Yeruva Pavankumar Reddya,
V. Srinivasadesikana,
Rengarajan Balamuruganb,
M. C. Linc and
Shaik Anwar
*a
aDepartment of Chemistry, School of Applied Sciences and Humanities, Vignan's Foundation for Science Technology and Research-VFSTR (Deemed to be University), Vadlamudi-522213, Guntur, Andhra Pradesh, India. E-mail: shaikanwarcu@gmail.com; drsa_sh@vignan.ac.in; Web: https://www.vignan.ac.in/bshanwar.php Tel: +91-8632344700
bSchool of Chemistry, University of Hyderabad, Gachibowli, Hyderabad, India 500046
cDepartment of Applied Chemistry, National Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan
First published on 16th February 2023
Substituted tetrahydrochromenes and dihydronaphthofurans are easily accessible by the treatment of β-tetralone with trans-β-nitro styrene derived Morita–Baylis–Hillman (MBH) acetates through a formal [3 + 3]/[3 + 2] annulation. The reaction proceeds through a cascade Michael/oxa-Michael pathway with moderate to good yields. A DFT study was carried out to account for the formation of the corresponding six and five-membered heterocycles via 6-endo-trig and 5-exo-trig cyclization.
Peng-Fei Xu et al. (Scheme 1, eqn (a)) synthesised tetrahydropyranoindoles through organocatalytic asymmetric C–H functionalization of indoles via [3 + 3] annulation through 6-endo trig cyclization.19 The Namboothiri group recently developed a metal free regioselective synthesis of α-carbolines via [3 + 3] annulation involving secondary MBH acetate (Scheme 1, eqn (b)).20 Previously, our group carried out a [3 + 3] cyclization reaction of β-naphthol with primary MBH acetate to study the scope of SN2′ vs. SN2 reaction.21 With our ongoing interest in using nitro styrene derived MBH adducts22 explored the reactivity of primary and secondary MBH acetate with β-tetralone 1 as our model reaction. Initially, the reaction carried out using β-tetralone 1 with primary MBH-acetate 2, predominantly gave a tetrahydrochromene 3 via [3 + 3] annulation involving 6-endo trig cyclization through Michael/oxa-Michael cascade process. The possible dihydronaphthofuran product was not observed under the present conditions as primary MBH acetate 2 acts as 1,3-biselectrophile instead of 1,2-biselectrophile (Scheme 1, eqn (c)).
On the other hand, the reaction of β-tetralone 1 with secondary MBH acetate 4 gave dihydronaphthofuran instead of the possible tetrahydrochromene product due to the 1,2-biselectrophile nature of secondary MBH acetate (Scheme 1, eqn (d)). The formation of dihydronaphthofuran 5 occurs in an SN2′ fashion via [3 + 2] annulation involving 5-exo-trig cyclization through Michael followed by intramolecular oxa-Michael reaction with the elimination of HNO2. Subsequently, we have carried out a DFT calculation to prove the formation of tetrahydrochromene 3 using primary MBH acetate 2 and dihydronaphthofuran 5 in the case of secondary MBH acetate 4.
Initially, we carried out the optimization conditions for constructing tetrahydrochromenes 3a using β-tetralone 1 with MBH nitro allylic primary acetate 2a with different bases and solvents. Reaction with organic base, i.e. DABCO using a polar aprotic solvent such as acetonitrile at room temperature gave the desired product in 27% (Table 1, entry 1). Using chlorinated solvents like CHCl3 and CH2Cl2 resulted in meagre yield (i.e., 22 and 19%, respectively) with the recovery of starting material (Table 1, entries 2 and 3). The yield of the product was increased to 40% in the presence of DMAP and THF solvent (Table 1, entry 4). We obtained similar yields i.e. 45 and 44% in the presence of triethylamine, triphenylphosphine respectively (Table 1, entries 5 and 6). The reaction carried out using an inorganic base such as K2CO3 in THF solvent led to an increase in yield i.e., 60% (Table 1, entry 7). A maximum yield of 77% was observed when the reaction was carried out in the presence of Cs2CO3 as base and THF as a solvent at room temperature for 4 h (Table 1, entry 8). The reaction with reduced base equivalents led to reduced yields concluded that 2.0 equiv. of Cs2CO3 is desirable to yield tetrahydrochromene 3a under the present reaction conditions (Table 1, entries 9–11). Further, increase of Cs2CO3 with 3.0 equiv. led to unclean reaction mixture with decreased yield of the product 3a (Table 1, entry 12). Notably, excellent diastereoselectivity of 99:
1 dr was retained in all the cases of solvent/base optimisation studies. The stereocenter of the compound 3a was further confirmed by 1H, 13C NMR, HRMS, and single crystal XRD23 (CCDC-2149875) (Table 2).
