Catalytic Asymmetric Thioacetalization of Aldehydes

Abstract

A catalytic enantioselective thioacetalization reaction has been developed. Various aldehydes react with unsymmetrical 1,3- or 1,2-dithiols to furnish chiral, enantioenriched thioacetals in excellent enantioselectivities upon treatment with a nitrated imidodiphosphoric acid catalyst. The transformation is assumed to proceed via a thionium ion intermediate.

Key words

thioacetals - imidodiphosphates - Brønsted acid catalysis

The synthesis of optically active organic sulfur compounds is of interest because of their high abundance in natural products and pharmaceuticals.[1] Sulfur-based scaffolds are also widely used as chiral ligands, auxiliaries, catalysts, and intermediates in chemical synthesis.[2] However, despite the high synthetic utility of (achiral) dithioacetals,[3] little attention has been given to the development of asymmetric methods for the synthesis of their chiral, enantiopure analogues, which may have interesting biological properties.[4] We now report highly enantioselective direct thioacetalization reactions of aldehydes with dithiols catalyzed by a nitrated imidodiphosphoric acid.[5]

Previous approaches towards enantioenriched dithioacetals involve either Diels–Alder reactions of dithioesters with dienes or electrophilic sulfenylations of sulfur-substituted active methines.[6] In contrast, the conceptually straightforward direct dithioacetalization of carbonyl compounds with dithiols has long remained unknown. Inspired by recent studies on chiral Brønsted acid catalyzed direct asymmetric acetalization reactions and related transformation, proceeding via oxocarbenium-[7] and iminium ions,[8] we became curious if an asymmetric thioacetalization, which would proceed via a thionium ion as the critical intermediate, would also be realizable. Remarkably though, while catalytic asymmetric reaction that proceed via iminium ions are well established, and those involving oxocarbenium ions are currently being developed,[7] [9] thionium ions, to our knowledge, have not previously been invoked as critical intermediate in a catalytic enantioselective transformation. Success in developing a catalytic asymmetric thioacetalization of aldehydes would therefore also constitute a proof-of-principle of the general utility of thionium ions in asymmetric catalysis.

We began our investigations by reacting 2-methylpropane-1,2-dithiol (1a) with hydrocinnamaldehyde (2a) to give dithiolane 3a in trifluorotoluene in the presence of 5 Å molecular sieves at room temperature (Table [1]). A catalytic amount of TRIP (4) was tested for the thioacetalization reaction, but did not lead to any conversion after 10 days (entry 1). Based on our previous studies regarding asymmetric spiroactelizations,[7c] O,O-acetalizations,[7d] [e] sulfoxidations,[10a] and carbonyl-ene cyclizations,[10b] we set to explore the ability of our chiral confined imidodiphosphoric acid catalysts to perform an asymmetric thioacetalization reaction. Indeed, both imidiodiphosphoric acids 5a and 5b afforded the expected thioacetal 3a with an excellent 98:2 er (entries 2 and 3). However, the reactivity at room temperature turned to be moderate and full conversion was obtained after 3 days.

Table 1 Reaction Development^a

Entry	Catalyst (mol%)	Time	Conv.b	erc
1	4 (5)	10 d	0%	–
2	5a (5)	3 d	full	98:2
3	5b (5)	3 d	full	98:2
4	6 (5)	2 h	full	98:2
5	6 (2)	24 h	full	98:2

^a Reactions were run on a 0.05 mmol scale.

^b Determined by ¹H NMR analysis.

^c Determined by HPLC analysis.

We have recently designed more active imidodiphosphoric acid catalysts by increasing their acidity either via backbone nitration or by replacing a P=O group with a P=NTf group.[9f] [g] Gratifyingly, the use of 5 mol% of unsymmetrical catalyst 6 led to significantly increased reactivity and product 3a was obtained with full conversion after only 2 hours with an er of 98:2 (entry 4). Lowering the catalyst loading to 2 mol% gave full conversion within 24 hours while retaining the excellent enantioselectivity (entry 5).

