Consideraciones en torno a la probabilidad de afectación de la libertad de empresa

Section 2.4: Copper Catalyzed Malonly Carbenoid Insertions into Indoles

During synthetic studies toward arboflorine (see Chapter 3), we had reason to revisit the malonyl carbenoid insertions into indole, as that chemical transformation would provide access to a key synthetic intermediate. The synthetic strategy to be applied to arboflorine called for a terminally substituted 3-ethyl sidechain with a 2-malonyl indole core. As the 3-substituted indole substrates in the dirhodium(II) tetraacetate catalyzed process proved to be inferior nucleophiles in the reaction with dimethyl

diazomalonate 2.127, a new reaction system required development. The results of these

efforts are the focus of the next section.1

Section 2.4.1: Results and Discussion

Section 2.4.1.1: Development of the Copper Catalyzed Malonly Carbenoid Insertions into Indoles

As was discussed in the previous section, the dirhodium(II) tetraacetate catalyzed diazomalonate decomposition and carbenoid insertion into indoles worked superbly for 2,3-unsubstituted substrates, but was not well suited for 2- or 3-substituted indole starting

materials and generally resulted in vastly decreased yields (Section 2.3.3). Since the direct functionalization of indoles by carbenoid insertion remains an attractive method of installing substitution on indoles, and as the direct installation of a malonate moiety into

the 2-position of a 3-substituted indole was required en route to arboflorine, we set out to

develop a new method for malonyl carbenoid insertion into indoles that would exceed the results found in the dirhodium(II) tetraacetate catalyzed reaction developed by Romelo Gibe.

Section 2.4.1.2: Reaction Optimization

Since the synthetic proposal for arboflorine called for a 3-substituted 2-malonyl indole, we decided to screen conditions for the metal catalyzed dimethyl diazomalonate

2.127 insertion into the 2-position of N-methyl skatole 2.77. A brief selection of these results and reaction optimizations are presented in table 2.1. Entry 1 shows the conditions previously developed by former Kerr group member Romelo Gibe, with a similar low

yielding result observed, though a lower ratio of dimethyl diazomalonate 2.127 was

employed. Copper catalysts, known to promote diazo decomposition and carbene formation, were next screened (entries 2 and 3) with no observable reaction at room

temperature.20 When the solvent was switched and the temperature was increased, both

copper(II) triflate and copper(II) acetylacetonate exhibited diazo decomposition reactivity, but only copper(II) acetylacetonate showed appreciable amounts of productive carbene insertion, and was thus chosen for further optimization. A slight decrease in reaction temperature by changing the solvent from toluene at reflux to benzene afforded a

modest increase in 2-malonyl-N-methylskatole 2.136. Much to our surprise, by lowering

Table 2.1 – Optimization Studies

Entry Solvent Temperature Time Catalyst

(mol %) Ratio 2.127:2.77 Yield 2.136 1 CH2Cl2 22 °C 7.5 h Rh2₍₁₀₎ (OAc)4 1:1 37% 2 CH2Cl2 22 °C 24 h Cu(acac)₍₁₀₎ 2 1:1 NR 3 CH2Cl2 22 °C 24 h Cu(OTf)₍₁₀₎ 2 1:1 NR 4 Toluene 110 °C 1 h Cu(OTf)₍₁₀₎ 2 1:1 ND

5 Toluene 110 °C 40 min Cu(acac)₍₁₀₎ 2 1:1 64%

6 Benzene 80 °C 75 min Cu(acac)2

(10) 1:1 75% 7 Benzene 80 °C 2 h Cu(acac)2 (5) 1:1 76% 8 Benzene 80 °C 6 h Cu(acac)₍₁₎ 2 1:1 82% 9 Benzene 80 °C 4 h Cu(acac)₍₁₎ 2 1:2 90% 10 Benzene 80 °C 6 h Cu(acac)₍₁₎ 2 1:1.5 88%

of slightly increased reaction times. Next, the ratio of dimethyl diazomalonate 2.127 to

N-methylskatole 2.77 was examined. Though 2:1 indole to dimethyl diazomalonate

provided the highest yield observed, a ratio of 1.5:1 was favoured for the reaction, since comparable results were obtained without the need for an extra half equivalent of indole substrate. Entry 10 represents the optimized reaction conditions for the copper catalyzed dimethyl malonyl carbenoid insertion into indoles.

Section 2.4.1.3: Examining the Reaction Scope

Having identified optimal conditions for malonyl carbenoid insertion into the

2-position of N-methylskatole 2.77, we next screened a variety of indole substrates in

carbenoid insertion. Table 2.2 shows the substrates and products of 3- and 2-substituted indole starting materials. Substitution at the 3-position with methyl, TBS-protected ethanol and methyl acetate were tolerant to the reaction with good to high yields observed

for carbenoid insertion (entries 1-4). It is interesting to note that both N-methyl and

N-benzyl substrates 2.77 and 2.145 gave comparable results. Entry 3b was done to show

that the reaction could be conducted on appreciable scale.41 Substitution at the 2 position

was also well tolerated under the reaction conditions (entries 5-7). Both 2-methyl 2.151

and the more sterically demanding 2-phenyl 2.152 substrates proceeded to incorporate a

3-malonate moiety in high yield. The 2-methyl ester substrate2.154 did not undergo the

reaction in as high yield as the other substrates, which is likely due to the electron withdrawing nature of the ester.

Table 2.2 – C2 and C3 Substitution

Table 2.3 demonstrates a variety of benzenoid substituted indole substrates. Both electron withdrawing and electron donating functional groups were well tolerated in the reaction, with encorporation of the malonate in the 3-position for all products. Entry 11 represents the only outlier in the series, with a lower yield of 55%. Currently the reasons

Table 2.3 – Indole Substrates with Benzenoid Substitution

The effects of N1 substitution were examined in the carbenoid insertion reaction in the following set of indole substrates (Table 2.4). As would be expected the electron

withdrawing N-t-butyl carbamate 2.163 and N-tosyl 2.165 substrates gave much reduced

yields in comparison to the electron rich N-benzyl substituted indole 2.166. Much to our

surprise when NH indoles were subjected to the reaction conditions, appreciable yields of C3 and C2 insertion products were observed (entries 16-18) without competitive NH

Table 2.4 –N-substituted Indole Substrates

Finally a 1,2,3-trimethylindole 2.170 was subjected to the carbenoid reaction

conditions to ascertain whether, or with what regioselectivity, carbenoid insertion would occur when the most reactive positions of the indole were occupied (Scheme 2.25). Suprisingly we observed malonate incorporation on the C2 methyl group. It is unclear whether this reaction proceeds through cyclopropanation of the indole followed by ring-opening and rearrangement or direct CH insertion on the methyl group takes place, and accordingly, this reaction certainly warrants further study.