RECURSOS: BALONES DE FUTBOL, AROS, CONOS, PLATILLO

Nitrosoarenes

Having investigated nitrones, imines and aldehydes, further dipolarophiles candidates were sought after. Nitroso compounds have been utilized in a variety of transformations,34 such as dienes in hetero-Diels–Alder cycloadditions35 and enophiles in nitroso-ene chemistry.36 The most intriguing reports originate in their dichotomous capacity to act as either nitrogen or oxygen transfer reagents in nitroso-aldol chemistry, which can be controlled by judicious catalyst choice.37 Surprisingly, nitrosoarenens have yet to see application in dipolar cycloaddition chemistry with strained ring systems such as DA cyclopropanes or cyclobutanes.

Investigations into the reactivity of nitrosoarenes and DA cyclobutanes began with examination of the reaction between cyclobutane 2-54 and nitrosobenzene (Table 2.9). While a variety of Lewis acids were found to catalyze the reaction, maximal yields were obtained with Yb(OTf)3. Additionally, decreasing the catalytic loading from 10 to 2

mol % dramatically increased product yield (compare entries 1 and 8).

Table 2.9. Catalyst Screening for the Cycloaddition Between DA Cyclobutanes and Nitrosoarenes

entry catalyst mol % yield (%)

1 Yb(OTf)3 10 60 2 Sc(OTf)3 10 55 3 La(OTf)3 10 22 4 Zn(OTf)2 10 61 5 Pr(OTf)3 10 63 6 Yb(OTf)3 5 72 7 Sc(OTf)3 5 61 8 Yb(OTf)3 2 92

With optimal conditions at hand, the scope of the cycloaddition was examined (Table 2.10). It was discovered that aryl halogen,38 ester, or ketone substituents were tolerated (entries 2 – 5). Strong electron-withdrawing groups afforded moderate yields (entries 6 and 7); however, a second, inseparable compound was detected comprising up to 33% of the isolated mixture. Substrates with weakly electron-donating substituents resulted in a substantially decreased yield (entry 8) and upon addition of a strongly electron-donating group (entry 9), only trace quantities of product were detected. Substrates that could sequester the Lewis acid did not react (entry 12), and hydroxamic acid–derived nitroso compounds did not participate in the reaction, and only cyclobutane decomposition was observed (entry 13).

Table 2.10. Examination of Nitrosoarene Compatibility in the (4 + 2) Cycloaddition

entry nitrosoarene regioselectivity yield (%)

1 Ar = C6H5 >20:1 92 2 Ar = p-C6H4Br >20:1 89 3 Ar = 2,4-C6H3Br2 >20:1 47 4 Ar = p-C6H4C(O)Me >20:1 69 5 Ar = p-C6H4CO2Et 13:1 82 6 Ar = p-C6H4CN 3:1 61 7 Ar = p-C6H4NO2 4:1 59 8 Ar = p-C6H4CH3 >20:1 29 9 Ar = p-C6H4OCH3 – trace 10 Ar = p-C6H4N(CH3)2 – –a 12 Ar = o-pyridine – –a 13 Ar = C(O)C6H5 – – b a

No reaction. bCyclobutane decomposition observed. Entries 4,7,8,9 were conducted by Tyler Schon.

A second Lewis acid catalyst screen was undertaken to improve reactivity with electron-rich nitrosoarenes and MgI2 was found to facilitate the reaction of para-methoxy

occurred (vide infra). Interestingly, when prolonged reaction times were used or when the isolated compound 2-90a was exposed to MgI2, deoxygenation occurred to afford

pyrrolidine 2-91a. The more electron-rich para-dimethylaminonitroso benzene (entry 2) afforded the pyrrolidine 2-91b directly, and isolation of the tetrahydrooxazine was not possible. It was also found that MgI2 could catalyze the reaction with 2-nitrosopyridine

(entry 3) or electron-deficient nitrosoarenes (compare Table 2.11, entry 4 and Table 2.10, entry 6); however, only the tetrahydrooxazines with electron donating groups (i.e., Table 2.11, entry 1 and 2) could be converted to the corresponding pyrrolidines with MgI2.

