Zinc-Catalyzed Transacetalization of N,O-Acetals into N,N-Acetals with Benzotriazoles, Indazoles, and Azides

This paper is dedicated to Professor Barry M. Trost to celebrate his career on the occasion of 20 years of Science of Synthesis.

Abstract

N,O-Acetals obtained from β-oxidation of ynamides underwent transacetalization with benzotriazoles, leading to N,N-acetals. The Zn(OTf)₂ efficiently catalyzed the process, and the reaction is further accelerated in hexafluoroisopropanol, providing a single N1-regiosiomer. The transacetalization conditions developed could be extended to other N-donors, such as 1H-indazole and TMSN₃ to afford the corresponding N,N-acetals.

Benzotriazoles are found as a core scaffold of a broad range of medicinal agents, such as anticancer, antifungal, antibacterial, antitubercular, and antiviral compounds.[1] They can be derivatized in a variety of methods, including addition to π-bonds[2] or metal carbene,[3] alkylation through nucleophilic substitution[4] or by radical mechanism,[5] and arylation.[6] However, a mixture of N1- and N2-regioisomers are typically produced, and few of the above methods are completely regioselective.[2a] [b] [3]

Oxidation of ynamides mediated by pyridine-N-oxides have gained intense interest because the resulting α-oxidation intermediates displayed an umpoled enolonium reactivity,[7] mediating addition of unmodified nucleophilic arenes, furnishing α-substituted carbonyl compounds I.[8] In contrast, we recently reported β-oxidation of ynamides promoted by mCPBA, furnishing β-keto-N,O-acetals II (Scheme [1], A).[9] We demonstrated that the subsequent transacetalization with secondary alcohols occurred in a highly enantioselective manner in the presence of a chiral phosphoric acid (Scheme [1], B), furnishing transacetalization product III.[9] In continuation of exploring the reactivity of N,O-acetals II, we report herein transacetalization with benzotriazoles to form benzotriazole derivatives IV, occurring in a highly regioselective manner (Scheme [1], C).

We set out to examine the substitution, employing N,O-acetal 1a and benzotriazole 2 for the optimization study (Table [1]). The reaction did not proceed in the absence of catalyst in CH₂Cl₂ at 60 ℃ (entry 1). However, addition of Lewis acids significantly improved the conversion (entries 2–6). Among them, Zn(OTf)₂ turned out to be the most potent Lewis acids, furnishing a mixture of N1- and N2-adducts (3a and 4a, respectively) in a combined 80% yield with N1/N2 (3a/4a) ratio of 5.7:1, upon heating at 60 ℃ for 60 h. The isomeric ratio (N1/N2) was not affected much by different Lewis acids, which later turned out to be a thermodynamic ratio.

Table 1 Screening of Conditions for Transacetalization of 1a ^a

Enry	Catalyst	Solvent	Time (h)	Yield of 3a/4a (%)b
1	none	CH2Cl2	48	0/0c
2	Fe(OTf)2	CH2Cl2	72	64/11
	Yb(OTf)3	CH2Cl2	72	48/8
3	Cu(OTf)2	CH2Cl2	72	38/5
4	In(OTf)3	CH2Cl2	60	49/7
5	Sc(OTf)3	CH2Cl2	60	55/8
6	Zn(OTf)2	CH2Cl2	60	68/12
7	HNTf2	CH2Cl2	72	54/9
8	HBF4·OEt2	CH2Cl2	84	50/6
9	CF3COOH	CH2Cl2	120	58/7
10	H3PO4	CH2Cl2	144	50/13
11	Zn(OTf)2	C6H6	72	65/13
12	Zn(OTf)2	Et2O	60	69/12
13	Zn(OTf)2	MeOH	48	88/0
14	Zn(OTf)2	i-PrOH	30	82/0
15	Zn(OTf)2	HFIP	9	91/0

^a The reaction was conducted with 1a (0.1 mmol) and 2 (0.3 mmol).

^b Yield was determined by crude ¹H NMR spectra, with CH₂Br₂ as an internal reference.

^c Starting 1a remained intact.

Brønsted acids also catalyzed the transacetalization, but the reaction took a much longer time, compared to Zn(OTf)₂ (Table [1], entries 7–10). We then screened solvents for the transacetalization. While CH₂Cl₂, C₆H₆, and Et₂O gave similar N1/N2 ratio, alcoholic solvents exclusively produced N1-adduct (entries 11–14). Finally, hexafluoroisopropanol (HFIP) gave a drastically improved conversion as well producing only 3a in 91% yield as measured by crude ¹H NMR spectrum.

