Synthesis of 2-imidazolones and 2-iminoimidazoles

Abstract

Convenient methods for the direct conversion of imidazolium salts to the corresponding 2-imidazolone or 2-imino imidazole derivatives have been developed. Treatment of the salt with commercial bleach leads to effective oxidation at C2 and the formation of the corresponding imidazolone. Alternatively, treatment of the salt with an N-chloro amide affords the corresponding protected 2-amino derivative in good yield.

A large number of natural products, most notably those of the Leucetta (e.g., 1–3)^1–3 and the oroidin families of alkaloids (e.g., 4 and 5)⁴ have been identified which contain either a 2-aminoimidazole or a 2-imidazolone moiety.^{5, 6} In the context of our approaches to these molecules,⁷ we have generally adopted a strategy which involves the functionalization of pre-existing imidazoles, with the late stage introduction of the 2-amino group, rather than the de novo construction of the heterocycle.⁷

Typically, the C2-amine is introduced via the azide, which in turn is incorporated via lithiation at C2, followed by reaction with TsN₃ or TrisN₃.^{8, 9} Whereas, the corresponding carbonyl moiety can be introduced by oxidation of the organometallic with a peroxide such as (TMSO)₂¹⁰ or (PhCO₂)₂.¹¹ This type of strategy has worked very well in a number of different settings both for us¹² and for other investigators,¹³ including en route to modestly complex natural products.

Recently, however, in the context of total syntheses of kealiiquinone (1)^{1, 11} and the 2-amino congener 2,² we found that this metallation-electrophile quench approach failed (Scheme 1).¹⁴ Specifically, the advanced intermediate 6 was in hand, and we had anticipated that C2-lithiation and then trapping with (TMSO)₂ or TsN₃ would provide kealiiquinone (1) or 2-amino-2-deoxykealiiquinone (2) (after reduction), respectively. This failure to complete these syntheses was immensely disappointing given that it occurred at such a late stage of the sequence. .Accordingly, we set out to identify potential solutions to the problem of introducing the C2 substituent onto these and related substrates.

Scheme 1.

Attempted C2-functionalization of an advanced kealiiquinone intermediate

As a result of this roadblock, we sought to develop a method for the direct functionalization at the C2-position that avoided metalation with strong (and potentially nucleophilic) bases. The Ohta group has been a significant contributor to the development of methods for the elaboration of simple imidazoles in the context of the total synthesis of several Leucetta alkaloids.¹⁵ They have demonstrated that 2-thio-substituted imidazoles 8 can be converted into imidazolones 11 via hydrolysis of the corresponding imidazolium salt 9 (X = SPh) presumably via 10 (Scheme 2).¹⁶ While this chemistry appears to work quite well, it does require the pre-functionalization of the imidazole by C2-metallation and treatment with (PhS)₂ (12→8, Scheme 2). This requirement adds a step and there are issues associated with odor. In our own setting, application of this chemistry was not considered attractive given the apparent sensitivity of 6 to metallation or the prospect of introducing the thio moiety at the outset of the sequence. From a mechanistic perspective, the Ohta chemistry can be viewed as proceeding via the amidinium species 9, where the thiophenyl moiety serves as a leaving group. Addition of water, loss of the thiophenyl group and deprotonation of the hydroxyl moiety then provides the imidazolone. We speculated that perhaps this process could be generalized, such that as long as there was an appropriate leaving group at C2 and that an imidazolium salt was employed, the hydrolysis reaction should proceed in a mechanistically similar fashion. Furthermore, there was no reason to suppose that the order of the reactions could not be interchanged such that the imidazolium salt 13 could be prepared first and then advantage could be taken of the relative ease of C2-deprotonation to form the carbene.¹⁷ Subsequent reaction of the carbene 14 with a suitable electrophile to provide the amidinium species 9, followed by hydrolysis would lead to the formation of the imidazolone, i.e., 12→13→9→11, in a one pot process from 13 (Scheme 2).¹⁶ Herein, we describe the development of an approach using a halonium source to activate the C2 position and subsequent basic hydrolysis.

Scheme 2.

Addition-elimination pathways to imidazolones

Given that our initial application of this chemistry would be directed towards the total synthesis of kealiiquinone (1), we examined benzimidazole derivatives as substrates. After some preliminary scouting experiments on two imidazolium salts 15a and 15b¹⁸ with bases (NaH,¹⁹ NaOH, Na₂CO₃, and K₂CO₃) and NCS, we settled on using either aqueous NaOH, NCS or Na₂CO₃, NCS in THF, from the four conditions examined (Table 1). Occasionally, with the stronger base we observed some hydrolysis (entries 3–5, Table 2) of the imidazolium salt and other unidentified side product formation rather than oxidation. This method was extended to include simple imidazoles in addition to benzimidazoles. The reaction is effective at producing the imidazolones in yields between 36–86%, and various combinations of nitrogen substituents are tolerated, including Bn, MOM, SEM and PMB (Table 2, Method A or B)). These yields are similar to those reported by Ohta and coworkers via the 2-thiobenzimidazole derivatives.¹⁶

Table 2.

