Thiol-Catalyzed Radical Decyanation of Aliphatic Nitriles with Sodium

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Letter Cite This: Org. Lett. 2018, 20, 2084−2087

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Thiol-Catalyzed Radical Decyanation of Aliphatic Nitriles with Sodium Borohydride Takuji Kawamoto,*,† Kyohei Oritani,† Dennis P. Curran,‡ and Akio Kamimura† †

Department of Applied Chemistry, Yamaguchi University, Ube, Yamaguchi 755-8611, Japan Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States

‡

S Supporting Information *

ABSTRACT: Radical decyanation of aliphatic nitriles was achieved in the presence of NaBH4 and a thiol. The reaction proceeds via a radical mechanism involving borane radical anion addition to nitrile to form an iminyl radical, which undergoes carbon−carbon cleavage. Reductive radical addition to acrylonitrile is followed by decyanation to give a two-carbon homologated product in a net radical ethylation reaction.

T

crossover methods require exceptionally powerful reducing agents to remove the nitrile. Classical methods include Na/ EtOH,6 Na/NH3, and Li/EtNH2.7 Modern methods include K/ crown-ether,8 potassium-graphite,9 K/HMPA/t-BuOH,10 and organic super electron donors.11 These conditions are harsh on functional groups, and the intermediate radicals are difficult to trap because they are rapidly reduced to anions. On the upside, the anions can be trapped with other electrophiles besides protons. Reductive decyanation by the radical hydrogen atom transfer method were first reported with Bu3SnH.12 In this reaction, the cyano group functions as a radical precursor and is abstracted by Bu3Sn•. Recently, we have introduced tris(trimethylsilyl)silane ((TMS)3SiH)13 and N-heterocyclic carbene boranes (NHCBH3)14 as easily separable and more environmentally friendly reagents. These conditions are mild, and the intermediate radicals can be trapped in other processes. However, the scope is narrow because suitable substrates are restricted to geminal dinitriles (malononitriles) and closely related molecules. Simple primary alkanenitriles are essentially inert to these reagents. Here, we report that decyanation of unactivated primary and secondary alkyl nitriles can be accomplished with sodium borohydride (NaBH4)15 and methyl thiosalicylate as a polarity reversal catalyst (Scheme 1, eq 3).16 Our studies commenced with the decyanation of pentadecanenitrile 1a (Table 1). A t-BuOH solution of 1a, NaBH4 (2.4 equiv), PhSSPh 3a, and t-BuOOt-Bu (0.8 equiv) was heated at 120 °C in a sealed tube. Under these conditions, PhSSPh is reduced by NaBH4 to PhSH. After 48 h, n-tetradecane 2a was obtained in 84% yield (GC-MS) (Table 1, entry 1). In contrast, 1,3-dimethylimidazol-2-ylidene borane (diMeImd-BH3) exhibited poor reactivity under the same conditions (10% yield, Table 1, entry 2). Notably, the conversion of 1a to 2a did not occur effectively in the absence of either PhSSPh 3a (10%, Table 1, entry 3) or t-BuOOt-Bu (0%, Table 1, entry 4). When the

he utility of nitriles as functional handles and activating groups is crucial to the strategic deployment of carbon− carbon bond-forming reactions.1,2 Though nitriles are valuable for their ability to facilitate carbon−carbon bond formation, the nitrile functionality is not always desired in downstream adducts. Excising a nitrile group by a reductive decyanation allows for the use of nitriles as traceless functional handles for assembling molecular complexity.3 In the past decade, several methods for transition-metal-catalyzed reductive decyanation reaction have been developed.4 In 2016, Hirao, Chiba, and co-workers reported reductive decyanation of alkyl nitrile with NaH/NaI or NaH/LiI.5 However, these systems are limited to tertiary alkyl nitriles and benzylic nitriles. Many reductive decyanation methods involve radical intermediates. There are two distinct approaches: (a) radical/anion cross over methods (Scheme 1, eq 1) and (b) radical hydrogen atom transfer methods (Scheme 1, eq 2). Radical/anion Scheme 1. Radical Reductive Decyanation Methods

