Formation of Pyrroloindolines via the Alkylation of Tryptamines with Trichloroacetimidates.

Abstract

Pyrroloindolines and related systems are present in a large number of complex natural products. These core structures have generated considerable synthetic interest, as many of the compounds possess challenging, elaborate structures and interesting biological properties. Recently we have focused on using trichloroacetimidates for the synthesis of these fascinating molecules. Trichloroacetimidates can be used as an electrophilic source of an alkyl group to form the pyrroloindoline directly from tryptamine derivatives. In this manner trichloroacetimidates provide a flexible solution to forming highly functionalized pyrroloindoline core structures, needing only a catalytic amount of a Lewis acid to effect the requisite transformations.

Graphical Abstract

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Introduction

Alkaloids containing a pyrroloindoline (hexahydropyrrolo[2,3-b]indole) constitute a large genus of natural products (Fig. 1A).[1] Hundreds of alkaloids with similar core structures have been isolated from a variety of terrestrial and marine sources. Many simple pyrroloindolines appear to be derived from tryptamine, while others are formed from tryptophan. Many of these systems also possess significant biological activity, especially as cholinesterase inhibitors.[2] Perhaps the best known pyrroloindoline with cholinesterase activity is physostigmine (1, Fig. 1) which has been used clinically to treat a variety of disorders.[3] Other biological activity has also been documented with these systems, as in the case of amauromine (5), a vasodilator[4] which also shows potent activity in the reversal of multiple drug resistance (MDR) in tumor cell lines.[5] Other similar structures have been shown to possess antibacterial activity[6] and inhibit biofilm formation.[7]

Figure 1.

(A) Examples of Complex Pyrroloindoline Natural Products and (B) Alkylation/Cyclization Route to Pyrroloindolines.

Given the diverse biological activity of these structures, synthetic organic chemists have been active in investigating the formation and decoration of the pyrroloindoline core, and these efforts have been reviewed.[1,8] One of the most popular approaches to the pyrroloindoline core is to treat a protected tryptamine (like 6, Fig. 1B) with an electrophile, alkylating the C3 position of the indole and leading to formation of the pyrroloindoline after cyclization of the tethered amine. Ganesan utilized allylic halides for this transformation in the presence of Lewis acids,[9] while others have used a strong base to activate the indole instead.[10] More recently transition metal catalysts have been utilized, employing a number of pi-allyl electrophiles to form pyrroloindolines.[11] Unsaturated aldehydes[12] and unsaturated ketones[13] have also been employed as electrophiles in these transformations, which are then converted to the desired pyrroloindoline systems.

Results and Discussion

We hypothesized that trichloroacetimidates could also function as electrophiles for the synthesis of functionalized pyrroloindolines. Trichloroacetimidates are best known for their role in the synthesis of allylic amines (the Overman rearrangement),[14] in th e formation of glycosidic bonds (the Schmidt glycosylation),[15] and for the formation of ethers.[16] Imidates also function as electrophiles in the alkylation of aromatic systems[17] and electron rich alkenes.[18] Our recent studies on indole alkylations with trichloroacetimidate electrophiles supported that the trichloroacetimidate is sufficiently reactive when activated with a Lewis or Brønsted acid to alkylate the indole at C3.[19] We therefore hypothesized that allylic and benzylic trichloroacetimidates may be used in an alkylation/cyclization process to access pyrroloindolines.

The use of trichloroacetimidates provides several advantages over alkyl halides. The imidate structure possesses a basic nitrogen, which can be activated under mild conditions by either Brønsted or Lewis acid catalysts. The use of alkyl halides to form pyrrolo indolines leads to multiple stoichiometric byproducts from both the promoter and the reactants. A similar reaction with trichloroacetimidates only requires a catalytic amount of a Brønsted acid, minimizing waste. Displacement of the imidate occurs under mild conditions, as these substitutions are facilitated by rearrangement of the imidate to the corresponding acetamide. This rearrang ement is exothermic and provides an additional driving force for displacement of the imidate, expediting Friedel-Crafts alkylation reactions.[17f] The imidate substitution reaction should therefore provide faster reaction rates, facilitating rapid product formation. Trichloroacetimidates are easily formed from alcohols in high yields from inexpensive trichloroacetonitrile,[20] and have recently found use in diversity oriented methods to access complex heterocyclic structures.[21]

