Dialkylation of Indoles with Trichloroacetimidates to Access 3,3-Disubstituted Indolenines

2-Substituted indoles may be directly transformed to 3,3-dialkyl indolenines with trichloroacetimidate electrophiles and the Lewis acid TMSOTf. These reactions provide rapid access to complex indolenines which are present in a variety of complex natural products and medicinally relevant small molecule structures. This method provides an alternative to the use of transition metal catalysis. The indolenines are readily transformed into spiroindoline systems which are privileged scaffolds in medicinal chemistry.


Results & Discussion
Our recent studies on promoter free substitution reactions with trichloroacetimidate electrophiles [68][69][70][71][72][73][74] led us to speculate that imidates may be reactive enough to participate in indole dialkylation without the need for a Lewis acid catalyst. Heating 2-methyl indole 14 and allyl trichloroacetimidate 11 in refluxing 1,2-dichloroethane (DCE) for 24 h showed no trace of alkylation product, however, so the use of TMSOTf as the Lewis acid was then investigated (Table 1). Previous investigations with indoles and trichloroacetimidates have demonstrated that TMSOTf is especially effective in these systems [65,66], and encouraging results were immediately obtained. Use of 20 mol% TMSOTf led to the formation of indolenine 15 with a 27% yield (Table 1, Entry 2). Increasing reaction time, temperature and using excess imidate were then evaluated, but these changes only led to modest increases in yield (entries [3][4][5]. Given that a more basic reaction media is being formed after the second alkylation (the imine on 15 is a functional base), it was considered that perhaps product inhibition was occurring, with the imine scavenging the Lewis acid and halting the reaction. An increase in the TMSOTf loading would therefore be necessary to obtain higher conversions. Increasing the amount of TMSOTf provided a 61% yield of 15 when a stoichiometric amount of the In a recent study on the alkylation of indoles utilizing trichloroacetimidate electrophiles [65], we observed a small amount of the dialkylated indolenine 13 as a side product from the TMSOTf catalyzed C3-alkylation of 2-methyl-5-nitroindole 10 with allyl imidate 11 in dichloromethane (DCM) (Scheme 1). While the formation of indolenines from 2,3-disubstituted indoles with imidates has been reported [66], the direct dialkylation of indoles could provide a rapid entry to 3,3-dialkyl indolenine intermediates from less substituted (and therefore less expensive) indole starting materials. This would provide an efficient alternative approach for the direct C3-dialkylation of indoles that does not rely on costly transition metal catalysts. The use of trichloroacetimidate electrophiles as the alkylating agent is attractive because they can be easily formed from readily available alcohols under mild conditions [67]. Intrigued by the potential of this dialkylation reaction, we began optimization studies to explore the scope of this Lewis acid promoted dearomatization reaction. In a recent study on the alkylation of indoles utilizing trichloroacetimidate electrophiles [65], we observed a small amount of the dialkylated indolenine 13 as a side product from the TMSOTf catalyzed C3-alkylation of 2-methyl-5-nitroindole 10 with allyl imidate 11 in dichloromethane (DCM) (Scheme 1). While the formation of indolenines from 2,3-disubstituted indoles with imidates has been reported [66], the direct dialkylation of indoles could provide a rapid entry to 3,3-dialkyl indolenine intermediates from less substituted (and therefore less expensive) indole starting materials. This would provide an efficient alternative approach for the direct C3-dialkylation of indoles that does not rely on costly transition metal catalysts. The use of trichloroacetimidate electrophiles as the alkylating agent is attractive because they can be easily formed from readily available alcohols under mild conditions [67]. Intrigued by the potential of this dialkylation reaction, we began optimization studies to explore the scope of this Lewis acid promoted dearomatization reaction. Scheme 1. Detection of the dialkylation product 13 during alkylation of 5-nitro-2-methyl-indole 10.

Results & Discussion
Our recent studies on promoter free substitution reactions with trichloroacetimidate electrophiles [68][69][70][71][72][73][74] led us to speculate that imidates may be reactive enough to participate in indole dialkylation without the need for a Lewis acid catalyst. Heating 2-methyl indole 14 and allyl trichloroacetimidate 11 in refluxing 1,2-dichloroethane (DCE) for 24 h showed no trace of alkylation product, however, so the use of TMSOTf as the Lewis acid was then investigated (Table 1). Previous investigations with indoles and trichloroacetimidates have demonstrated that TMSOTf is especially effective in these systems [65,66], and encouraging results were immediately obtained. Use of 20 mol% TMSOTf led to the formation of indolenine 15 with a 27% yield (Table 1, Entry 2). Increasing reaction time, temperature and using excess imidate were then evaluated, but these changes only led to modest increases in yield (entries [3][4][5]. Given that a more basic reaction media is being formed after the second alkylation (the imine on 15 is a functional base), it was considered that perhaps product inhibition was occurring, with the imine scavenging the Lewis acid and halting the reaction. An increase in the TMSOTf loading would therefore be necessary to obtain higher conversions. Increasing the amount of TMSOTf provided a 61% yield of 15 when a stoichiometric amount of the Scheme 1. Detection of the dialkylation product 13 during alkylation of 5-nitro-2-methyl-indole 10.