With the conditions optimized above, we inspected substitution of various N,O-acetal substrates 1 with benzotriazole (BT, 2, Scheme [2]). Substitution of 1a could be repeated in 4 mmol scale with an identical efficiency (9 h), affording the product 3a in 87% isolated yield. Polycyclic aromatic (3b,c) and heteroaromatic (3d,g) groups could be accommodated in the ketone moiety. Electron-rich (3h–j) as well as electron-poor (3k–t) aryl groups also underwent smooth transacetalization including sterically demanding ones (3i,k). Substrates with an aliphatic ketone (3t–v) afforded the transacetalization products smoothly, with a slightly decreased yield. Change of R¹ and R² groups as in 1w–y were also well tolerated, providing the corresponding N,N-acetals 3w–y in good yields.

Importantly, the currently developed conditions for the transacetalization to N,N-acetals can be extended to other N-donor compounds (Scheme [3]). For example, substitution of 1a with 1H-indazole 5 proceeded as efficiently under otherwise identical conditions, affording N-substitution product 6a in 75% yield in 10 h. The identity of 6q, i.e., whether it was the C- or N-adduct, was determined from the DEPT spectrum, and whether it was the N1- or N2-isomer, the identity of 6q was based on the NOE spectra. The generality with 1H-indazole was briefly examined, and the products 6b,i,q were obtained smoothly in 10–16 h. Employing TMSN₃, an azide could also be incorporated into the N,N-acetal 7a (68%) in 12 h. Synthesis of other N,N-acetals bearing an azide moiety also went smoothly, affording 7b,f,h,i,p in good yields in 6–18 h.

To support the mechanism of the current regioselective transacetalization, we carried out the following experiments. From the regioisomeric mixture of 3a/4a (N1/N2 = 6:1), the N1 isomer 3a was purified and was subjected to the reaction conditions. As in Scheme [4, 3a] isomerized into the 8:1 mixture of 3a/4a, upon heating at 80 °C in the presence of Zn(OTf)₂ in CH₂Cl₂. In contrast, a mixture of 3a/4a (3:1) isomerized into 3a exclusively in HFIP (Scheme [5]). These indicated the reversible interconversion between 3a and 4a, and the equilibrium is shifted depending on solvents, presumably through a keteniminium ion. We attempted an enantioselective trans-acetalization of 1a with benzotriazole in the presence of (R)-TRIP or (R)-TCyP (10 mol%) in CH₂Cl₂ at 60 °C; we obtained 3a in 60–62 % yield after 72 h, unfortunately as a racemic form (0% ee).

Considering the novelty of the obtained scaffolds, we explored synthetic transformations as described in Scheme [6]. Reduction of the ketone group in 3a with NaBH₄ furnished 8a as 3:1 diastereomeric mixture in good yields (Scheme [6], eq. 1), reflecting stability of the product in the absence of the flanking ketone. We attempted modification of benzotriazole under radical conditions.[10] However, surprisingly, desulfuration of 3a into 9a occurred, presumably via hydrogen atom abstraction at the acetal center (Scheme [6], eq. 2). An attempted Cu-catalyzed [3+2] cycloaddition of azide 7a [11] resulted in reduction into an imidate 10 (Scheme [6], eq. 3). This transformation may have occurred through oxidative addition of Cu(I) to the N–N bond in the azides, followed by reductive elimination. These transformation demonstrates the utility of the N,N-acetals obtained in this study.

To summarize, we developed herein transacetalization conditions converting N,O-acetals 1 into the N,N-acetals 3 using benzotriazole, indazole, and azides.[12] The reaction is significantly accelerated by the combination of Zn(OTf)₂ catalyst and HFIP solvent under which conditions substitution with benzotriazole occurred with a complete regioselectivity. Further work on the enantioselective N,N-transacetalization is currently underway in the laboratory.

• References and Notes

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• 1b Suma BV, Natesh NN, Madhavan V. J. Chem. Pharm. Res. 2011; 3: 375
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• 7f Kaldre D, Maryasin B, Kaiser D, Gajsek O, González L, Maulide N. Angew. Chem. Int. Ed. 2017; 56: 2212
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For Brønsted acid catalyzed approaches, see:
• 8a Patil DV, Shin S. Asian J. Org. Chem. 2019; 8: 63
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• 8b Patil DV, Kim SW, Nguyen QH, Kim H, Wang S, Hoang T, Shin S. Angew. Chem. Int. Ed. 2017; 56: 3670
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• 8e Um T.-W, Lee G, Shin S. Org. Lett. 2020; 22: 1985
  CrossrefPubMedSearch in Google Scholar