Initially we focused on the reaction of N-methyl tryptamine 9 which could serve as a system to access intermediates which could be used in the synthesis of pseudophrynamine 272A 3. Protected tryptamine 9 was synthesized from tryptamine via alkylation of the indole nitrogen with sodium hydride and methyl iodide followed by protection of the tryptamine α-amine with p-toluenesulfonyl chloride.[22] Allyl imidate 10 was chosen as the initial electrophile, and when exposed to tryptamine 9 in the presence of CSA (30 mol%) a low yield of the desired alkylation/cyclization product was obtained (Table 1). An initial rapid screening of solvents (CH₂Cl₂, 1,2-DCE, THF, CF₃C₆H₅) showed that α, α, α-trifluorotoluene gave the best yield, and this was then employed in future reactions. Increasing the reaction temperature or the amount of CSA did not improve the yield, so other catalysts were investigated. Lewis acids gave better yields of the products, with TMSOTf proving to be superior to BF₃•OEt₂, providing a 74% yield of the desired product 11 under the optimized reaction conditions. No alkylation of the nitrogen of the sulfonamide was observed even though sulfonamides have been alkylated with imidates previously.[23] This is attributed to the greater reactivity of the electron rich indole ring. Relatively high catalyst loadings were necessary to achieve good conversion in a reasonable time (compare entries 10 and 11), this may be due to the number of Lewis basic gro ups in the substrate which compete for the Lewis acid. The use of the TMSOTf proved to be necessary, as TfOH itself did not give good conversion and led instead to significant decomposition of the starting materials (Table 1, entry 15).

Table 1.

Optimization of Dialkylation Reaction Conditions

Entry	Catalyst	mol%	Temp. (°C)	Time (h)	Yield 11 (%)
1	CSA	20	25	12	trace
2	CSA	30	25	15	8
3	CSA	50	25	15	11
4	CSA	30	80	15	12
5	BF3•OEt2	20	25	12	32
6	BF3•OEt2	25	25	15	36
7	BF3•OEt2	30	25	24	27
8	BF3•OEt2	20	80	8	22
9	BF3•OEt2	20	80	15	19
10	TMSOTf	20	25	8	58
11	TMSOTf	25	25	18	74
12	TMSOTf	30	25	12	63
13	TMSOTf	20	80	12	52
14	TMSOTf	20	80	18	47
15	TfOH	25	25	18	0a

^aA complex mixture resulted.

The results in Table 1 support the proposed mechanism shown below (Scheme 2). Initially the imidate and the TMSOTf react to form the activated imidate complex A. The tryptamine then is alkylated by the allyl group, which can occur through either an S_N1 or S_N2 mechanism, providing iminium ion B and silyl acetamide C. The iminium ion B then undergoes a rapid cyclization to the pyrroloindoline D, a protonated form of the observed product. The silyl acetamide C can transfer the silyl group to another imidate, regenerating the activated imidate complex A and leaving the trichloroacetamide anion E behind. The anion E is stabilized by the nearby electron withdrawing groups, with trichloroacetamide having a pKa of 11,[16d] therefore its generation is not energetically difficult. Proton transfer from the protonated pyrroloindoline to the trichloroacetamide anion completes the reaction and provides the observed products of the transformation: pyrroloindoline 8 and trichloroacetamide F.

Scheme 2.

Alkylation/Cyclization of Tryptamine 33.

