Concise One-Pot Preparation of Unique Bis-Pyrrolidinone Tetrazoles

Abstract

A one-pot, two-step synthesis of bis-pyrrolidinone tetrazoles has been established via the Ugi-Azide reaction using methyl levulinate, primary amines, isocyanides and azidotrimethylsilane with subsequent acid treatment to catalyze the lactam formation. The efficiency of the protocol was established followed by a successful transition to library production in four 24-well plates.

Derivatization of isocyanide based MCR products such as those from the Ugi reaction, followed by a post-condensation modification have received massive attention in medicinal chemistry for the pursuit of generating collections of small molecules with high molecular diversity.^1–6 Interestingly, substitution of the carboxylic acid in the generic Ugi MCR with azidotrimethylsilane (TMSN₃) makes it possible to afford 1,5-disubstituted tetrazoles, 1 (Scheme 1),^7–8 an effective conformational mimic for the cis-amide bond conformation.^9–10

Scheme 1.

General Ugi-Azide reaction

Exploration of the Ugi-Azide MCR using a variety of diverse reagents have led to the creation of unique scaffolds as exemplified by ketopiperazine-tetrazoles,⁸ azepine-tetrazoles,^11–12 benzodiazepine-tetrazoles,¹³ and quinoxaline-tetrazoles.¹⁴ This letter reports the establishment of unique methodology which utilizes keto-esters (methyl levulinate 2) along with primary amines, isocyanides, and TMSN₃ to afford novel peptidomimetic-like bis-pyrrolidinone tetrazoles 3 (Scheme 2).

Scheme 2.

General synthetic route to access bis-pyrrolidinone tetrazole 3

The pilot reaction during optimization of the sequence utilized methyl levulinate 2, 2-thiophenemethylamine 4, 2,6-dimethylphenyl isocyanide 5 and TMSN₃ to generate 5-(1-(2,6-dimethylphenyl)-1H-tetrazol-5-yl)-5-methyl-1-(thiophen-2-ylmethyl)pyrrolidin-2-one 7 (Scheme 3). After allowing the mixture to stir overnight at room temperature, the Ugi condensation product 6 was typically observed in high yield (LC-MS > 90% A% purity as judged by UV214 and ELS) (Scheme 3). Subsequent microwave irradiation (100 °C, 5 min) failed to deliver the desired bis-heterocyclic product 7 (Table 1, entry 2). However, very encouragingly simple addition of a 10% solution of trifluoroacetic acid (TFA) in 1,2-dichloroethane (DCE) into the on-going Ugi reaction afforded γ-lactam formation in good to moderate yield (Table 1, entry 3). Indeed, to the best of the authors’ knowledge, we believe this is the first example of TFA-mediated γ-lactam formation. The yield was also further improved with the use of excess keto-ester and isocyanide (Table 1, entry 4).

Scheme 3.

Synthesis of 5-(1-(2,6-dimethylphenyl)-1H-tetrazol-5-yl)-5-methyl-1-(thiophen-2-ylmethyl)pyrrolidin-2-one 7

Table 1.

Optimization for the pilot synthesis of 7

Entry	Conditions	2	4	5	TMSN3	Yield of 7 (%)
1	25°C, 24 h	1.0 eq	1.0 eq	1.0 eq	1.0 eq	-
2	μwave 100 °C, 10 min	1.0 eq	1.0 eq	1.0 eq	1.0 eq	-
3	10% TFA in DCE, μwave 100 °C, 10 min	1.0 eq	1.0 eq	1.0 eq	1.0 eq	40
4	10% TFA in DCE, μwave 100 °C, 10 min	1.5 eq	1.0 eq	2.0 eq	1.0 eq	56
5	10% TFA in DCE, 25°C, 24 h	1.5 eq	1.0 eq	2.0 eq	1.0 eq	58
6	15% TFA in DCE, 25°C, 24 h	1.5 eq	1.0 eq	2.0 eq	1.0 eq	59
7	20% TFA in DCE, 25°C, 24 h	1.5 eq	1.0 eq	2.0 eq	1.0 eq	61
8	10% TFA in DCE, 25°C, 24 h	1.0 eq	1.0 eq	1.0 eq	2.0 eq	39

With these encouraging results from the pilot study in-hand, a small library comprised of eight compounds (Figure 1) was synthesized to further validate this one-pot, two-step synthetic protocol by varying the primary amine and isocyanide inputs. Predictably, given their poor nucleophilicity, use of anilines as the amine component resulted in lower yields (14 and 15).