The aldehyde scope of the enantioselective thioacetalization reaction was investigated next (Table [2]). Reacting aldehyde 2a with dithiol 1a furnished product 3a in 90% isolated yield and with an er of 98:2 (entry 1).[11] The use of pentanal led to the formation of product 3b with 84% yield and an excellent er of 98:2 (entry 2). Isovaleraldehyde and the α-branched aldehyde 2d gave access to the corresponding dithiolanes 3c and 3d with good yields and excellent enantioselectivities (entries 3 and 4). A significantly lower er of 74:26 of product 3e was obtained when benzaldehyde was subjected to the reaction conditions (entry 5). Our method can also be applied to acetalizations with a 1,3-dithiol to access six-membered thioacetals.[12] 1,3-Dithiane 3f was obtained with slightly lower er (90:10) compared to the corresponding dithiolane (entry 6 vs. entry 1). In addition, lower yield was obtained due to the non-negligible formation of the corresponding enethiol ether (see Supporting Information). Thioacetalization of (E)-cinnamaldehyde with 4,4-dimethyl-2-phenethyl-1,3-dithiane (1b) proceeded with good enantioselectivity giving product 3g with an er of 92:8 (entry 7). Pentanal and isovaleraldehyde could be employed in the reaction to give product 3h and 3i with enantiomeric ratios of 89:11 and 91.5:8.5, respectively (entries 8 and 9). Replacing isovaleraldehyde with α-branched aldehyde 2d resulted in lower enantioselectivity (er = 85.5:14.5) and reactivity (51% yield, entry 10).

Table 2 Reaction Scope^a

Entry	Temp	Time	Product	Yield (%)	erb
1	r.t.	24 h	3a	90	98:2
2	r.t.	24 h	3b	84	98:2
3	r.t.	24 h	3c	82	98.5:1.5
4	r.t.	24 h	3d	86	99:1
5	r.t.	38 h	3e	88	74:26
6c	0 °C	24 h	3f	73	90:10
7c	–20 °C	2 d	3g	80	92:8
8c	0 °C	24 h	3h	46	89:11
9c	0 °C	2 d	3i	73	91.5:8.5
10c	0 °C	6 d	3j	51	85.5:14.5

^a Reactions were run on a 0.2 mmol scale in trifluorotoluene with 40 mg of 5Å MS.

^b Determined by HPLC analysis or GC analysis.

^c 5 mol% of catalyst were used.

Based on our previous studies on the O,O-acetalization reaction of aldehydes,[7d] we suggest the following mechanism (Scheme [1]). Nitrated imidodiphosphate catalyst 6 activates both the aldehyde and the dithiol simultaneously to lead to the formation of S,O-hemiacetal–imidodiphosphoric acid complex A. Protonative dehydration of complex A results in the formation of the crucial thionium ion intermediate B. Cyclization directed by the chiral imidodiphosphate anion leads to enantioenriched product 3 with regeneration of the catalyst.

Scheme 1 Postulated mechanism

In summary, we have developed an enantioselective direct thioacetalization reaction of aldehydes with dithiols. Various enantioenriched dithiolanes and dithianes have been obtained with excellent enantioselectivities and in high yields.

Acknowledgment

Generous support by the Max-Planck-Society and the European Research Council (Advanced Grant ‘High Performance Lewis Acid Organocatalysis, HIPOCAT’) is gratefully acknowledged. We thank our technician team and the members of our NMR, MS, GC and HPLC departments for their excellent service.

