3-Pyridylnitrene, 2- and 4-pyrimidinylcarbenes, 3-quinolylnitrenes, and 4-quinazolinylcarbenes. Interconversion, ring expansion to diazacycloheptatetraenes, ring opening to nitrile ylides, and ring contraction to cyanopyrroles and cyanoindoles

Summary Precursors of 3-pyridylnitrene and 2- and 4-pyrimidinylcarbenes all afford mixtures of 2- and 3-cyanopyrroles on flash vacuum thermolysis, but 3-cyanopyrroles are the first-formed products. 3-Quinolylnitrenes and 4-quinazolinylcarbenes similarly afford 3-cyanoindoles. 2-Pyrimidinylcarbenes rearrange to 3-pyridylnitrenes, but 4-pyrimidinylcarbenes and 4-quinazolinylcarbenes do not necessarily rearrange to the corresponding 3-pyridylnitrenes or 3-quinolylnitrenes. The ring contraction reactions are interpreted in terms of ring opening of either the nitrenes or the diazacycloheptatetraenes to nitrile ylides.

In contrast, 3-pyridylnitrene (10) undergoes a different type of ring opening to the observable nitrile ylide 11 and subsequently the ketenimine 12 (Scheme 3) [13]. Nitrile imines [14] and nitrile ylides [15,16] may have either allenic or propargylic structures, and for this reason their cumulene-type IR absorptions can occur over a wide frequency range, 1900-2300 cm −1 , depending on substituents. The IR absorption of 11 was observed at 1961 cm −1 , indicating an allenic structure. Nitrene 10 can also undergo ring expansion to two diazacycloheptatetraenes 15 and 16 via the azirenes 13 and 14 (Scheme 3) [13]. The diazacycloheptatetraenes were not observed directly in this study, but aza-and diazacycloheptatetraenes have been observed in several other cases [1, 17,18] and the ring-expansion reactions have been the subject of detailed theoretical investigation [19].

3-Pyridylnitrene
Flash vacuum thermolysis (FVT) of 3-azidopyridine (9) yields predominantly 3-cyanopyrrole (8,Scheme 4). Under the mildest conditions, FVT of 9 at 370 °C/10 −3 mbar generates 8 and 7 in a 3:1 ratio. A temperature increase to 500 °C causes the ratio to drop to 1.2:1 due to the thermal interconversion of 7 and 8 [10,20]. The reaction mechanism was probed by calculations at the B3LYP/6-31G* level, which has been found to be adequate for other, similar reactions [11,13,17,21]. The transition state for the ring opening of the cyclic ketenimine 16 to the (s,Z)nitrile ylide 11 lies 5 kcal/mol above the open shell singlet nitrene S 1 10, i.e., the barrier is only 11 kcal/mol above the cyclic ketenimine 16. This is lower than the barrier for direct ring opening of the nitrene 10 itself (16 kcal/mol) (Scheme 4 and Figure 1) [13]. Thus, while both the nitrene 10 and the ketenimine 16 may undergo ring opening with rather low activation barriers, the ring opening of the ketenimine has the lowest barrier. Both of these reactions can take place with ease under conditions of FVT. With a low barrier for ring opening, recyclization of the nitrile ylide 11 now becomes the energetically most favourable mechanism of formation of 3-cyanopyrrole (8) via the 3H tautomer 18 with a barrier of only 10 kcal/mol above the S 1 nitrene or 16 kcal/mol above the nitrile ylide (Scheme 4 and Figure 1). This explains why 3-cyanopyrrole (8) is the predominant isomer, in contrast to the reaction of 2-pyridylnitrene, where 2-cyano- Figure 1: Energy profile for the ring opening and ring contraction in 3-pyridylnitrene 10 and 1,6-diazacyclohepta-1,2,4,6-tetraene (16, energies in kcal/ mol at the B3LYP/6-31G* level).
pyrrole is formed preferentially [11]. In the analogous case of 3-quinolylnitrene, 3-cyanoindole is formed exclusively under mild FVT conditions [21]. A direct, concerted ring contraction in 3-pyridylnitrene would be possible (via 17 and 18, Scheme 5), but such reactions have considerably higher activation barriers, ca. 30 kcal/mol in the case of phenylnitrene [22]. A transition state for the concerted ring contraction of 3-pyridylnitrene (10) to 3H-3-cyanopyrrole (18) was not found, but we calculate a barrier of 23 kcal/mol for the concerted ring contraction to 2-cyano-2H-pyrrole (17, Figure 1). Furthermore, a higher proportion of 2-cyanopyrrole would be expected if Scheme 5 was operating. Concerted ring contraction in the 7-membered ring ketenimine 16 is also possible [22], but this type of reaction has an even higher activation energy. The lowest-energy path for (di)azacycloheptatetraenes to undergo ring contraction is by ring opening.
The nitrile ylide 11 is not directly observable under FVT conditions, because the barriers for its reactions are very low. The calculated barrier for cyclization to 3-cyano-3H-pyrrole (18) is 16 kcal/mol (Scheme 6 and Figure 1).