Table 2.11. MgI2 Catalyzed (4 + 2) Cycloadditon of DA Cyclobutanes and Nitrosoarenes

entry nitrosoarene product yield (%)

1 Ar = C6H4OCH3 2-90a 26

2 Ar = p-C6H4N(Me)2 2-91b 21

3 Ar = o-pyridine 2-90b 28

4 Ar = p-C6H4CN 2-90b, 2-89i 13, 22

Entries 1-4 conducted by Naresh Vemula.

Two additional alkoxy-activated cyclobutane dicarboxylates were investigated and found to display analogous reactivity with nitrosoarenes under Yb(OTf)3 or MgI2

Table 2.12. Alternative Cyclobutanes in the (4 + 2) Cycloaddition with Nitrosoarenes

entry cyclobutane product yield

Yb(OTf)3 MgI2 1 Ar = C6H5 2-92, 45% - 2 Ar = p-C6H4OMe - 2-93, 35% 3 Ar = p-C6H4NMe2 - 2-94, 15% 4 Ar = C6H5 2-95, 21% - 5 Ar = p-C6H4OMe - 2-96, 38%

Entries 1-5 conducted by Naresh Vemula.

The stereo- and regiochemistry of the tetrahydrooxazines and pyrrolidines were established by a combination of single crystal X-ray and NMR analyses. X-ray quality crystals of compound 2-89b (Table 2.10, entry 2) and 2-93b (Table 2.12, entry 2) were obtained and the ORTEP structures are depicted in Figure 2.6. The structures unambiguously establish both the regiochemistry of the cyclization and the relative stereochemistry at the ring fusion.

Figure 2.6. X-ray Crystal Structures of 2-89b and 2-93

While the structure of 2-89b was firmly established by single crystal X-ray diffraction, we set out to identify the structures of the product mixtures formed with electron-deficient nitrosoarenes (Table 2.10, entries 5–7). The major product in each of the cases was found to have nOe and 15N-1H HMBCAD interactions that were consistent with those observed for 2-89b (Figure 2.7). The minor component of the mixtures showed nOe interactions suggesting a cis ring fusion, and 15N-1H HMBCAD data indicated that a regioisomer, rather than a diastereomer, was formed.

Figure 2.7. Key 1H-1H nOe and 15N-1H HMBCAD Correlations for Structural Determination of 2-89

Once again, the mechanism of the transformation has not yet been intensively investigated, though it is currently believed to occur through a zwitterionic intermediate.

With regards to the formation of pyrrolidine products from the tetrahydrooxazines, a plausible mechanism is proposed in Scheme 2.20. A net reduction is occurring, and it is believed that MgI2 is acting as the reductant in this case, as 50 mol % was required to

effect the transformation. Following formation of the tetrahydrooxazine, coordination of oxygen by MgI2 occurs (2-98). The acetal is cleaved and the resulting oxacarbenium ion

is attacked by the pendant nitrogen atom (2-99). Finally, the initially displaced iodide reacts with the attached Lewis acid, causing the N-O bond reduction and producing I2,

MgO, and the pyrrolidine (2-101). Theoretically, one full equivalent of MgI2 is required

for the transformation; however, maximum yields were observed only for 50 mol % of MgI2. Additionally, the fate of the I2 in this reaction was not determined, as attempts to

detect I2 were not successful. The low yield of the process also proved troublesome, as

decomposition occurs which convolutes the process of determining the operational mechanism.

Scheme 2.20. Mechanism of Pyrrolidine Formation

In conclusion, we have developed the first example of a dipolar cycloaddition between DA cyclobutanes and nitrosoarenes. The regiochemistry and stereochemistry of the cycloadducts has been determined by a combination of NMR and X-ray diffraction analyses. The reaction proceeds well with electron-deficient or neutral nitrosoarenes to form tetrahydrooxazines; however, other nitroso reagents are currently outside the scope

of this reaction. Though the cycloaddition of DA cyclobutanes and nitrosoarenes is a fascinating process, the poor yields even after extensive optimization studies leave much to be desired.