Figure 1.

Example analogs (x% = overall yield)

Although microwave irradiation expedites the process, it is worth mentioning that each step can be performed at room temperature (Table 1, Entry 5). Stoichiometry studies performed at room temperature (Entries 6, 7 and 8) failed to significantly increase yields of final product. The procedure was thus progressed to 4 24-well plate production (Scheme 4) with an assortment of primary amines 16 {1–24} and isocyanides 17 {1–4} where subsequently, final products were purified by in-house mass-triggered purification platforms, successfully yielding 84 products 18 from the 96 reactions.

Scheme 4.

Synthesis of bis-pyrrolidinone tetrazoles 18

The reaction seemed robust for a wide range of primary amines and isocyanides, Figure 2. Table 2 presents both isolated yields and purities of final target molecules demonstrating the generality of the protocol. Notably, 2,6-dichlorobenzylamine 16 {2}, which performed well in the Ugi reaction, did not undergo any cyclization upon addition of TFA, possibly due to strong steric and electronic effects. In addition, two amines, 4-morpholinoaniline 16 {11} and 1-benzylpiperidin-4-amine 16 {22} produced Ugi congeners which underwent ring formation in only low yield (8–23%, eight examples). Likewise, sterically hindered cyclohexylamine 16 {23} produced no final cyclized product. Taken as a whole, 84 compounds were obtained with overall yields ranging from 2–84% with 82 compounds having purity greater than 95% [as judged by UV absorbance at 214 nm, 254 nm and evaporative light scattering (ELS)].

Figure 2.

Diversity reagents 16 {1–24} and 17 {1–4}

Table 2.

Yield and purity (%) of the 96-well plate production of 18 {1–24, 1–4}

R1NH2 (16)	R2NC (17)
	1		2		3		4
	Y	P	Y	P	Y	P	Y	P
1	nr	-	46	100	57	100	53	98
2	nr	-	un	-	un	-	un	-
3	nr	-	45	100	45	100	66	100
4	nr	-	45	100	50	100	65	100
5	69	97	42	100	53	100	64	98
6	49	100	36	100	38	100	55	100
7	50	100	39	100	50	100	54	100
8	57	100	42	100	50	100	62	100
9	57	100	42	100	55	100	49	100
10	56	98	41	100	51	100	60	100
11	23	70	16	100	8	100	13	100
12	47	100	34	100	50	100	53	100
13	46	100	41	100	48	100	63	100
14	49	100	nr	-	38	100	59	100
15	38	100	27	100	43	100	47	100
16	45	100*	47	100	27	100	8	100*
17	56	100	44	100	58	100	61	100
18	51	100	39	100	39	100	61	100
19	26	100	23	100	29	100	33	100
20	55	100	51	100	61	100	83	95
21	59	100	44	100	64	100	72	100
22	7	93*	22	100*	6	100*	2	100*
23	un	-	un	-	un	-	un	-
24	28	96	24	100	18	100	55	100

Y = Yield (%); P = Purity (%) based on UV 214 nm; nr = not recovered/lost during purification; un = no cyclization to 18 observed;

^*purity based on ELS

Virtual libraries derived from reagents used in both the initial pilot and plate based library (7, Figure 1 and 2) were also enumerated to establish their uniqueness relative to a collection of over 400,000 chemically diverse small molecules in the NIH molecular libraries small molecule repository (MLSMR).¹⁵ As such, principle component analysis (PCA)¹⁶ demonstrates the unique spatial occupancy of the bis-pyrrolidinone tetrazole scaffold when compared to 942 nearest MLSMR neighbors described herein Figure 3, with no substructure match in the MLSMR and only minor overlap in similarity space with its nearest neighbors.

Figure 3.

Similarity space occupied by the bis-pyrrolidinone tetrazoles library (blue dots) relative to the 942 nearest neighbors in MLSMR (red dots).

In summary, a one-pot, two-step protocol for large scale production of libraries of bis-pyrrolidinone tetrazoles has been successfully developed using the tethered keto-ester methyl levulinate 2, primary amines, isocyanides and azidotrimethylsilane through the use of the Ugi-Azide reaction followed by subsequent lactam formation under acidic conditions. Due to the robustness of the described methodology, future studies will continue to expand readily available molecular diversity delivering scaffolds of interest, in particular to chemists involved in file enhancement programs.