Graphical Abstract:
Amines such as 1,2,3,4-tetrahydroisoquinoline undergo redox-neutral annulations with 2-methyl-3,5-dinitrobenzaldehyde and closely related substrates. Acetic acid serves as the solvent and sole promoter of these transformations which involve dual C–H functionalization.
Among methods that enable the α-C–H bond functionalization of amines,1 redox-annulations of cyclic amines hold a unique place as they incorporate the concurrent functionalization of the amine nitrogen atom via C–N bond formation (Scheme 1).2–6 Thus, redox-annulations rapidly generate polycyclic amines from simple building blocks, only requiring carboxylic acids (typically AcOH or BzOH) as catalysts or promoters. Ortho-substituted benzaldehydes 1 are common substrates for redox-annulations, forming products 2 via C–N and concurrent α-C–X or α-C–C bond formation (eq 1). In the case of α-C–C bond formation, the presence of electron-withdrawing groups on the ortho-substituent appears to be required. For instance, simple o-tolualdehyde is insufficiently activated and fails to undergo annulation. Recently, the Wang group3c,3d and we2j independently found that 2-alkylquinoline-3-carbaldehydes (e.g., 3) and related pyridine derivatives are sufficiently reactive to allow for the formation of products such as 4 via redox-annulation (eq. 2). We were curious to learn whether electron-deficient o-tolualdehydes 5 would also be amenable to annulation, generating products 6 containing the core structure of the tetrahydroprotoberberine family of natural products (eq 3).7 Here we report the first examples of such a reaction.
Scheme 1.
Selected Redox-Annulations of Amines
The electron-deficient 2-methyl-3,5-dinitrobenzaldehyde (5a) was selected as a starting point to evaluate the proposed redox-annulation process, utilizing 1,2,3,4-tetrahydroisoquinoline (THIQ) as the model amine (Table 1).8 Under the optimized conditions (entry 1), product 6a was obtained in 81% yield upon heating of 5a (0.1 M concentration) with two equiv of THIQ in acetic acid solvent for a period of 2 h. A range of other conditions provided product 6a in variable albeit lower yields. For instance, a reduction in the amount of acid (by using toluene as a cosolvent) was detrimental, as was a reduction in the amount of THIQ (entries 2–6). Slow addition of aldehyde 5a, a strategy sometimes useful for improving the yields of certain redox-annulations, was not advantageous (entry 7). A reaction performed at a reduced temperature of 80 °C did not result in the formation of any detectable amounts of 6a after 12 h (entry 8).
Table 1.
Reaction Developmenta
 | |||
|---|---|---|---|
| entry | deviation from optimized conditions | time (h) | yield (%) |
| 1 | none | 2 | 81 |
| 2 | 1 equiv of AcOH in PhMe (0.1 M) | 6 | 38 |
| 3 | 20 equiv of AcOH in PhMe (0.1 M) | 6 | 46 |
| 4 | PhMe/AcOH = 1:1 (0.1 M) | 2 | 69 |
| 5 | 1.3 equiv of THIQ | 2 | 41 |
| 6 | 1.2 equiv of BzOH in PhMe (0.1 M) | 2 | 36 |
| 7 | slow addition of 5a over 15 h | 15 | 75 |
| 8 | reaction performed at 80 °C | 12 | - |
All yields correspond to isolated yields of chromatographically purified product.
The scope of the amine redox-annulation with 2-methyl-3,5-dinitrobenzaldehyde (5a) is outlined in Scheme 2. A range of THIQ’s with various substituents on the benzene ring readily underwent annulation to provide products 6 in moderate to good yields. 1-Aryl-THIQ’s engaged 5a to form tetrahydroprotoberberines 6 containing a tetrasubstituted stereogenic center. Both electron-donating and electron-withdrawing substituents on the aryl-group were tolerated. A reaction of 1-phenyl-1,2,3,4-tetrahydro-β-carboline with 5a resulted in the formation of product 6o in 54% yield. In regard to modifying the aldehyde starting material 5, introduction of a chlorine or bromine substituent in the para-position of the formyl group was tolerated, enabling the preparation of products 6p–s. Other modifications of the aldehyde 5 (e.g., removal of one of the nitro groups, replacement of one of the nitro groups with a different electron-withdrawing group, or change of the methyl group to ethyl) resulted in substrates that failed to undergo redox-annulations with THIQ under a variety of conditions, including microwave heating at 200 °C for a period of 15 min.
Scheme 2.
Scope of the Redox-Annulation
a Reactions were performed at a 0.2 M concentration of 5.
In summary, we have achieved redox-annulations of THIQ and substituted analogs with 2-methyl-3,5-dinitrobenzaldehyde (5a). These reactions provide rapid access to new tetrahydroprotoberberines.
ACKNOWLEDGMENT
Financial support from the NIH−NIGMS (Grant R01GM101389) is gratefully acknowledged. We thank Dr. Tom Emge (Rutgers University) for X-ray crystallographic analysis.
Footnotes
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data including the X-ray crystal structure of product 6b. This material is available free of charge via the Internet at http://pubs.acs.org.
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