2-and 4-pyrimidinylcarbenes
FVT of tetrazolylpyrimidines of type 19 causes elimination of N 2 to generate 4-and 2-diazomethylpyrimidines 20, which can ring-close to the corresponding 1,2,3-triazolopyrimidines 21 (Scheme 7) [23]. Endothermic ring-chain valence isomerization of the type 21 → 20, with free energies of activation of 18-22 kcal/mol in solution, has been demonstrated for 1,2,3triazolo[1,5-a]pyrimidines [24] but not for 1,2,3-triazolo[1, 5c]pyrimidines [25,26]. However, 7-benzyl-3-ethoxycarbonyl-1,2,3-triazolo[1,5-c]pyrimidin-5-ol and its diazo valence tautomer, 6-(2-diazoethoxycarbonylmethylene)-2-(α-hydroxybenzyl)pyrimidin-4-(2H)-one, have been reported [27]. We find that FVT of the 4-and 2-(5-tetrazolyl)pyrimidines 22-24 also affords cyanopyrroles (Scheme 8). FVT of 2-(5tetrazolyl)pyrimidine (22) affords a ca. 1:1 ratio of 2-and 3-cyanopyrroles (Scheme 8). The results of FVT of tetrazoles 23 and 24 are collected in Table 1. The formation of different mixtures of the three cyanodimethylpyrroles 25-27 depending on the conditions can be explained in terms of chemical activation. The formation of (hetero)arylcarbenes and their rearrangement to (hetero)arylnitrenes and cyanopyrroles are strongly exothermic reactions. Consequently, when the reaction is performed in the low-pressure gas phase, the reaction products carry excess thermal (rovibrational) energy, which facilitates the sigmatropic shifts of H, CN, and CH 3 , which will cause interconversion of the cyanopyrroles [28]. In many cases, this cannot be completely avoided, even by using the mildest possible FVT temperatures, but an increase in pressure (1 hPa N 2 ) will help to remove excess thermal energy and so preserve the initial reaction products. Therefore, as seen in Table 1, it can be concluded that the dimethylcyanopyrrole 25 is the primary reaction product of 23, and 27 is the predominant product from 24. That chemical activation is the cause is seen in the fact that FVT of the individual dimethylcyanopyrroles 25 and 27 afford mixtures very similar to those obtained from 23 and 24, respectively, but a temperature of 800 °C is required for this, whereas 400 °C suffices in the FVT of the tetrazoles (Table 1).
Following the analysis of the ring contraction in 3-pyridylnitrene (10) by ring expansion and ring opening to a nitrile ylide (Scheme 4 and Figure 1), we can interpret the reactions in terms of ring expansion of the pyrimidinylcarbenes 28 and 33 to diazacycloheptatetraenes 29 and 34, ring contraction to 3-pyridylnitrenes 30 and 35 and/or ring opening to nitrile ylides 31 and 37, and ring closure to cyanopyrroles (Scheme 9).  In the case of the 4-pyrimidinylcarbene 28 a direct ring opening of the diazacycloheptatetraene 29 to the nitrile ylide 31 is possible. However, in the case of the 2-pyrimidinylcarbene 33, the first-formed diazacycloheptatetraene 34 cannot open directly to a nitrile ylide but must first rearrange to the 3-pyridylnitrene 35. Either the 3-pyridylnitrene 35 or the second diazacycloheptatetraene 36 may then undergo ring opening to the nitrile ylide 37. Sigmatropic shifts of H, CN, or CH 3 in the 3H-pyrroles 32 and 38 lead to the final products.
We have previously reported strong evidence for the ring expansion of a 2-pyrimidinylcarbene 39 to a diazacycloheptatetraene 40 and subsequent ring contraction to a 3-pyridylnitrene 41, which undergoes cyclization to afford the pyridoindole (4-azacarbazole) 42 (Scheme 10) [29]. The alternative ring expansion/ring contraction/recyclization to the pyrimidoisoindole 43 also takes place [29]. The formation of 42 is important, as it demonstrates that 2-pyrimidinylcarbenes can rearrange to 3-pyridylnitrenes, whereas 4-pyrimidinylcarbenes do not necessarily rearrange to 3-pyridylnitrenes (see 55 below).
The ketenimine 46 was again converted to ylide 47 on photolysis at 310-390 nm. We assume the nitrene 45 is formed initially, but it is converted to 46 and 47 at the same wavelength. As in the examples described above, the ring opening to the ylide 47 may take place either from the nitrene or from the cyclic ketenimine, although we only observed the latter reaction directly. It was possible to cycle many times between these two intermediates ( Figure 2 and Figure 3), but eventually signal intensity was lost, probably because another reaction, the cyclization to the isocarbazole 49, took place. This reaction is analogous to the photocyclization of o-biphenylylnitrene to isocarbazole [30]. As shown below, the indoloquinoline 50 is indeed a major product under FVT conditions. It is possible that 49 could contribute to the observed visible spectrum, but it obviously cannot explain the IR spectrum. The same visible spectrum was obtained by photolysis of 44 embedded in Preparative FVT of azide 44 at 400-800 °C affords the indoloquinoline 50 in 52-60% yield (Scheme 12). Importantly, smaller amounts of amine 51 and the ring-contraction product 2-phenyl-3-cyanoindole (48, 21-15%) were also isolated.
Formation of amines is diagnostic for triplet nitrenes, even in low-pressure gas-phase reactions [10,22]. The 3-cyanoindole 48 is expected to be formed by cyclization of the nitrile ylide 47 in the same way that the 3-cyanoindole is obtained from the unsubstituted 3-quinolylnitrene [21]. The three products, 48, 50 and 51 were formed even on thermolysis of 44 in solution.
The data demonstrate that carbene 55 does not convert thermally to nitrene 45. In other words, although carbene-nitrene rearrangements are known to occur [1,19] (see, e.g., Scheme 1 and Scheme 10 above), they may be bypassed when ring opening to nitrile ylides becomes more favourable.

