4-Iminocyclobutenones: Synthesis and Building-Blocks of Aminohydroquinones and Annulated Quinolines

: Two methods are presented for the synthesis of the title compounds starting from cyclobutenediones: an alkoxide substitution approach and a Staudinger reaction. Unsaturated lithiumorganyls may be added to the remaining carbonyl group and on heating lead to ring enlargement in a cascading process. 4-Alkenyl or 4-aryl derivatives yield aminophenols or -naphthols; 4-alkynyl compounds give cyclopenta-annulated quinolines.

Cyclobutenones have attracted wide attention as synthetic building-blocks primarily due to their facile electrocyclic ring opening to reactive conjugated ketenes, intermediates that lead to a variety of useful stable products. This chemistry has been studied by a number of research groups. [1][2][3][4][5] An important feature of the methodology rests on the simple substitution of an alkoxy group in the readily available dialkyl squarates 1 by a variety of other substituents upon treatment with carbanions to give 3 in a one-pot reaction sequence. 6-8 Subsequent 1,2-addition of unsaturated organometallics yields 4 which sets the stage for an electrocyclic cascade to, for example, hydroquinones 6 via the corresponding dienylketene 5 (Scheme 1).
Compared to cyclobutene(di)ones, the corresponding heteroanalogues have received relatively little attention. Thione derivatives have been prepared as such 9 or as thioacetals 10,11 and there are scattered reports on cyclobutenimines although no general synthesis is available. [12][13][14] The present study fills this gap and opens the door for a comparison of the cyclobutenone chemistry outlined in Scheme 1 with that of the nitrogen congeners.
The final step in the conversion of 1 into 3 involves the displacement of trifluoroacetate in 2 by water in an S N 2¢ reaction; analogously, alcohols can be used to supply cyclobutenone acetals. [6][7][8] We now find that amines can be employed to give iminocyclobutenones. Thus, treatment of 1 (R 1 = i-Pr) with anilines or 3-aminopyridine yields iminocyclobutenones 7, the title compounds of the present study (Scheme 2). For the given examples, yields are good to excellent (Table 1); however, imines formed with alkylamines, with the exception of N-tert-butylamine, were found to be too sensitive to hydrolysis during workup, thus giving cyclobutenediones 3 as the final product.  Another limitation of the method described in Scheme 2 was found in attempts to use 4-aminopyridine. Here, no reaction was observed apparently due to the reduced nucleophilicity of the conjugated amino group. However, we found that the Staudinger reaction 15 of cyclobutenediones 3 (R 1 = i-Pr, R 2 = Ph) with iminophosphoranes offers an alternative (Scheme 3). This method gave an even better yield of iminocyclobutenone 7a and, furthermore allowed the synthesis of imine 7f bearing the 4-pyridyl substituent ( Table 1).

Scheme 3 Staudinger reaction of cyclobutenedione 3
In general, iminocyclobutenones 7 are characterized by IR absorptions at approximately 1690 cm -1 (imino stretch) and 1750 cm -1 (carbonyl stretch); the 13 C NMR spectra show resonances for the imino and carbonyl carbons at approximately 165 and 188 ppm, respectively. Interestingly, only one set of NMR data is observed though inversion at the imino nitrogen should be slow on the NMR time scale (vide infra for 16, 22, 27). This indicates that only one isomer is formed, but there is no clue as to structure assignment.
As noted above, additions of sp 2 -hybridized carbon-based nucleophiles to cyclobutenediones provide 1,2-adducts and they can function as precursors to a variety of ring expanded products via an electrocyclic cascade (Scheme 1). It was of interest to study analogous reactions of iminocyclobutenones 8 and 9 where it is an open question as to whether a dienylketenimine intermediate 12 will allow ring-closure reactions similar to those observed for the more electrophilic 16 dienylketenes 5 (Scheme 1).
Lithiumorganyls give a smooth 1,2-addition to the carbonyl group in iminocyclobutenones 7 (Scheme 2). The reaction mixture may be quenched with water to give tertiary alcohols 8 or the alkoxide intermediate may be methylated to provide ethers 9 (Table 2); alcohol 8e can be silylated to silyl ether 10 (Scheme 2). Products 8, 9 can be isolated without competing hydrolysis of the imino unit. However, hydrolysis can be achieved by stirring with dilute hydrochloric acid to give the corresponding oxo compound as shown for the conversion of imine 8b into cyclobutenone 11 (Scheme 4).

