Lithiation and Electrophilic Substitution of Dimethyl Triazones

Abstract

The lithiation and electrophilic substitution of dimethyl triazones is described. Directed lithiation or tin-lithium exchange of dimethyl triazones afforded the corresponding dipole stabilized nucleophiles that were trapped with various electrophiles. Keto-triazone derivatives accessed by acylation of such nucleophiles were readily converted to the corresponding imidazolone heterocycles.

Complex-induced proximity effects have been utilized extensively to functionalize otherwise unactivated sites of a molecule.ⁱ In particular, the metalation and electrophilic substitution of carbon centers adjacent to a nitrogen bearing an electron withdrawing group has been studied extensively,ⁱⁱ and several examples of the directed lithiation of alkyl urea derivatives have been reported.ⁱⁱⁱ However, there have been no previous reports of the lithiation of alkyl triazone derivatives. While triazones have found great utility in protection of primary amines,^iv their potential use to mask urea functional groupings has received far less attention.^v In the context of our studies concerning the total synthesis of the agelastatin alkaloids,^vi we employed metalated triazone 1 as a synthetic equivalent of metalated urea 2 to access functionalized urea derivative 3 (Scheme 1). Herein, we report our observation on the directed lithiation and electrophilic substitution of 1,3-dimethyl triazones in addition to derivatization of related keto-triazones to the corresponding imidazolone heterocycles.

Scheme 1.

Use of the metalated triazone 1 as a synthetic equivalent of a metalated urea 2.

For these studies, we prepared several 1,3-dimethyl triazones by direct condensation of dimethyl urea (4), formalin, and various primary amines (Table 1).^iva,ivb Trimethyl triazone 6a was prepared in 42% yield after purification by vacuum distillation (Table 1, entry 1). The isopropyl and mesityl triazones (6b and 6c) were obtained in 20% and 21% yields, respectively (Table 1, entries 2 and 3). Notably, the benzyl and p-toluene triazones 6d and 6e were both readily prepared on greater than 30 gram scale in 91% and 71% yield, respectively (Table 1, entries 4 and 5), and could be efficiently purified by recrystallization from hexanes, rendering them particularly attractive urea surrogate from a preparative standpoint.

Table 1.

Synthesis of triazones

Entry	Amine	Time (h)	Yield of 6 (%)
1	5a, R = Me	24	42a
2	5b, R = iPr	24	20b
3	5c, R = Mesityl	48	21b
4	5d, R = Bn	17	91c
5	5e, R = C6H4-p-Me	19	71c

^aPurified by distillation.

^bPurified by silica gel flash column chromatography.

^cPurified by recrystallization from hexanes.

We next examined the directed lithiation of 1,3-dimethyl triazones. Treatment of the 1,3-dimethyl triazone derivatives with one equivalent of s-butyl lithium at −78 °C in THF followed by quenching with deuterium oxide afforded the corresponding triazone products with complete deuterium incorporation at the methyl group α to the nitrogen (Table 2). Under optimal conditions the lithiation of the methyl and benzyl triazones 6a and 6d, respectively, with s-butyl lithium followed by quenching with deuterium oxide afforded the corresponding monodeuterated products in moderate yields (41% and 50%, respectively; Table 2, entries 1 and 3). Unfortunately, these reactions were plagued by the rapid formation of self-condensation byproducts via addition of the lithiated triazone to the C2-carbonyl of another triazone. The yields for the formation of the deuterated benzyl triazone were identical when quenched after 10, 30, or 60 min periods, which suggests that once formed, the lithiated triazone intermediates were stable at −78 °C for up to one hour (Table 2, entries 3–5). Interestingly, the mesityl and toluyl triazones 6c and 6e, respectively, underwent the lithiation and deuteration sequence with greater efficiency to afford the monodeuterated products 7c and 7e in 95% and 85% yield, respectively (Table 2, entries 2 and 6). Importantly, we observed that the formation of undesired self-condensation byproducts was significantly suppressed with these substrates. It should be noted that the use of s-butyllithium was found to be optimal for the lithiation of dimethyl triazones. Attempted use of n-butyllithium as the base additive predominantly led to undesired addition of the butyl group to the C2 carbonyl group of the urea. Alternatively, the use of t-butyllithium as the base additive resulted in formation of a complex mixture of products consistent with indiscriminate lithiation of the triazone substrates at undesired positions. Furthermore, metal amides were ineffective as the base additive at −78 °C and their use at higher temperatures was complicated by decomposition of lithiated triazone intermediates. Finally, inclusion of other common additives such as tetramethylethylenediamine (TMEDA) or hexamethylphosphoramide (HMPA) in combination with s-butyllithium gave no clear advantage.

Table 2.

Directed lithiation and deuterium incorporation of 1,3-dimethyl triazone

Entry	Substrate	Time (min)	Yield of 7a (%)
1	6a, R = Me	10	41
2	6c, R = Mes	15	95
3	6d, R = Bn	10	50
4	6d, R = Bn	30	50
5	6d, R = Bn	60	50
6	6e, R = C6H4-p-Me	15	85

^aProducts showed complete monodeuterium incorporation at C7.

