Enantioselective C2-Alkylation of Indoles through a Redox-Relay Heck Reaction of 2-Indole Triflates

 

 

Nicholas J. Race+, Qianjia Yuan+, and Matthew S. Sigman

 

 

Indole is a privileged scaffold in a wide variety of research areas, including natural product synthesis, pharmaceuticals, agrochemicals, and material science.[1] As a result, numerous synthetic methods have been developed for the synthesis and functionalization of indole. Catalytic, enantioselective function- alization of the indole core represents an intensive area of re- search, with most methods exploiting the inherent nucleophi- licity at the C3 position for enantioselective Friedel–Crafts-like chemistry (Scheme 1 A).[2] For example, we recently reported a palladium-catalyzed dehydrogenative relay-Heck arylation of indole derivative A and trisubstituted alkenols to afford alde- hydes of type B (Scheme 1 C).[3] Given that palladation  of indole is proposed to occur in a Friedel–Crafts-like manner (A!C,  Scheme 1 C),[4]  functionalization  of  the  C3  position  is observed exclusively.

 

In contrast, methods to enantioselectively functionalize the indole C2 position are much less developed.[5] In fact, incorpo- ration of a substituent at indole C3 is typically required to pro- mote electrophilic substitution at C2. Therefore, prefunctionali- zation of the indole is a strategy used to ensure a site-selective reaction. As an example, Macmillan reported a singular case of a conjugate addition reaction of C2-bearing indole potassium trifluoroborate salts to enals using secondary amine catalysis.[6] Given that many natural products and pharmaceutically relevant core structures contain a stereocenter adjacent to the C2 position (Scheme 1 B),[7–9] we considered strategies to apply a redox-relay Heck type reaction[10] using an appropriately func- tionalized indole starting material for the purposes of enantio- selective indole C2 functionalization. By coupling this starting material with a diverse selection of alkene coupling partners,  we would be able to streamline access to a wide variety of enantioenriched molecular scaffolds.

 

Two design elements were considered to accomplish such a reaction: 1) as indole derived triflates are readily accessible from simple oxindole starting materials and the corresponding alkenyl triflates have been demonstrated as excellent coupling partners in related Heck reactions,[10d–f] these  electrophiles were selected for investigation and 2) the nature of the indole nitrogen substituent was deemed important with an electron- withdrawing group possibly required to prevent the Pd from migrating towards the indole (Scheme 1 D).[10d] This was hy- pothesized on the basis of previous mechanistic work wherein the Pd-catalyst has the propensity to migrate toward more electron rich features of the alkyl chain. Indeed, use of disubsti- tuted alkenols in the dehydrogenative arylation  with  indole did not lead to the desired relay product as a consequence of the electron-rich indole nucleus (Scheme 1 C). Specifically, inter- mediate  D  underwent  selective  b-hydride  elimination  of  R2 (R2 = H) and subsequent reinsertion of the PdII-hydride afforded PdII-alkyl E, which decomposed via expulsion of Pd0 as promot- ed by the electrons on the indole nitrogen.

 

On the basis of the design principles described  above,  a series of four indole triflates (1–4) were synthesized with differ- ent substituents on the indole nitrogen. These substrates were evaluated with cis-3-hexen-1-ol (5) under previously reported conditions reported for alkenyl triflates, which use a Pd0 pre- catalyst and a chiral pyridine-oxazoline ligand (Table 1).

No desired reaction was observed with either methyl-, phenyl-, or acetyl-substituted indole triflate 1–3 due to decomposition of the starting materials under the reaction conditions (Table 1, entries 1–3). The desired reaction was observed with ethyl car- bamate-protected indole triflate 4 wherein aldehyde 6 was iso- lated in 19 % yield and 95:5 er (Entry 4). Addition of two equiv- alents of alkenol 5 increased the yield to 28 % (Entry 5). Given that the Heck reaction generates an equivalent of TfOH every catalyst turnover, we hypothesized that buildup of acid could be problematic, including decomposition of the starting mate- rial through carbamate deprotection. To improve the yield, a variety of basic additives were examined in the reaction includ- ing K2CO3, 3,5-di-tert-butyl-4-methylpyridine, and Ca(OH)2 (En-tries 6–8).[10f] Addition of one equivalent of Ca(OH)2 improved the yield of aldehyde 6 to 47 %, with no loss in enantioselectiv- ity. The yield of 6 was improved further to 55% by increasing the catalyst loading to 5 mol% (Entry 9).