Experimental General
The apparatus and procedures for preparative FVT [31] and for Ar matrix isolation [11,32,33] were as previously described.
KBr and CsI windows were used for IR spectroscopy. FVT products were isolated in liquid nitrogen (77 K) in the preparative thermolysis, and at 22-25 K in Ar matrices for IR experiments. IR spectra of the Ar matrices were measured at 7-10 K with a resolution of 1 cm −1 . Photolyses were done through quartz by using a 75 W low pressure Hg lamp (254 nm) or a 1000 W high pressure Hg/Xe lamp equipped with a monochromator and appropriate filters. A water filter was used to remove infrared radiation, and a 7.5% NiSO 4 or a NiSO 4 /CuSO 4 solution (7.5 and 2.5%, respectively) to remove visible light where required. Analytical gas chromatography used a 10% OV 17 column programmed at 120-180 °C at 2°/min with N 2 as carrier gas at 0.6 bar. Preparative gas chromatography used a 20% Carbowax column at 200 °C with H 2 as carrier gas at 60 mL/min.

FVT of 2-(5-tetrazolyl)pyrimidine (22): A portion of 22
(300 mg) was sublimed into the pyrolysis tube at 170 °C and pyrolysed at 600 °C/10 −3 mbar in the course of 12 h. The resulting pyrolysate (120 mg) was identified as a 1:1 mixture of 2-and 3-cyanopyrroles 7 and 8 by comparison of the 1 H NMR, IR and mass spectra with those of authentic materials. Yields were determined by GC as above [10].   FVT at 300-600 °C the product was isolated on a KBr window at 77 K for IR spectroscopy. No reaction was observable below 400 °C. The 4-diazomethyl-2-phenylquinazoline (54) was detectable by absorption at 2095 cm −1 in the 400 °C experiment. In each case, at FVT temperatures of 400-600 °C, 3-cyano-2-phenylindole (48) was the only other identified product, characterized by its absorption at 2220 cm −1 .

Supporting Information
Supporting Information File 1 Computational details, calculated and experimental IR spectra, and calculated electronic transitions.