Entry | Base | Solvent | Time (h) | Yield (%) | drb |
---|---|---|---|---|---|
a Unless otherwise noted, reactions were carried out by and (0.11 mmol) of 1 with (0.11 mmol) of 2a using 0.22 mmol of a base in 1 ml of THF solvent.b Determined by 1H-NMR analysis of crude reaction mixture.c Reaction was carried out using 0.5 equiv. of Cs2CO3.d Reaction was carried out using 1.0 equiv. of Cs2CO3.e Reaction was carried out using 1.5 equiv. of Cs2CO3.f Reaction was carried out using 3.0 equiv. of Cs2CO3. | |||||
1 | DABCO | CH3CN | 5 | 27 | 99![]() ![]() |
2 | DABCO | CH2Cl2 | 5 | 22 | 99![]() ![]() |
3 | DABCO | CHCl3 | 5 | 19 | 99![]() ![]() |
4 | DMAP | THF | 5 | 40 | 99![]() ![]() |
5 | TEA | THF | 5 | 45 | 99![]() ![]() |
6 | PPh3 | THF | 5 | 44 | 99![]() ![]() |
7 | K2CO3 | THF | 4 | 60 | 99![]() ![]() |
8 | Cs2CO3 | THF | 4 | 77 | 99![]() ![]() |
9c | Cs2CO3 | THF | 8 | 50 | 99![]() ![]() |
10d | Cs2CO3 | THF | 5 | 61 | 99![]() ![]() |
11e | Cs2CO3 | THF | 4 | 65 | 99![]() ![]() |
12f | Cs2CO3 | THF | 4 | 60 | n.d |
Based on the best optimized conditions, we studied the scope of different nitro allylic MBH primary acetates (2a–e) with β-tetralone 1. The reaction accommodates various electron rich substituents on the primary MBH acetates (2a–e). The electron rich substituent contaning 2b gave 76% yield for the benzyloxy product 3b. The substrate having meta-OMe and para–OMe gave the desired product 3c and 3d with 71 & 68% of yield, respectively. Furthermore, using fluoro substituent at para position of the MBH adduct gave the product 3e with 72% yield. Reaction carried out using 6-bromo tetralone 1b gave the corresponding product 3f in 68% of yield. Notably, remarkable diastereoselectivity of 99:
1 dr was observed in all the cases of base screening and substrate scope of MBH primary acetate.
Encouraged, by the high diastereoselectivity for various tetrahydrochromenes derivatives 3a–e, we pursued our studies towards asymmetric synthesis of 3a using different chiral catalysts (I–IV). We observed the poor ee for the product formation in the presence of cinchona based squaramide catalyst I & BINAM based urea catalyst II (Table 3, entries 1 and 2). BINAM derived thiourea catalyst III resulted in a 10% enantiomeric excess (Table 3, entry 3). We obtained a moderate enantiomeric excess (49% ee) with good diastereoselectivity (99:
1) in the presence of thiourea based hydrogen bonding catalyst IV (Table 3, entry 4). The use of various Lewis base catalysts also could not enhance the enantioselectivity.