 

As the next step, we set out to demonstrate the reaction’s utility for accessing a wide range of molecular architectures bearing a secondary stereogenic center a to an indole C2 posi- tion. Use of simple allylic alcohols 7 and 8 afforded the corre- sponding aldehydes 9 and 10 in 72 %  (94:6 er)  and  70 %  yield (95 :5 er), respectively (Scheme 2). As highlighted in the introduction, access to aldehydes bearing a b-substituted C2-indole is possible via iminium ion catalysis.[6] We therefore chose to focus our attention on alkene substrates that provide products not accessible using these methods. For example, coupling of   4 and diol 11[12] afforded lactol 12 in 86 % yield, 1.8:1 d.r. The enantiomeric excess for this product (92.5 :7.5 er) was mea- sured after oxidation of the crude lactol to the lactone (see Supporting Information). To the best of our knowledge, enan- tioselective conjugate additions to lactones at the indole C2 position is unknown. Use of benzylether-substituted allylic al- cohol 13 afforded the desired product 14 in modest yield but excellent enantioselectivity. Racemic secondary allylic alcohol 15 afforded the corresponding ketone 16 in good yield and enantioselectivity.  The  yield  of  ketone  16  in  this  reaction is> 50 %, which suggests the stereocenter formed in the product   is under catalyst control and this reaction is not a kinetic resolution. Finally, we explored the use of an allylic alcohol bearing      a primary tosyl-protected alcohol (17). Under our reaction con- ditions, the (formal) alkylation occurs selectively between the indole C2 and the alkene carbon distal to the primary unpro- tected alcohol to give 18 in good  yield  and  enantioselectivity. The resulting tosylate and aldehyde provide useful functional groups for further product manipulation.

 

Next, we examined the functional group tolerance of the re- action with respect to substituents on the indole ring using homoallylic alcohol 5 (Scheme 3 A).[13] Functional groups com- patible with this chemistry include chloride (6 b), esters (6 c), alkyl ethers and silyl ethers (6d and 6 f), boronic esters (6 e), and bromide (6 g). It is worth noting that the palladium cata- lyst initiates selectively at the indole triflate in the presence of the aryl bromide.

 

The ability to access enantioenriched secondary alkyl stereo- centers adjacent to the indole C2 position remotely to the al- dehyde functional group is highlighted in Scheme 3 B.  Primary and secondary bis-homoallylic alkenols 19 and 21 afforded the corresponding relay-Heck  products  20  and  22  in  moderate yield and enantioselectivity. Accessing these types of enan- tioenriched products using conventional approaches, for exam- ple, using alkylation chemistry, would be  extremely  challeng-  ing.

 

More recently our group has explored alkenes bearing vari- ous unique functional groups (Scheme 4). As an example, cou- pling of indole triflate 4 and enol ether 24 provided aldehyde 23.[14] This reaction affords an enantioenriched secondary ether adjacent to the indole C2 position, a product not accessible using reported organocatalytic approaches. Use of commercial- ly-available cis-4-nonenal 25 afforded a,b-unsaturated alde- hydes 26 a–c in high yield  and good  enantioselectivity.[15] These products are attractive because it is  well-established that enantioselective intramolecular cyclizations of related mol- ecules can be promoted by secondary amines.[16] It is also pos- sible to use ene-lactam 27 as a coupling partner in this chemistry, leading to products 28 a--c in excellent yield and slightly diminished enantioselectivity.[17] This reaction provides rapid and modular access to the core of natural products and drug candidates (vide supra).

 

Finally, we wanted to highlight how this indole C2 alkylation process  provides  highly  modular  enantioselective   formal access to tricyclic indole 31, which  is  a  key  precursor  to  an  S1P1 agonist reported by Merck (Scheme 5).[9] Initially, Merck developed a route involving the de novo construction of the indole framework providing efficient access to the indole core. However, it relies on the use of traditional chiral auxiliary chemistry to set the absolute stereochemistry. The relay-Heck reaction  conveniently  combines  two  simple  building  blocks  and sets the stereochemistry during C@C bond construction providing a modular strategy to such scaffolds. In the  event, indole triflate 4f and alkene 13 are coupled  in moderate yield  but excellent enantioselectivity. Processing of the aldehyde through three steps (oxidation, esterification, deprotection) af- forded indole 30 in 24 % yield from triflate 4f (96 :4 er). This molecule can be further manipulated to produce S1P1 agonist precursor 31 as established by Merck.[9] Optical rotation com- parison of 30 to the literature allowed us to  confirm  the abso- lute stereochemistry of our product to be (S). This stereochem- ical outcome is consistent with our  previously  reported  model for enantioselective induction in relay-Heck  reactions.[10a]  All other compounds were assigned by analogy to 30, considering that switching the alkene geometry results in the opposite enantiomer of product being formed.

 

In conclusion, we have reported an enantioselective C2- alkylation of indole via a redox-relay Heck reaction of indole triflate and alkenes. This reaction provides access to a wide se- lection of alkylated indole derivatives bearing a stereocenter adjacent to the C2 position and is tolerant of a range of func- tional groups. We highlighted this method by demonstrating  its utility for providing modular formal access to a key tricyclic indole core of a S1P1 agonist precursor. This methodology offers a new disconnection for synthetic chemists and enables the modular exploration of new chemical space in the search for new lead drug compounds.

 

Acknowledgements

The work was supported by National Institute of Health (NIGMS R01GM063540). Q.Y. acknowledges Shanghai Jiao Tong University for a postdoctoral fellowship.

Conflict of interest

The authors declare no conflict of interest.