• References and Notes

• 1a Damini LA. Sulphur-Containing Drugs and Related Organic Compounds. Wiley; New York: 1989
• 1b Patani GA, LaVoie EJ. Chem. Rev. 1996; 96: 3147
• 1c Christophersen C, Anthoni U. Sulfur Rep. 1986; 4: 365
• 2a Metzner P, Thuillier A. Sulfur Reagents in Organic Synthesis . Academic Press; New York: 1995
• 2b Toru T, Bolm C. Organosulfur Chemistry in Asymmetric Synthesis . Wiley-VCH; Weinheim: 2008
• 3a Kocieński PJ. Protecting Groups . Thieme; Stuttgart: 2005
• 3b Greene TW, Wuts PG. M. Protective Groups in Organic Synthesis . John Wiley and Sons; New York: 1999
• 3c Page PC. B, van Niel MB, Prodger JC. Tetrahedron 1989; 45: 7643
• 3d Luh T.-Y. J. Organomet. Chem. 2002; 653: 209
• 3e Seebach D, Corey EJ. J. Org. Chem. 1975; 40: 231
• 3f Eliel EL, Hartmann AA, Abatjoglou AG. J. Am. Chem. Soc. 1974; 96: 1807
• 4a Rutenber E, Fauman EB, Keenan RJ, Fong S, Furth PS, de Montellano PR. O, Meng E, Kuntz ID, DeCamp DL, Salto R, Rosé JR, Craik CS, Stroud RM. J. Biolog. Chem. 1993; 268: 15343
• 4b Smith EM, Swiss GF, Neustadt BR, McNamara P, Gold EH, Sybertz EJ, Baum T. J. Med. Chem. 1989; 32: 1600
• 5 This work has first been described in the PhD thesis of JHK (‘Brønsted acid catalyzed asymmetric acetalizations’, University of Cologne, published online in November 2015, http://kups.ub.uni-koeln.de/6422/). After the completion of our studies and during the preparation of this manuscript, Zhou et al. reported a chiral phosphoric acid catalyzed thioacetalization of salicylaldehydes: Yu J.-S, Wu W.-M, Zhou F. Org. Biomol. Chem. 2016; 14: 2205
• 6a Dentel H, Chataigner I, Le Cavelier F, Gulea M. Tetrahedron Lett. 2010; 51: 6014
• 6b Jiang H, Cruz DC, Li Y, Lauridsen VH, Jørgensen KA. J. Am. Chem. Soc. 2013; 135: 5200
• 6c Liao K, Zhou F, Yu J.-S, Gao W.-M, Zhou J. Chem. Commun. 2015; 51: 16255
• 7a Čorić I, Vellalath S, List B. J. Am. Chem. Soc. 2010; 132: 8536
• 7b Čorić I, Müller S, List B. J. Am. Chem. Soc. 2010; 132: 17370
• 7c Čorić I, List B. Nature 2012; 483: 315
• 7d Kim JH, Čorić I, Vellalath S, List B. Angew. Chem. Int. Ed. 2013; 52: 4474
• 7e Kim JH, Čorić I, Palumbo C, List B. J. Am. Chem. Soc. 2015; 137: 1778
• 7f Čorić I, Vellalath S, Müller S, Cheng X, List B. Top. Organomet. Chem. 2013; 44: 165
• 7g Sun ZK, Winschel GA, Borovika A, Nagorny P. J. Am. Chem. Soc. 2012; 134: 8074
• 7h Mensah E, Camasso N, Kaplan W, Nagorny P. Angew. Chem. Int. Ed. 2013; 52: 12932
• 7i Khomutnyk YY, Argüelles AJ, Winschel GA, Sun Z, Zimmerman PM, Nagorny P. J. Am. Chem. Soc. 2016; 138: 444
• 7j Chen Z, Sun J. Angew. Chem. Int. Ed. 2013; 52: 13593
• 8a Rowland GB, Zhang H, Rowland EB, Chennamadhavuni S, Wang Y, Antilla JC. J. Am. Chem. Soc. 2005; 127: 15696
• 8b Liang Y, Rowland EB, Rowland GB, Perman JA, Antilla JC. Chem. Commun. 2007; 4477
• 8c Li G, Fronczek FR, Antilla JC. J. Am. Chem. Soc. 2008; 130: 12216
• 8d Ingle GK, Mormino MG, Wojtas L, Antilla JC. Org. Lett. 2011; 13: 4822
• 8e Cheng X, Vellalath S, Goddard R, List B. J. Am. Chem. Soc. 2008; 130: 15786
• 8f Vellalath S, Čorić I, List B. Angew. Chem. Int. Ed. 2010; 49: 9749
• 8g Rueping M, Antonchick AP, Sugiono E, Grenader K. Angew. Chem. Int. Ed. 2009; 48: 908
• 9a Reisman SE, Doyle AG, Jacobsen EN. J. Am. Chem. Soc. 2008; 130: 7198