Scheme 4 Hydrolysis of iminocyclobutenone 8b
It should be noted that product 11 is regioisomeric with 4 (R 1 = i-Pr, R 2 = Ph, R 3 = Me), formed directly from dione 3. Thus, the imino group in 7 functions as a protective group for one oxo unit directing the addition of the lithiumorganyl to the otherwise less reactive vinylogous ester unit in 7. In fact, the imino group appears to be a general and efficient protective group in cyclobutenone chemistry.
Thermolysis of cyclobutenimines 8a,b in refluxing p-xylene followed by rapid workup to avoid oxidation gave aminophenols 14a,b as the sole product (Scheme 5). This result is consistent with the paradigm that the ring expansion of iminocyclobutenes proceeds via a mechanism analogous to that described for the corresponding cyclobutenones (Scheme 1), that is, the switch from an intermediate dienylketene to a dienylketenimine does not change the reaction route. It may be noted that heat is required; the ring expansion is obviously not sufficiently supported by the oxy-anion, formed as an intermediate on  To emphasize once again the regiocontrol available with iminocyclobutenones as compared to the related cyclobutenones, note that aminophenol 14b (arising from 8b, Scheme 5) bears a substitution pattern different from that of the hydroquinone that would arise form the corresponding cyclobutenone 4 (Scheme 1).
The thermolysis studies were extended to include the ring expansion of 4-aryl analogues. This resulted in a viable route to aminonaphthols as shown for the ring expansion of 8c (Scheme 6). However, the initially formed air-sensitive aminonaphthol 15 was not isolated, but oxidized (Ag 2 O) 17 directly to iminonaphthoquinone 16, isolated in 59% yield (Scheme 6). The NMR spectra of 16 are quite complex obviously due to slow inversion at the imino nitrogen and formation of E/Z isomers.
The ring expansion studies were further expanded to include the ethers 9 (Scheme 7). For example, thermolysis of 9a gave aminonaphthalene 18 (X = H) in 81% yield. For the 3-tolyl and 3-methoxy derivatives 9b,c there are two possible options for ring closure, p-('attack a') or osubstitution ('attack b') relative to substituent X. Not unexpectedly, mixtures of 18/19 were formed with a clear preference for the 'p-product' 18 (Table 3). This is in line with the smaller steric shielding of position 'a' and with a polarized transition state of the electrocyclic process. The same competition of two substitution pathways was observed earlier for the cyclization of the ketene congeners of ketenimines 17. 18 In that case, the cyclization was found to be less selective, demonstrating the higher electrophilicity and thus lower selectivity for the ketene attack as compared to the ketenimine. In addition, the smaller carbonyl group in ketenes relative to the imino unit in 17 would be expected to further reduce selectivity.
While there is no reason to doubt the concerted nature of the electrocyclizations of dienylketenes such as 5 or dienylketenimines such as 12, ring closure of the corresponding enynylketene intermediates arising from 8d-j and 10 is likely proceed via a diradical intermediate as was observed for the corresponding 4-alkynylcyclobutenones. 19,20 Interestingly, the phenyl group on the imino nitrogen allows additional delocalization of an unpaired electron and apparently this opens additional avenues for cyclization. For example, thermolysis of 4-alkynylcyclobutenimines 8d-g results in a novel cyclization mode, yielding cyclopenta-annulated quinolines 25 (Scheme 8, Table 4). This unusual structure was unambiguously established by an X-ray structural analysis of 25a ( Figure 1). 21 Scheme 5 Thermolysis of 4-alkenylcyclobutenimines 8a,b    Formation of 25 arises from diradical ring closure on the o-position in the N-phenyl substituent. Moreover, the primary cyclization product 24 apparently undergoes dehydrogenation. Possible hydrogen acceptors might be iminoquinones as formed from diradical 21. In fact, an iminoquinone 22 could be isolated from 8f; other dehydrogenation partners are conceivable and may also account for the relatively low yield of 25 in the complex product mixture.
Interestingly, 4-pyridyl derivatives 8i,j follow the same pathway as 4-aryl derivatives 8d-g (Table 4). However, starting from the unsymmetrical 4-(3-pyridyl) compound 8i, two cyclization modes are possible and both were confirmed by the isolation of 25eA and 25eB (Scheme 8, Table 4). A characteristic spectroscopic feature of 25eA is a broad singlet in the 1 H NMR spectrum at d = 9.44 for H-9 (Scheme 8).
The dehydrogenation of intermediate 24 was suppressed by starting with the silyl ether 10 (R 3 = TMS). Here, 26, a silylated tautomer of alcohol 24, was isolated (Scheme 9). Evidence for the suggested structure comes from the 1 H NMR spectrum showing the cyclopentyl methine hydrogen at 5.53 ppm and from NOE experiments.

Scheme 9
Ring enlargement of 4-silyl ether 10 and of N-mesityl derivative 8h In accord with the suggested mechanism, N-mesityl derivative 8h where methyl substitution prevents the cyclization to a 25-type product gives cyclopentene 27. This is assumed to arise via a H-atom abstraction from the proximal hydroxy group in a diradical intermediate analogous to 23A (R 3 = H).
The structure of 27 was established by a single-crystal Xray investigation ( Figure 2). 22 Interestingly, the observed E-configuration of the exocyclic C=C unit in 27 speaks against an intramolecular hydrogen transfer from the hydroxy group in 23A (R 3 = H). Although the yields of products 22 (16%), 25 (7-49%), 26 (19%), 27 (53%) have yet to be optimized, these unusual structures give new evidence of the versatility of iminocyclobutenone chemistry.