Entry | Catalyst | Time (h) | Yield (%) | ee (%) |
---|---|---|---|---|
a All the reactions were carried out with (0.11 mmol) of 1, (0.11 mmol) of 2a, (0.22 mmol) of base and 10 mol% in 1 ml of THF solvent. | ||||
1 | I | 4 | 59 | <2 |
2 | II | 4 | 60 | <2 |
3 | III | 4 | 60 | 10 |
4 | IV | 4 | 63 | 49 |
We next focused our studies on understand the reactivity of secondary MBH acetate 4a using β-tetralone 1. Interestingly, the reaction followed an SN2′ Michael/intramolecular oxa-Michael pathway to form dihydronaphthofuran 5a via [3 + 2] annulation instead of an alternate path resulting in the formation of chromene product via 3 + 3 annulation (i.e., Scheme 1; eqn (d)). To recognize the optimal reaction condition, we carried out the reaction in the presence of Cs2CO3 in THF solvent to get the desired dihydronaphthofuran 5a in 35% yield (Table 4, entry 1). Next, we investigated the influence of chlorinated solvents on the product formation 5a. Solvents such as CH2Cl2, CHCl3, and CCl4 failed to enhance the yield for the product formation (Table 4, entries 2–4). Furthermore, an organic base such as TEA in THF gave the required product 5a with 46% of yield (Table 4, entry 5). A drop in the yield was observed using DABCO in presence of a polar aprotic solvent such as acetonitrile (Table 4, entry 6). Unfortunately, the yield drastically dropped to 27% using triphenylphosphine as a base (Table 4, entry 7). Finally, a good yield was observed with an inorganic base, i.e. K2CO3 using acetonitrile as a solvent to furnish the desired product 5a in 72% of yield (Table 4, entry 8).
Entry | Base | Solvent | Time (h) | Yield (%) |
---|---|---|---|---|
a Unless otherwise noted, reactions were carried out with (0.11 mmol) of 1 with (0.11 mmol) of 4a using 0.22 mmol% of base in 1 ml of acetonitrile solvent.b Reaction was carried out using 0.5 equiv. of K2CO3.c Reaction was carried out using 1.0 equiv. of K2CO3.d Reaction was carried out using 1.5 equiv. of K2CO3.e Reaction was carried out using 3.0 equiv. of K2CO3. | ||||
1 | Cs2CO3 | THF | 6 | 35 |
2 | Cs2CO3 | CH2Cl2 | 4.5 | 31 |
3 | Cs2CO3 | CHCl3 | 4.5 | 27 |
4 | Cs2CO3 | CCl4 | 4.5 | 16 |
5 | TEA | THF | 5 | 46 |
6 | DABCO | CH3CN | 6 | 41 |
7 | PPh3 | CH3CN | 5 | 27 |
8 | K2CO3 | CH3CN | 4 | 72 |
9b | K2CO3 | CH3CN | 7 | 59 |
10c | K2CO3 | CH3CN | 6 | 63 |
11d | K2CO3 | CH3CN | 5 | 68 |
12e | K2CO3 | CH3CN | 4 | 65 |
The reaction with reduced base equivalents, led to reduced yields confirming that 2.0 equiv. of K2CO3 is desirable to yield dihydronaphthofuran 5a at room temperature within 4 h (Table 4, entries 9–11). It was observed that a low yield was obtained when the reaction was carried out with 3.0 equiv. of base (Table 4, entries 12).
Utilizing the established optimized reaction conditions, i.e. (Table 4, entry 8), the substrate scope of this formal [3 + 2] annulation was explored towards the construction of substituted dihydronaphthofurans 5b–g (Table 5). The meta-OMe and para-OMe on the phenyl ring gave the good yield of 67 and 62%, respectively, for products 5b and 5c. The di substituted 2,4-dimethoxy, and 2,5-dimethoxy containing substrates gave a moderate yield of 60 and 58% for the desired products 5d and 5e. The substrate with benzyloxy substituent at the para position of the phenyl ring also gave the desired product 5f in 70% of yield. A reaction carried out using substrate 1b resulted in product 5g in 58% yield (Table 5).
To further demonstrate our protocol's practical and scalable utility, we have carried out the gram scale preparation of tetrahydrochromene 3a and dihydronaphthofuran 5a in 66 and 70% of yield. We observed the retention of diastereoselectivity i.e., 99:
1 of tetrahydrochromene 3a, even at the gram scale condition (Scheme 2).
We have successfully applied the synthetic utility for dihydronaphthofuran 5a. Reduction of the ester group in 5a was feasible using LAH in THF to afford the desired alcohol product 6 with 60% of yield. Using KOH, the ester group in dihydronaphthofuran 5a was hydrolysed to the corresponding acid derivative 7 in 70% yield. The amidation reaction of 7 with aniline accomplished oxidation of the tetralone ring providing the N-phenyl-2-(1-phenylnaphtho[2,1-b]furan-2-yl)acetamide product 8 in 67% of yield (Scheme 3).