Substrate screen

entry	conditions	yield (%)	substrate	product
1	B	84	R = Bn; X = I	R = Bn
	C	85
			15a	16a
2	B	83	R = PMB, X = I	R = PMB
	C	81
			15b	16b
3	A	46	R = MOM, X = Cl	R = MOM
	B	81
			15c	16c
4	A	49	R = SEM, X =Cl	R = SEM
	C	79
			15d	16d
5	A	50
	C	88
			15e	16e
6	B	86	R = Bn	R = Bn
	D	79
			15f	16f
7	B	72	R = Me	R = Me
	D	71
			15g	16g
8	B	37	R = Bn	R = Bn
	D	39
			15h	16h
9	B	48	R = SEM	R = SEM
	D	36
			15i	15i
10	B	52
	D	67
			15j	16j

Condition A = 1 M Na₂CO₃, NCS, THF; Condition B = 2 M NaOH, NCS, Condition C = 10 equiv, NaOCl, THF, rt; Condition D = NaOCl, 1 equiv NaOH, THF, rt.

Table 1.

Preliminary base screen

entry	substrate	conditions	product/yield (%)
1		NaH, THF then NCS	69
2		2 M NaOH, NCS, THF	84
3		1 M Na2CO3, NCS, THF	68
4		1 M K2CO3, NCS, THF	62
5		NaH, THF then NCS	53
6		2 M NaOH, NCS, THF	83
7		1 M Na2CO3, NCS, THF	66
8		1 M K2CO3, NCS, THF	62

While these procedures worked reasonably well, it occurred to us that the same transformation might be accomplished through the addition of household bleach (NaOCl), which could serve as both the base and as the source of a chloronium ion. Accordingly, we were delighted to observe that upon treatment of the substrates in Table 2 (Method C) with bleach at 0 °C resulted in the smooth conversion into the corresponding imidazolones in excellent yield and purity. In some cases, we found that yields were improved and chlorination side reactions were minimized by the reduction of the amount of bleach and addition of NaOH (Method D).

From the substrates depicted in Table 2, it can be observed that most of the imidazolones are relatively simple, and in reality for our purposes we needed this chemistry to be successful on more elaborate substrates. In the context of our kealiiquinone endeavors, imidazolium salt 17¹⁴ containing a lactone moiety was available, and thus we subjected it to the oxidation chemistry. Gratifyingly, this substrate underwent oxidation to provide the corresponding imidazolone in good yield upon treatment with bleach (Scheme 3).

Scheme 3.

C2-Oxidation of an advanced kealiiquinone intermediate

At this stage, we do not know whether this reaction proceeds mechanistically via carbene 14 as depicted in Scheme 2, or whether the alternative mechanism outlined in Scheme 4 is more likely. It is of note that related observations of nucleophilic substitution of 2-haloimidazolium salts have been reported in the literature.^{20, 21} While these observations do not prove that the 2-chloroimidazolium salt is formed in the course of the oxidation, they demonstrate that it is a competent intermediate in this chemistry. In the latter case, hydoxide adds to the imidazolium salt 15 to form 19,²²O-chlorination and then base-induced elimination of HCl from 20 results in the formation of the carbonyl moiety. Alternatively, with hypochlorite ion (either produced in situ or added directly), this may give species 20 directly, which upon base-induced elimination provides the corresponding imidazolone.

Scheme 4.

Possible mechanistic pathways for imidazolium salt oxidation

While the mechanistic details of this reaction remain unclear pending further investigation, we reasoned that other reagents that contain a nucleophilic site and an appropriately positioned leaving group may also participate in this chemistry. Specifically, it was hypothesized that N-chloro amides would permit the direct introduction of an amino moiety. We were delighted to observe that upon treatment of imidazolium salt 15a with chloramine-T the imino imidazole 21 was formed in 55% yield (Scheme 5). Increasing the equivalents of chloramine T to 2.2 improved the yield of 21 to 95%. While this result was encouraging, the tosyl group is not always easy to remove and thus we briefly examined other N-chloroamides (prepared in situ from the corresponding carbamates by treatment with t-BuOCl).²³ Both the benzimidazole 15a and simple imidazole derivative 15h undergo amination with both the benzyl and t-butyl chlorocarbamate providing the corresponding imino derivative in good yields (Scheme 5).^24,25

Scheme 5.

Introduction of a 2-imino moiety

In summary, we have discovered a convenient procedure for the direct conversion of imidazolium salts to imidazolones by treatment with NCS/aqueous base or hypochlorite. A range of substrates participate in this chemistry, including benzimidazole, simple imidazole derivatives and more elaborate benzimidazole derivatives. Similarly, the use of N-chloro amides allows the incorporation of a 2-amino substituent. This process occurs at room temperature or below and avoids the use of strong bases and transition metal catalysts. Current investigations are directed towards determining the mechanistic details, extending the scope of this chemistry and applying it in the total synthesis of various alkaloids.

Figure 1.

2-Imidazolone natural product.