For the Zn-catalyzed addition of N-hydroxybenzotriazoles, see:
• 8f Im J, Shin SI, Cho C.-G, Shin S. J. Org. Chem. 2020; 85: 6935
  CrossrefPubMedSearch in Google Scholar
• 9 Nguyen NH, Nguyen QH, Biswas S, Patil DV, Shin S. Org. Lett. 2019; 21: 9009
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• 10 Singh AS, Kumar D, Mishra N, Tiwari VK. ChemistrySelect 2017; 2: 224
  CrossrefSearch in Google Scholar
• 11 Shao C, Wang X, Zhang Q, Luo S, Zhao J, Hu Y. J. Org. Chem. 2011; 76: 6832
  CrossrefPubMedSearch in Google Scholar
• 12 Synthesis of 3 – Typical Procedure for 3a In a 4 mL vial, the N,O-acetal 1a (38.2 mg, 0.1 mmol), benzotriazole (2, 35.7 mg, 0.3 mmol), and Zn(OTf)₂ (3.6 mg, 0.01 mmol) were dissolved in hexafluoroisopropanol (HFIP, 1 mL). The reaction mixture was then heated to 60 °C for 9 h, when the reaction was judged to be complete (TLC). The mixture was concentrated to dryness, and the residue was purified by SiO₂ flash chromatography (EtOAc/n-hexane/CH₂Cl₂ = 1:15:5) to afford 3a (30 mg, 87%) as a white solid; mp 108–110 ℃. ¹H NMR (400 MHz, CDCl₃): δ = 8.11 (d, J = 9.2 Hz, 1 H), 7.92 (s, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 7.3 Hz, 2 H), 7.63 (t, J = 15.4 Hz, 1 H), 7.55 (t, J = 14.9 Hz, 1 H), 7,48 (t, J = 15.4 Hz, 1 H), 7.38 (t, J = 13.9 Hz, 2 H), 3.10 (s, 3 H), 2.94 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 189.0, 145.8, 134.5, 133.5, 132.4, 129.1, 128.5, 125.0, 120.5, 109.7, 71.4, 38.9, 31.3. HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₆N₄O₃S⁺: 344.0938; found: 344.0941.

• References and Notes

• 1a Ren Y, Zhang L, Zhou C. -H, Geng R. -X. Med. Chem. 2014; 4: 640
  Search in Google Scholar
• 1b Suma BV, Natesh NN, Madhavan V. J. Chem. Pharm. Res. 2011; 3: 375
  Search in Google Scholar
• 2a Xu K, Thieme N, Breit B. Angew. Chem. Int. Ed. 2014; 53: 7268
  CrossrefPubMedSearch in Google Scholar
• 2b Chen S.-W, Zhang G.-C, Lou Q.-X, Cui W, Zhang S.-S, Hu W.-H, Zhao J.-L. ChemCatChem 2015; 7: 1935
  CrossrefSearch in Google Scholar
• 2c Duan H, Yan W, Sengupta S, Shi X. Bioorg. Med. Chem. Lett. 2009; 19: 3899
  CrossrefPubMedSearch in Google Scholar
• 2d Yan W, Ye X, Weise K, Petersen JL, Shi X. Chem. Commun. 2012; 48: 3521
  CrossrefPubMedSearch in Google Scholar
• 3 Wang K, Chen P, Ji D, Zhang X, Xu G, Sun J. Angew. Chem. Int. Ed. 2018; 57: 12489
  CrossrefPubMedSearch in Google Scholar
• 4a Katritzky AR, Chang H.-X, Wu J. Synthesis 1994; 907
• 4b Niedermann K, Früh N, Senn R, Czarnieckim B, Verel R, Togni A. Angew. Chem. Int. Ed. 2012; 51: 6511
  CrossrefPubMedSearch in Google Scholar
• 4c Yan W, Wang Q, Chen Y, Petersen JL, Shi X. Org. Lett. 2010; 12: 3308
  CrossrefPubMedSearch in Google Scholar
• 5a Wu J, Zhou Y, Zhou Y, Chiang C.-W, Lei A. ACS Catal. 2017; 7: 8320
  CrossrefSearch in Google Scholar
• 5b Aruri H, Singh U, Sharma S, Gudup S, Bhogal M, Kumar S, Singh D, Gupta VK, Kant R, Wishwakarma RA, Singh PP. J. Org. Chem. 2015; 80: 1929
  CrossrefPubMedSearch in Google Scholar
• 6a Liu Y, Yan W, Chen Y, Petersen JL, Shi X. Org. Lett. 2008; 10: 5389
  CrossrefPubMedSearch in Google Scholar
• 6b Lee H.-G, Won J.-E, Kim M.-J, Park S.-E, Jung K.-J, Kim BR, Lee S.-G, Yoon Y.-J. J. Org. Chem. 2009; 74: 5675
  CrossrefPubMedSearch in Google Scholar