The β-tetralone 1 reacting with nitro allylic secondary MBH acetate 4a produced the dihydronaphthofuran derivatives, 5a–g, which is observed experimentally as shown in Table 5. The anion of β-tetralone 1 was considered for the DFT calculation. Here, an anion of β-tetralone interacts with the MBH nitro allylic secondary acetate 4a has produced a complex with a binding energy of −11.47 kcal mol−1. The anion path was considered for the theoretical calculation due to the abstraction of a proton by the base, initiating the reaction observed experimentally. The anion is displacing the acetate via SN2′ fashion has produced the intermediate (S-int1) as C–C bond formation with the barrier energy of 11.20 kcal mol−1. The formation of S-int1 is stable exothermically than the complex (S-cmplx). The S-TS2 was shown to be an acetate leaving group with a barrier energy of 5.98 kcal mol−1 and produced the product with new C–C bond formation and with dissociation the acetate group. The S-int2 initiate the proton transfer to produce the S-int3 with the stable intermediate. The barrier energy for the proton transfer has been observed as 24.49 kcal mol−1 showed in Fig. 2. The formation of S-int3, readily undergo for five-member cyclisation. As shown in Fig. 2, the S-int3 has produced S-int4 via S-TS4 with a barrier energy of 44.29 kcal mol−1. The higher barrier energy observed for cyclisation is accountable for the concern carbon has the electron-withdrawing nitro group. The highest energy barrier for cyclisation has considered as the rate determining step (RDS) for the secondary acetate path. Thus, the nitro group leave immediately after five-member ring cyclisation as HONO with the barrier energy of 24.25 kcal mol−1 and produced the observed product 5a. The relative energy of 5a was observed to be −12.72 kcal mol−1 showing the stability of the product. In the secondary acetate path, we have studied the possibility of a six-member ring formation. However, the barrier energy was observed to be 77 kcal mol−1 (S-Ts3a) and it observed as unfavourable path.
We have explained a plausible mechanism for the formation of tetrahydrochromene 3a and dihydronaphthofuran 5a in correlation to density functional theory (Fig. 1 and 2). The β-tetralone 1 generates the nucleophile A in the presence of a base. The nucleophile A attacks at α-position on the benzylic carbon atom of primary MBH-acetate 2a to generate intermediate B. This initial Michael attack involves the migration of double bond with the elimination of acetic acid via SN2′ reaction. Further deprotonation in the form of keto–enol tautomerism generates a nucleophilic oxygen atom to facilitate the oxa-Michael attack at γ-carbon atom of intermediate B. This intramolecular oxa-Michael addition favors 6-endo trig cyclization with [3 + 3] annulation to furnish the desired product 3a.
The possible alternate pathway involving oxa-Michael attack at the β-carbon atom of B′ is disfavoured for forming fused furan ring. Due to the 1,3-biselectrophilic nature of primary MBH acetate there exists a ring strain associated with undergoing the 5-exo-trig cyclization via [3 + 2] annulation (Scheme 4). The formation of 5a initiates with the attack of nucleophile A at the α-position of the benzylic carbon atom of secondary MBH-acetate 4a. This initial Michael addition involves migration of double bond and elimination of acetic acid through effective SN2′ reaction to generate intermediate C. Further deprotonation followed by tautomerism results in nucleophilic oxygen which undergoes intramolecular oxa-Michael reaction at the β-position of 4a to give intermediate D with [3 + 2] annulation via 5-exo-trig cyclization. Further elimination of HONO under basic conditions results in 5a as the favoured product. Alternate oxa-Michael attack on γ-position of intermediate C′ was disfavoured for a possible [3 + 3] annulation via 6-endo-trig cyclization. This alternate pathway towards the 4H-pyran precedes through D′ with 1,2-elimination of HONO is disfavoured.
![]() | ||
Scheme 4 Plausible mechanism for the construction of tetrahydrochromene 3a and dihydronaphthofuran 5a. |
Footnote |
† Electronic supplementary information (ESI) available. CCDC 2149875. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2ra08163f |
This journal is © The Royal Society of Chemistry 2023 |