Diels-Alder construction of regiodifferentiated meta-amino phenols and derivatives.

Synthetic access to regiodifferentiated meta-amino phenols is described. The strategy relies upon distinct deprotonation conditions to afford regioisomeric thermodynamic and kinetic dienes that undergo a tandem Diels-Alder and retro-Diels-Alder sequence with assorted acetylenic dienophiles to afford a range of aromatic products.

meta-Amino phenol (m-APhOH) and meta-amino pyridinol (m-APyOH) derivatives are important building blocks for natural product synthesis. They have proven themselves as privileged pharmaceutical scaffolds[1] and serve as inhibitors of JNK[2] and CGRP,[3] modulators of the delta-opioid receptor,[4] and efficacious treatment for neurological and psychiatric maladies,[5] Alzheimer’s disease,[6] and various carcinomas.[7] However, differentially substituted m-APhOHs and m-APyOHs, particularly those displaying electron-deficient amino functionality, are tedious to construct by aryl nitration–reduction–protection regimes, palladium mediated cross-coupling sequences,[8] and other strategies,[9] such as conventional Diels–Alder sequences.[10]

Herein, we report a new strategy to secure these important aromatic materials by way of a regioselective deprotonation of various cyclic vinylogous amides, a plan loosely based upon Danishefsky’s preliminary observations regarding the synthesis of pseudo-symmetric resorcinylic materials.[11]

Our process enables rapid access to regiodifferentiated aromatic materials using two isomeric dienes derived from a common cyclic vinylogous amide and uncovers equilibria between the resulting dienes, which has often been overlooked.[12] The skeletons of our regioisomeric aromatic products are found in compounds resembling tetrapetalone A (1) and the CGRP inhibitor (2) (Figure 1).[13,3]

Figure 1

Products containing m-APhOHs and m-APyOHs.

Cyclic vinylogous amides (5a–c, Table 1) were prepared by condensation of the appropriate 1,3-cyclohexadione (3a–3c) with benzyl amine and acylation with benzyl chloroformate.[14] Our process continued with regioselective deprotonation of the vinylogous amides (5a–c, Table 1) to form either the thermodynamic or the kinetic enolate.[15] Enolate interception with TBSCl furnished the corresponding dienes (7a–c, 6a–c, Table 1). For example, vinylogous amide 5a was subjected to deprotonation with KHMDS under thermodynamic enolization conditions. Addition of TBSCl afforded the diene (7a) as the sole product (Table 1, entry 1), which proved stable for over a month when frozen in benzene. Deprotonation of 5a with KHMDS under kinetic enolization conditions and addition of TBSCl afforded the diene (6a) in an ∼7:1 ratio of 6a:7a. However, Schlosser’s conditions (n-BuLi, KOt-Bu) reproducibly increased the ratio to >10:1, despite a lower yield (Table 1, entry 2).[16] We sought to improve the kinetic/thermodynamic diene ratio by varying the Y and Y′ substituents using vinylogous amides 5b and 5c. While thermodynamic dienes (7b–c) formed selectively as before (Table 1, entries 3, 5), the selectivity for kinetic dienes (6b–c) failed to improve (Table 1, entries 4, 6). We envisioned that submission of these respective dienes and a dienophile would facilitate the Diels–Alder (DA) and retro-Diels–Alder (r-DA) reaction and lead to the desired aromatic products in a controlled and predictable manner.[17]

Table 1

Regioselective Deprotonation and Diene Formation

entry	CVA	kinetic diene (k-D)	thermodynamic diene (t-D)	deprotonation method ratio k-D/t-D
1b,d	5a	6a	7a	C, <1:20
2b,d	5a	6a	7a	A, >10:1
3b	5b	6b	7b	C, <1:20
4b	5b	6b	7b	B, ∼4:1
5c	5c	6c	7c	C, <1:20
6c	5c	6c	7c	B, >10:1

Method A: KOt-Bu (1.5 equiv), n-BuLi (1.5 equiv), −78 °C, THF (0.02 M), 20 min; 5a–c (1.0 equiv), 10 min; TBSCl (1.4 equiv), −78 °C to rt. Method B: KHMDS (1.2 equiv), THF (0.02 M), −78 °C, 5a–c (1.0 equiv), 10 min; TBSCl (1.4 equiv), −78 °C to rt. Method C: 5a–c (1.3 equiv), KHMDS (1.0 equiv), THF (0.02 M), 0 °C, 5 h; TBSCl (1.1 equiv), 0 °C to rt.

T = 150 °C for DA/r-DA sequence.

T = 100 °C for DA/r-DA sequence.

Preferred conditions.