We then evaluated the reactivity of various electrophiles with the lithiated triazones (Table 3). The lithiated triazones underwent nucleophilic addition to α,β-unsaturated aldehydes (Table 3, entry 1–3) and benzaldehyde (Table 3, entry 4) in moderate yields (47–70%). Methyl ester derivatives were suitable electrophiles for this chemistry and afforded the corresponding keto-triazone products (Table 3, entries 5–13). The use of 2.5 equivalents of the triazone nucleophile resulted in full and efficient conversion of methyl benzoate (12) to ketone 22 (Table 3, entry 5). In more challenging cases, an increase in the equivalents of the nucleophile led to an increase in the yield of the desired adduct (Table 3, entries 6–8, and 11–12). The use of excess lithiated triazone allowed for the generation of the desired keto-triazones 25c and 25e from methyl ester 15, which contains an acidic lactam N–H proton (Table 3, entry 11–13). However, when a large excess of lithiated triazone was used, we sometimes observed the formation of minor double-addition byproducts. The lithiated triazone could also be trapped with trialkyltin chlorides to afford versatile and stable α-stannylated triazones 26d–e and 27d–e (Table 3, entry 14–17)–substrates that allowed for a more practical C–C bond formation (vide infra).^vii,viii

Table 3.

Triazone addition to various electrophiles

Entry	Substrate	Electrophile	Triazone (equiv)	Product	Yielda(%)
1b	6d		2		70
2b	6d		2		17
3b	6d		1.7		47
4b	6d		1.7		65
5	6a		2.5		91
6b	6d		2		21
7b	6d		4		49
8b	6d		6		70
9	6a		2		37
10b	6d		6		80
11	6c		3.5		50
12	6c		4		72
13c	6e		4		65
14d	6d	Bu3SnCl 16	1		45
15e	6e	Bu3SnCl 16	1		64
16	6d	Cy3SnCl 17	2		90
17e	6e	Cy3SnCl 17	1		45

^aIsolated yield after purification.

^bTMEDA (2 equiv) was used as an additive.

^cHMPA (2 equiv) was used as an additive.

^d1.5 equivalent of trialkyltin chloride was used.

^e1.1 equivalent of trialkyltin chloride was used.

Mes: mesityl

Despite the successful direct lithiation of 1,3-dimethyl triazones described above, the formation of triazone self-condensation byproducts complicated the reaction, and an excess of the triazone was needed to form the desired products efficiently (Table 3, entries 8 and 10). In order to address this issue, we evaluated whether tin-lithium exchange could generate the lithiated triazones with greater efficiency.^ix When stannyl triazone 26d was treated with one equivalent of n-butyllithium at −78 °C in THF, the desired lithiated triazone intermediate was obtained quantitatively. Importantly, the rapid rate of tin-lithium exchange completely suppressed the formation of self-condensation byproducts. This method required only two equivalents of lithiated triazone (via tin-lithium exchange) to convert methyl ester 14 to ketone 24d in 74% yield (Table 4, entry 1) as compared to the six equivalents required using the direct lithiation route (Table 3, entry 10). Additionally, conversion of methyl ester 15 to the corresponding keto-triazone 25 using reagents generated through tin-lithium exchange afforded the desired keto-triazone products in higher yields than the direct lithiation protocol previously described (Table 4, entries 2–4).

Table 4.

Nucleophilic addition of the lithiated triazone obtained by tin-lithium exchange

Entry	Substrate	Electrophile	Stannane(equiv)	Product	Yielda (%)
1	26d, R = Bn		2		74
2	26a, R = Me		3		62
3	26d, R = Bn		3.5		83
4	26e, R = C6H4-p-Me		3.5		80
			3.5

^aIsolated yield after purification.

Finally, we investigated the synthesis of imidazolones from keto-triazones.^vi,x To our delight, the triazone moiety in 28 could be readily hydrolyzed in the presence of aqueous hydrochloric acid in methanol at 23 °C. The 2,3-disubstituted imidazolone 30 was obtained in 83% yield through a condensative cyclization of a putative keto-urea intermediate 29 (Scheme 2).^vi,xi

Scheme 2.

Formation of imidazolone 30 from keto-triazone 28. Reagents and Conditions: (a) 0.5 N HCl (2 equiv), MeOH, 23 °C, 83%. PMB: p-methoxybenzyl

The alkylation of these versatile keto-triazones provides an expedient route to trisubstituted imidazolones. For example, the methylation of keto-triazone 31 occurred efficiently via its deprotonation with sodium hydride followed by treatment of the corresponding enolate with methyl iodide to afford keto-triazone 32 in 91% yield (Scheme 3). When the methylated keto-triazone 32 was treated with aqueous hydrochloric acid in methanol at 63 °C, 2,4-dimethyl-3-phenyl imidazolone 33 was obtained in 100% yield.

Scheme 3.

Formation of trisubstituted imidazolone 33. Reagents and Conditions: (a) NaH (1.2 equiv), MeI (2 equiv), DMF, 0→23 °C, 91%; (b) 0.5 N HCl (2 equiv), MeOH, 63 °C, 100%.

In summary, we have described the utility of 1,3-dimethyl triazones in the introduction of a urea functional grouping through directed lithiation to afford dipole-stabilized lithiated triazone intermediates that can be trapped with various electrophiles (Table 3). We have also shown that stannylated triazones prepared from such lithiated triazones provide a highly efficient source of the desired lithiated triazones and can lead to significant improvement in more complex unions (Table 4). The resulting keto-triazones not only provide further opportunity for introduction of additional substituents but they also serve as excellent precursors for the corresponding imidazolone heterocycles.