3-Isopropoxy-4-N-(phenyl)imino-2-phenylcyclobut-2-en-1-ones 7a-e; General Procedure
Under N 2 , a 100 mL one-necked round-bottomed flask equipped with a magnetic stirring bar and rubber septum was charged with THF (30 mL) and PhBr (2.0 mL, 19 mmol) and cooled to ca. -78°C for 15 min. Then n-BuLi (11.3 mL of a 1.6 M solution in hexane, 18.1 mmol) was added in a dropwise manner. The reaction mixture was stirred for 30 min at ca. -78°C, then transferred via cannula under positive pressure of N 2 to a 250 mL one-necked round-bottomed flask equipped with a magnetic stirring bar and rubber septum, charged with THF (40 mL) and 1 8,23 (R 1 = i-Pr; 3.0 g, 15.1 mmol) and also kept at -78°C. The resulting solution was treated with TFAA (2.7 mL, 19.4 mmol) followed by the addition of a freshly distilled arylamine (for 7a-d; 20 mmol or the quantity given below) or pyridylamine (for 7e; 20 mmol or the quantity given below) in a dropwise manner and subsequently warmed to r.t. This solution was stirred for ca. 2 h when TLC analysis indicated no change in the product pattern. This was followed by a brine quench (15 mL) and the aqueous phase was extracted with Et 2 O (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried (MgSO 4 ), filtered, and concentrated to a viscous dark yellow oil. Column chromatography of the oil (elution with 20:1 mixture of hexanes-EtOAc) furnished the product. Note that occasionally after chromatography there was an impurity that had a similar R f value as 7, which could be removed by sublimation in a Büchi microsublimation oven attachment at 100°C (0.1-0.2 mm Hg) or the desired product was obtained by recrystallization from CH 2 Cl 2 -pentane.

4-Substituted
Cyclobutenimines 8a-f,h,j, 9a-c; General Procedure A 250 mL one-necked round-bottomed flask equipped with a magnetic stirring bar and rubber septum was charged with THF (200 mL) and 7 (1.9 mmol or the amount given below). After 15 min at ca. -78°C, the corresponding organyllithium compound (2.1 mmol) was added in a dropwise manner. Upon consumption of starting material as confirmed by TLC analysis, at -20°C brine (20 mL) (for 8a-f,h-j) or methyl triflate (for 9a-c) was added and the reaction was allowed to warm to r.t. The aqueous phase was extracted with Et 2 O (2 × 100 mL), dried (MgSO 4 ), filtered, and concentrated to a viscous yellow oil. Column chromatography (elution with a 10:1 mixture of hexanes-EtOAc) gave the pure product 8 or 9.

4-(N-Phenylamino)-3-isopropoxy-2-phenylphenol (14a)
A 100 mL round-bottomed flask equipped with a stirring bar and reflux condenser was charged with a solution of 8a (223 mg, 0.7 mmol) in p-xylene (50 mL) and refluxed for 1.5 h. When TLC analysis had confirmed consumption of starting material, the solvent was evaporated followed by column chromatography (elution

3-Isopropoxy-2,N-diphenyl-p-naphthaquinonimine (16)
A 100 mL round-bottomed flask equipped with a stirring bar, reflux condenser, and gas inlet/outlet (argon) was charged with a solution of 8c (253 mg, 0.7 mmol) in p-xylene (60 mL) and refluxed for 15 h. Upon consumption of starting material, the solvent was removed in vacuo to give an oil, which was dissolved in a mixture of freshly distilled benzene (70 mL), KHCO 3 (392 mg, 2.8 mmol), and Ag 2 O (381 mg, 2.8 mmol) under a blanket of N 2 and stirred for 2 h. The reaction mixture was filtered through a bed of Celite, concentrated, and the product isolated as a viscous red oil. Column chromatography (gradient elution with 10:1 → 5:1 mixtures of hexanes-EtOAc); red-wine colored oil; yield: 150 mg (59%); complex E/Z mixture.

Thermolysis of 4-Aryl-4-methoxycyclobutenimines; General Procedure
A 100 mL round-bottomed flask equipped with a stirring bar and reflux condenser was charged with 9 (0.6 mmol) in PhCl (40 mL) and refluxed for 9.5 days. Upon consumption of starting material, the solvent was removed in vacuo to a viscous yellow oil and product 18,19 isolated by column chromatography (gradient elution with 30:1 → 20:1 hexanes-EtOAc).