Individual submission of thermodynamic dienes (7a–c) and excess dimethyl acetylenedicarboxylate (DMAD) to thermal conditions facilitated the tandem DA and r-DA reaction to form compound 8 in all cases. However, we chose to focus on diene 7a because of its low cost and ease of preparation. Thermodynamic diene 7a participates in the reaction sequence with assorted dienophiles to afford desired products 8–16 in good yields (Table 2). Acetylenes mono- or disubstituted with an electron-withdrawing group both participate in the DA and subsequent r-DA reaction. However, the 3-bromo- and 3-chloro-propionaldehyde (entry 6) resulted in lower isolated yields. In the case employing an acetylene with nonequivalent electron-withdrawing groups (entry 7), an isomeric product mixture was obtained. The major product, 15a, arose from the ketone acting as the predominant directing group (15a:15b, 2:1). Remarkably, ethyl cyanoformate proceeded to afford the silyl-protected m-APyOH 16 (entry 8), a core widely found as the corresponding pyridone in natural and synthetic products.[3]

Table 2

Cycloadditions with Thermodynamic Diene 7a

Reaction yields based on the diene 7a as the limiting reagent. Dienophile equivalents.

2 equiv.

4 equiv.

10 equiv.

Dienophile used without purification.

Yield of 14 based on the corresponding isolated phenol, characterized as such.

Mixture of regioisomers 15a:15b (2:1); major product 15a pictured.

Combined yield.

The mixture of regioisomers 15a and 15b (Table 2, entry 7) proved inconsequential in one context.[18] Upon submission to potassium hexamethyldisilazide both isomers converged by cyclization to the diketone 17 in a 76% yield (Scheme 1).

Scheme 1

Convergent Closure of Regioisomers 15a and 15b

Additional chemical manipulations further demonstrate the utility of these new aromatic materials (Scheme 2). Hydrogenolysis of bis-protected m-APhOH 8 provided the aniline 18 in 96% yield, while stirring m-APyOH 12 with acid afforded the pyridone 19 in 90% yield.[19]

Scheme 2

Aniline and Pyridone Formation Conditions

Submission of the individual kinetic dienes (6a–c, Table 1) to similar thermal conditions with excess DMAD dienophile gave the anticipated product 20. However, a significant amount of undesired regioisomer 8, resulting from diene 7a, was also isolated. Isomeric ratios among the phenol products were nearly identical for dienes 6a–c. As done in the thermodynamic case, we chose to focus on diene 6a, which was submitted to the same reaction conditions as diene 7a with a similar assortment of acetylenes (Table 3). Despite a starting diene ratio of >10:1, 6a:7a, two isomeric products always formed: the expected products (20–24) from the kinetic diene 6a, and their respective regioisomers resulting from the thermodynamic diene 7a. Since the product ratios failed to reflect the initial diene ratio, we suspected that perhaps the regioisomeric dienes undergo reaction at different rates or that the ratio of 6a:7a changes during the course of the reaction. The best outcomes were observed with bis(trifluoroethyl)acetylene dicarboxylate (entry 2) and the propargylic aldehyde (entry 5), which are presumably more reactive dienophiles. Ethyl cyanoformate appeared to undergo successful reaction, but the product proved difficult to isolate. All isolated products (20–24) exhibit hindered rotation about the N–Ar bond due to the steric encumbrance of the neighboring group. Variable temperature experiments demonstrated free rotation, although it was difficult to fully resolve their 13C spectra. A variety of Lewis acids were investigated in an attempt to improve these isomeric ratios. However, in our hands, most caused degradation of the diene to the cyclic vinylogous amide 5a.

Table 3

Cycloadditions with Kinetic Diene 6aa

Diene ratio was >10:1 6a:7a.

Reaction yields based on the diene 6a as the limiting reagent. Dienophile equivalents.

2 equiv.

4 equiv.

Characterized as the corresponding phenol.

To better understand the apparent isomerization,[20] a deuterated system was synthesized (Scheme 3). Diene 6d was prepared by repetitive formation of 7a and deuteration of the intermediate thermodynamic siloxydiene with acetic acid-d4 to enrich the γ-position, which eventually resulted in 80% deuterium incorporation for 6d. Upon heating, the nondeuterated diene 6a had been found to equilibrate from >10:1 to 7:1 over 24 h to 5:1 over 3 days, and to 2:1 over 7 days. However, under strictly thermal conditions, the deuterated diene 6d did not behave similarly to afford diene 7d (Scheme 3). Upon heating the deuterated diene 6d with the acetylenic dienophile DMAD, aromatics 20 and 8d arose in a 2:1 ratio by analysis of the crude NMR. This suggests that the dienophile might facilitate the formation of 7d perhaps via a charge-transfer complex, or zwitterionic intermediate.[21] However, this notion was not probed further.

Scheme 3

Deuterium Study

To establish the tolerance and utility of this strategy, we prepared the sophisticated diene derivative 25 in six steps and 12% yield from dimedone 3a, using a mild SmI2-mediated cyclization recently developed in our lab to construct the methylated tetramic acid (Scheme 4).[22] Application of our standard thermal conditions to a mixture of diene 25 and DMAD afforded the anticipated aromatic compound, which was desilylated by prolonged heating or exposure to fluoride and afforded compound 26a along with its minor regioisomer (not pictured) (2:1) in an 85% combined yield.

Scheme 4

Application toward Tetrapetalone A

This work demonstrates that dimedone 3a can be used to prepare a plethora of highly functionalized m-APhOHs and a m-APyOH. This strategy is tolerant of a wide range of nitrogen appended functional groups that would not be amenable to preparation by any other existing method.