Results & Discussion
Our recent studies on promoter free substitution reactions with trichloroacetimidate electrophiles [68][69][70][71][72][73][74] led us to speculate that imidates may be reactive enough to participate in indole dialkylation without the need for a Lewis acid catalyst. Heating 2-methyl indole 14 and allyl trichloroacetimidate 11 in refluxing 1,2-dichloroethane (DCE) for 24 h showed no trace of alkylation product, however, so the use of TMSOTf as the Lewis acid was then investigated (Table 1). Previous investigations with indoles and trichloroacetimidates have demonstrated that TMSOTf is especially effective in these systems [65,66], and encouraging results were immediately obtained. Use of 20 mol% TMSOTf led to the formation of indolenine 15 with a 27% yield (Table 1, Entry 2). Increasing reaction time, temperature and using excess imidate were then evaluated, but these changes only led to modest increases in yield (Entries [3][4][5]. Given that a more basic reaction media is being formed after the second alkylation (the imine on 15 is a functional base), it was considered that perhaps product inhibition was occurring, with the imine scavenging the Lewis acid and halting the reaction. An increase in the TMSOTf loading would therefore be necessary to obtain higher conversions. Increasing the amount of TMSOTf provided a 61% yield of 15 when a stoichiometric amount of the Lewis acid was employed (Entry 7). Further increasing the amount of TMSOTf did not significantly improve the yield, nor did heating the reaction. Little indole starting material 14 was isolated from the reaction, with the rest of the mass balance being a mixture of overalkylation products (alkylation can also occur at C5 and C7 of the indole ring). Lewis acid was employed (Entry 7). Further increasing the amount of TMSOTf did not significantly improve the yield, nor did heating the reaction. Little indole starting material 14 was isolated from the reaction, with the rest of the mass balance being a mixture of overalkylation products (alkylation can also occur at C5 and C7 of the indole ring). The indole dialkylation was then evaluated with regard to the indole nucleophile. The addition of either electron donating or electron withdrawing groups to the 5-position of the indole was tolerated, with yields in the 40%-70% range being observed (Table 2). Interestingly, the 5-nitro-2methyl indole 10 provided the diallylation product 13, which is not accessible using palladium catalysis, as N-alkylation is favored when this indole is employed [6]. Changing the alkyl group at the 2-position of the indole was also explored. Use of indole (Entry 7) provided only a complex mixture of products, and this substrate was not pursued further. A more moderate yield was obtained with 2-phenylindole, likely due to steric effects from the larger group at the indole 2-position. Indole 2-carboxylic acid methyl ester 14h was not reactive under these conditions, returning the starting indole and decomposed imidate from the reaction mixture. While many of these yields are moderate, it is important to realize that two reactions are actually occurring in sequence during the dialkylation, so the yield may perhaps be best thought of in terms of a sequence of two separate steps proceeding a ~75% yield where isolation and purification of the intermediate 3-alkylindole is avoided. The indole dialkylation was then evaluated with regard to the indole nucleophile. The addition of either electron donating or electron withdrawing groups to the 5-position of the indole was tolerated, with yields in the 40%-70% range being observed (Table 2). Interestingly, the 5-nitro-2-methyl indole 10 provided the diallylation product 13, which is not accessible using palladium catalysis, as N-alkylation is favored when this indole is employed [6]. Changing the alkyl group at the 2-position of the indole was also explored. Use of indole (Entry 7) provided only a complex mixture of products, and this substrate was not pursued further. A more moderate yield was obtained with 2-phenylindole, likely due to steric effects from the larger group at the indole 2-position. Indole 2-carboxylic acid methyl ester 14h was not reactive under these conditions, returning the starting indole and decomposed imidate from the reaction mixture. While many of these yields are moderate, it is important to realize that two reactions are actually occurring in sequence during the dialkylation, so the yield may perhaps be best thought of in terms of a sequence of two separate steps proceeding a~75% yield where isolation and purification of the intermediate 3-alkylindole is avoided.
The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21)(22)(23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.  The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21-23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.    With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.   With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.  With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.  With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps. With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc) 3 , which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps. Oddly, the spiropiperidine 27 showed a multiplet in the 1 H NMR at 0.28 ppm that integrated for a single hydrogen resonance. A proton with this chemical shift was not congruent with the proposed structure, so some additional studies were performed. A COSY experiment verified that the upfield proton was part of the piperidine ring. Some molecular modeling studies indicated that this unusual chemical shift is likely to be attributed to diamagnetic anisotropy from the aromatic ring of the toluenesulfonamide, which prefers to reside on the opposite face of the pyrroline ring as the methyl group due to steric effects. This holds the -system of the sulfonamide in a position to shield one of the protons on the piperidine ring (Ha, Figure 2). The molecular modeling predicts that in the lowest energy conformation Ha is only ~2.8 Å from the center of the aromatic ring. This upfield chemical shift is consistent with literature reports of similar spiropiperidine-indanes [75]. In further support of this rationale, in structures where the C2 position of the pyrroline is unsubstituted [76], or there is no aromatic sulfonamide [77], no similar upfield shifts are observed in the 1 H NMR.

