pz coefficient for 4-C than for 1-C and a slightly more positive partial charge at 4-C; the results are summarized in Table 1.0][21] (1) and all enamines 28 were prepared according to known procedures.For semiempirical calculations the AMPAC software package was employed. 29