For reviews, see:
• 7a Yeom H.-S, Shin S. Acc. Chem. Res. 2014; 47: 966
  CrossrefPubMedSearch in Google Scholar
• 7b Zhang L. Acc. Chem. Res. 2014; 47: 877
  CrossrefPubMedSearch in Google Scholar

For selected examples, see:
• 7c Arava S, Kumar JN, Maksymenko S, Iron MA, Parida KN, Fristrup P, Szpilman AM. Angew. Chem. Int. Ed. 2017; 56: 2599
  CrossrefPubMedSearch in Google Scholar
• 7d Li L, Shu C, Zhou B, Yu Y.-F, Xiao X.-Y, Ye LW. Chem. Sci. 2014; 5: 4057
  CrossrefSearch in Google Scholar
• 7e Li L, Zhou B, Wang Y.-H, Shu C, Pan Y.-F, Lu X, Ye LW. Angew. Chem. Int. Ed. 2015; 54: 8245
  CrossrefPubMedSearch in Google Scholar
• 7f Kaldre D, Maryasin B, Kaiser D, Gajsek O, González L, Maulide N. Angew. Chem. Int. Ed. 2017; 56: 2212
  CrossrefPubMedSearch in Google Scholar

For Brønsted acid catalyzed approaches, see:
• 8a Patil DV, Shin S. Asian J. Org. Chem. 2019; 8: 63
  CrossrefSearch in Google Scholar
• 8b Patil DV, Kim SW, Nguyen QH, Kim H, Wang S, Hoang T, Shin S. Angew. Chem. Int. Ed. 2017; 56: 3670
  CrossrefPubMedSearch in Google Scholar
• 8c Kim SW, Um T.-W, Shin S. Chem. Commun. 2017; 53: 2733
  CrossrefPubMedSearch in Google Scholar
• 8d Nguyen QH, Nguyen NH, Kim H, Shin S. Chem. Sci. 2019; 10: 8799
  CrossrefPubMedSearch in Google Scholar
• 8e Um T.-W, Lee G, Shin S. Org. Lett. 2020; 22: 1985
  CrossrefPubMedSearch in Google Scholar

For the Zn-catalyzed addition of N-hydroxybenzotriazoles, see:
• 8f Im J, Shin SI, Cho C.-G, Shin S. J. Org. Chem. 2020; 85: 6935
  CrossrefPubMedSearch in Google Scholar
• 9 Nguyen NH, Nguyen QH, Biswas S, Patil DV, Shin S. Org. Lett. 2019; 21: 9009
  CrossrefPubMedSearch in Google Scholar
• 10 Singh AS, Kumar D, Mishra N, Tiwari VK. ChemistrySelect 2017; 2: 224
  CrossrefSearch in Google Scholar
• 11 Shao C, Wang X, Zhang Q, Luo S, Zhao J, Hu Y. J. Org. Chem. 2011; 76: 6832
  CrossrefPubMedSearch in Google Scholar
• 12 Synthesis of 3 – Typical Procedure for 3a In a 4 mL vial, the N,O-acetal 1a (38.2 mg, 0.1 mmol), benzotriazole (2, 35.7 mg, 0.3 mmol), and Zn(OTf)₂ (3.6 mg, 0.01 mmol) were dissolved in hexafluoroisopropanol (HFIP, 1 mL). The reaction mixture was then heated to 60 °C for 9 h, when the reaction was judged to be complete (TLC). The mixture was concentrated to dryness, and the residue was purified by SiO₂ flash chromatography (EtOAc/n-hexane/CH₂Cl₂ = 1:15:5) to afford 3a (30 mg, 87%) as a white solid; mp 108–110 ℃. ¹H NMR (400 MHz, CDCl₃): δ = 8.11 (d, J = 9.2 Hz, 1 H), 7.92 (s, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.79 (d, J = 7.3 Hz, 2 H), 7.63 (t, J = 15.4 Hz, 1 H), 7.55 (t, J = 14.9 Hz, 1 H), 7,48 (t, J = 15.4 Hz, 1 H), 7.38 (t, J = 13.9 Hz, 2 H), 3.10 (s, 3 H), 2.94 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 189.0, 145.8, 134.5, 133.5, 132.4, 129.1, 128.5, 125.0, 120.5, 109.7, 71.4, 38.9, 31.3. HRMS (EI): m/z [M]⁺ calcd for C₁₆H₁₆N₄O₃S⁺: 344.0938; found: 344.0941.

• Supplementary Material