General Experimental Information
All anhydrous reactions were run under a positive pressure of argon. Dichloromethane (DCM) was dried by passage through an alumina column. 1,2-Dichloroethane (DCE) was freshly distilled from calcium hydride before use. Silica gel column chromatography was performed using 60 Å silica gel (230−400 mesh). Melting points are uncorrected. The indoles used in this study were purchased from commercial sources. Oddly, the spiropiperidine 27 showed a multiplet in the 1 H NMR at 0.28 ppm that integrated for a single hydrogen resonance. A proton with this chemical shift was not congruent with the proposed structure, so some additional studies were performed. A COSY experiment verified that the upfield proton was part of the piperidine ring. Some molecular modeling studies indicated that this unusual chemical shift is likely to be attributed to diamagnetic anisotropy from the aromatic ring of the toluenesulfonamide, which prefers to reside on the opposite face of the pyrroline ring as the methyl group due to steric effects. This holds the -system of the sulfonamide in a position to shield one of the protons on the piperidine ring (H a , Figure 2). The molecular modeling predicts that in the lowest energy conformation H a is only~2.8 Å from the center of the aromatic ring. This upfield chemical shift is consistent with literature reports of similar spiropiperidine-indanes [75]. In further support of this rationale, in structures where the C2 position of the pyrroline is unsubstituted [76], or there is no aromatic sulfonamide [77], no similar upfield shifts are observed in the 1 H NMR. Oddly, the spiropiperidine 27 showed a multiplet in the 1 H NMR at 0.28 ppm that integrated for a single hydrogen resonance. A proton with this chemical shift was not congruent with the proposed structure, so some additional studies were performed. A COSY experiment verified that the upfield proton was part of the piperidine ring. Some molecular modeling studies indicated that this unusual chemical shift is likely to be attributed to diamagnetic anisotropy from the aromatic ring of the toluenesulfonamide, which prefers to reside on the opposite face of the pyrroline ring as the methyl group due to steric effects. This holds the -system of the sulfonamide in a position to shield one of the protons on the piperidine ring (Ha, Figure 2). The molecular modeling predicts that in the lowest energy conformation Ha is only ~2.8 Å from the center of the aromatic ring. This upfield chemical shift is consistent with literature reports of similar spiropiperidine-indanes [75]. In further support of this rationale, in structures where the C2 position of the pyrroline is unsubstituted [76], or there is no aromatic sulfonamide [77], no similar upfield shifts are observed in the 1 H NMR.

General Experimental Information
All anhydrous reactions were run under a positive pressure of argon. Dichloromethane (DCM) was dried by passage through an alumina column. 1,2-Dichloroethane (DCE) was freshly distilled from calcium hydride before use. Silica gel column chromatography was performed using 60 Å silica gel (230−400 mesh). Melting points are uncorrected. The indoles used in this study were purchased from commercial sources.

General Experimental Information
All anhydrous reactions were run under a positive pressure of argon. Dichloromethane (DCM) was dried by passage through an alumina column. 1,2-Dichloroethane (DCE) was freshly distilled from calcium hydride before use. Silica gel column chromatography was performed using 60 Å silica gel (230−400 mesh). Melting points are uncorrected. The indoles used in this study were purchased from commercial sources.

Synthesis of 3,3 -Disubstituted Indolenines
General procedure for C3-dialkylation of indoles. In a flame dried flask, the imidate (2.5 equiv) was dissolved in anhydrous DCE (0.3 M) followed by the addition of the indole (1.0 equiv). To this solution freshly distilled TMSOTf (1.0 equiv) was added and the resulting mixture was stirred at room temp. or heated to reflux for 3 h. After cooling to room temperature, the reaction mixture was quenched with 10 mL 1 M NaOH. The organic layer was separated and the aqueous layer was extracted with DCM (3 × 5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using the listed solvent system.

Conclusions
A new method for the synthesis of 3,3-dialkyl indolenines has been developed utilizing the Lewis acid promoted alkylation of indoles with trichloroacetimidates. This method is differentiated from past methods in that it does not depend on transition metal mediated alkylation or the use of strong base, instead a Lewis acid and a trichloroacetimidate leaving group are utilized to perform the alkylation. Notably even electron poor indoles undergo the dialkylation, which are difficult substrates for other alkylation reactions. The indolenines generated from this reaction provide ready access to spirocyclic structures which are useful platforms for the development of three dimensional architectures that may interact with more complex biological receptors of interest to the medicinal chemistry community.