The use of different trichloroacetimidates in the alkylation-cyclization reaction was then examined (Table 2). Use of prenyl trichloroacetimidate initially provided a complex mixture of products. In this case better results were obtained with CSA as the catalyst, which provided product 12 in 58% yield. This was due to more side product formation with TMSOTf, perhaps due to the greater reactivity of the prenyl imidate. Propargyl imidate also participated in the reaction, providing a 61% yield of the pyrroloindoline product 13. The use of tert-butyl trichloroacetimidate was also evaluated, which appeared challenging, as this reaction would form two vicinal all carbon quaternary centers which can be a difficult endeavor.[24] Gratifyingly, the reaction proceeded smoothly and gave a 72% yield of pyrroloindoline product 14. A series of benzyl trichloroacetimidates were also evaluated (15–21, Table 2). Benzyl electrophiles decorated with electron withdrawing groups tended to provide better yields in the reaction, which is consistent with previous studies with the alkylation of indoles with trichloroacetimidates.[19] This may be due to the propensity of the more reactive electron rich sy stems to react unselectively and give complex mixtures of polyalkylation products, as was observed with 4-methoxylbenzyl trichloroacetimidate which gave only a complex mixture from which none of the desired 21 could be isolated. Changing the catalyst to CSA or BF₃•OEt₂ with the 4-methoxylbenzyl trichloroacetimidate did not improve the reaction. The phthalamidylmethyl imidate[25] also participated in the alkylation/cyclization, providing access to complex heterocyclic system 22 in 77% yield.

Table 2.

Evaluation of the Effect of the Imidate Structure on the Alkylation/Cyclization.

^aCSA (25 mol%) was used as the catalyst.

^bA complex mixture resulted.

The generality of the transformation with respect to tryptamine was then investigated (Table 3). The protecting group on the α-amine of the tryptamine could be varied to other sulfonamides (as in 25 and 26) or a carbamate (like 27) and the alkylation/cyclization still was the preferred product. The carboxylic acid of indole-3-acetic acid was also a useful terminator of the cyclization, and no ester formation was observed in the alkylation cyclization reaction to form 28 even though imidates have been used to form esters previously.[26] Again, this is likely due to the electron rich nature of the indole heterocycle. Amides were also successfully employed in the cyclization as shown in the formation of 29, although in a more modest yield which may be due to the poor solubility of the amide substrate in α, α, α-trifluorotoluene. Additionally the indole nitrogen could be functionalized with an allyl group leading to the formation of 30. Structures like 30 may be useful in the synthesis of the flustramine-type pyrroloindoline alkaloids. Substitution on the indole benzene ring was also examined, with the presence of a chloride or a methoxy group both being well tolerated as shown in the formation of 31 and 32.

Table 3.

Evaluation of the Effect of the Tryptamine Structure on the Alkylation/Cyclization.

The alkylation/cyclization of tryptamine 33, which has an unsubstituted indole nitrogen, was also briefly evaluated (Scheme 2). The transformation provided an inseparable mixture of the mono-C3a alkylated product 34 and the dialkylated product 30. Indoline has been shown to be an effective nucleophile for imidates under similar conditions,[27] so the formation of the dialkylated product is perhaps not surprising and could prove useful for accessing pyrroloindolines like flustramine 2. However after further experimentation (increased amounts of TMSOTf, increased amounts of imidate (up to 5 equiv.), heating, and combinations of these changes were explored) conditions to form either the dialkylated product 30 or the monoalkylated product 34 as the sole product could not be determined, limiting the usefulness of the method in this case. The lack of reactivity of pyrroloindoline 34 in the imidate alkylation may be due to steric factors, since branching at the C2 position orients the tosyl group near the indoline nitrogen, creating congestion around the basic nitrogen.

Conclusion

A new alkylation/cyclization method was developed for the synthesis of pyrroloindolines utilizing tryptamine derivatives and trichloroacetimidate electrophiles. The reaction provides the desired pyrroloindolines in moderate to excellent yields and is tolerant of a number of different groups on the indole nitrogen and the tryptamine α-amine. This methodology may be useful for the synthesis of natural products of this class as well as for the study of their structure activity relationships.

Scheme 1.

Proposed mechanism.

Highlights.

• Pyrroloindolines can be formed by Lewis acid catalyzed alkylation using trichloroacetimidates

• Electron poor imidates and/or indoles perform best as polyalkylation is lower

• tert-Butyl trichloroacetimidate participates well leading to the formation of two contiguous quaternary centers