• 9b Terada M, Tanaka H, Sorimachi K. J. Am. Chem. Soc. 2009; 131: 3430
• 9c Zhang Q.-W, Fan C.-A, Zhang H.-J, Tu Y.-Q, Zhao Y.-M, Gu P, Chen Z.-M. Angew. Chem. Int. Ed. 2009; 48: 8572
• 9d Brak EN, Jacobsen EN. Angew. Chem. Int. Ed. 2013; 52: 534
• 9e Tsui GC, Liu L, List B. Angew. Chem. Int. Ed. 2015; 54: 7703
• 9f Das S, Liu L, Zheng Y, Alachraf MW, Thiel W, De CK, List B. J. Am. Chem. Soc. 2016; 138: 9429
• 9g Liu L, Kaib P, Tap A, List B. J. Am. Chem. Soc. 2016; 138: 10822
• 9h Zhao C, Chen BS, Seidel D. J. Am. Chem. Soc. 2016; 138: 9053
• 9i Gheewala CD, Collins BE, Lambert TH. Science 2016; 351: 961
• 10a Liao S, Čorić I, Wang Q, List B. J. Am. Chem. Soc. 2012; 134: 10765
• 10b Liu L, Leutzsch M, Zheng Y, Alachraf MW, Thiel W, List B. J. Am. Chem. Soc. 2015; 137: 13268
• 11 Representative Procedure for the Synthesis of a Dithiolanes Freshly distilled hydrocinnamaldehyde (2a, 26.0 μL, 0.2 mmol, 1 equiv) was added to a mixture of 2-methylpropane-1,2-dithiol (1a, 29 μL, 0.24 mmol, 1.2 equiv), catalyst 6 (5.8 mg, 4 μmol, 2 mol%), and 5 Å MS (40 mg) in α,α,α-trifluorotoluene (2 mL). The mixture was stirred vigorously at r.t. for 24 h and then treated with an aqueous saturated solution of NaHCO₃. The aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. Purification was performed by column chromatography on silica gel using 2% EtOAc in hexane as the eluents to obtain product 3a as a colorless oil (43 mg, 90% yield); er = 98:2. ¹H NMR (500 MHz, CDCl₃): δ = 7.31–7.26 (m, 2 H), 7.22–7.17 (m, 3 H), 4.52 (t, J = 7.0 Hz, 1 H), 3.09 (d, J = 11.5 Hz, 1 H), 2.96 (d, J = 11.5 Hz, 1 H), 2.75 (m, 2 H), 2.19–2.15 (m, 2 H), 1.59 (s, 3 H), 1.55 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 141.0, 128.6, 128.5, 126.1, 77.4, 77.2, 76.9, 60.3, 53.2, 50.9, 40.7, 35.4, 29.7, 29.4. HRMS (APPI pos.): m/z calcd for C₁₃H₁₉O₂ [M + H]⁺: 239.0928; found: 239.0924. [α]_D ²⁵ –20.2 (c 1.00, CHCl₃). HPLC (Chiralpak OJ-H, n-heptane–i-PrOH = 99:1, flow rate: 0.5 mL/min, λ = 254 nm): t _R (minor) = 14.76 min, t _R (major) = 16.89 min.
• 12 Representative Procedure for the Synthesis of Dithianes Freshly distilled hydrocinnamaldehyde (26.0 μL, 0.2 mmol, 1 equiv) was added to a mixture of 2-methylpropane-1,3-dithiol (1b, 29 μL, 0.4 mmol, 1.2 equiv), catalyst 6 (14.6 mg, 10 μmol, 5 mol%), and 5 Å MS (40 mg) in α,α,α-trifluorotoluene (2 mL). The mixture was stirred vigorously at 0 °C for 24 h and then quenched with an aqueous saturated solution of NaHCO₃. The aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification was performed by column chromatography on silica gel using 30% CH₂Cl₂ in hexane as the eluents to get product 3f as a colorless oil (37 mg, 73% yield); er = 90:10. ¹H NMR (500 MHz, CDCl₃): δ = 7.30–7.27 (m, 2 H), 7.21–7.18 (m, 3 H), 4.16 (t, J = 7.2 Hz, 1 H), 3.09 (ddd, J = 15.4, 12.6, 3.1 Hz, 1 H), 2.86 (m, 2 H), 2.74 (ddd, J = 15.4, 4.5, 3.1 Hz, 1 H), 2.05 (m, 2 H), 1.88–1.77 (m, 2 H), 1.34 (s, 3 H), 1.28 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 140.9, 128.5, 128.4, 126.0, 43.1, 41.5, 39.5, 36.5, 32.5, 32.0, 26.7, 26.5. HRMS (EI, FE): m/z calcd for C₁₄H₂₀S₂ [M]: 252.1006; found: 252.1006. [α]_D ²⁵ –54.9 (c 0.85, CHCl₃). HPLC (Chiralpak Cellucoat RP, MeCN–H₂O = 60:40, flow rate: 1 mL/min, λ = 207 nm): t _R (minor) = 9.90 min, t _R (major) = 10.84 min.