Received: February 21, 2018 Published: March 8, 2018 © 2018 American Chemical Society

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DOI: 10.1021/acs.orglett.8b00626 Org. Lett. 2018, 20, 2084−2087

Letter

Organic Letters Table 1. Screening of Reaction Conditionsa

Table 2. Substrate Scope for Reductive Decyanationa

entry

1

variation from the standard conditions

yield (%)

1 2 3 4 5 6 7e 8

1a 1a 1a 1a 1b 1b 1b 1a

none diMeImd-BH3 instead of NaBH4 without PhSSPh without t-BuOOt-Bu none 3b (0.4 equiv) instead of PhSSPh 3b (0.4 equiv) instead of PhSSPh, 1 mmol scale 3b (0.4 equiv) instead of PhSSPh

84b 10b 10b 0b 40c 71d 68d 77b

a Standard conditions: 1 (0.5 mmol), NaBH4 (2.4 equiv), PhSSPh (0.2 equiv), t-BuOOt-Bu (0.8 equiv), t-BuOH (2 mL), 120 °C, 48 h. b Determined by GC using n-decane as an internal standard. c Determined by 1H NMR using CHCl2CHCl2 as an internal standard. d Isolated yield after silica gel column chromatography. e1 mmol scale.

secondary nitrile 2-(4-methoxybenzyl)-hexanenitrile (1b) was reduced under the standard conditions with PhSSPh, the yield of 2b was only 40% (Table 1, entry 5). A further screening of polarity reversal catalysts revealed that methyl thiosalicylate 3b,17 which is commercially available and has inoffensive odor, afforded 2b in 71% yield after silica gel column chromatography (Table 1, entry 6). The reaction at 1 mmol scale of 1b gave 2b in 68% yield (Table 1, entry 7). The reaction of 1a with methyl thiosalicylate 3b gave decyanation product 2a in 77% yield (Table 1, entry 8). To learn about the scope, we then applied the reaction conditions of Table 1, entries 6 and 7, to preparative decyanation reactions of various aliphatic nitriles. These results are shown in Table 2. Decyanation of 5-(4-methoxy-phenoxy)pentane-nitrile (1c) gave reduced product 2c and bicyclic ether 2c′ in a combined yield of 77% with a ratio of 83/17 (Table 2, entry 1). Ether 2c′ is a homolytic aromatic substitution product that results from radical cyclization to the arene ring, followed by oxidative rearomatization.18 Substrate 1d with a mesityl(2,4,6trimethylphenyl) ring gave only the direct reduction product 2d in 63% yield (Table 2, entry 2). Here, the 2-methyl substituents block radical cyclization to the arene. The reaction of 2methyltridecanenitrile (1e) with methyl thiosalicylate gave ntridecane 2e in 59% yield (Table 2, entry 3). When PhSSPh was used, instead of methyl thiosalicylate, the yield of 2e was improved to 72% (Table 2, entry 4). The yields of the target products 2f−2j (Table 2, entries 5−9) from the secondary alkyl nitriles 1f−1j were moderate to good, ranging from 42% for 2h (Table 2, entry 7) up to 78% for 2f (Table 2, entry 5). However, secondary alkyl nitrile 1k having a cyanide substituent on the benzene ring gave a poor yield of 2k (3%) with recovery of 1k (95%) (Table 2, entry 10). No decyanation product was observed with typical tertiary alkyl nitrile 1l (Table 2, entry 11).

a

Standard conditions: 1 (0.5 mmol), NaBH4 (2.4 equiv), methyl thiosalicylate (0.4 equiv), t-BuOOt-Bu (0.8 equiv), t-BuOH (2 mL), 120 °C, 48 h. bIsolated yield after silica gel column chromatography. c The ratio was determined by 1H NMR analysis after silica gel column chromatography. dDetermined by GC-MS using n-decane as an internal standard. ePhSSPh 3a was used instead of methyl thiosalicylate 3b. fDetermined by 1H NMR using CHCl2CHCl2 as an internal standard. gWithout methyl thiosalicylate 3b. hBu4NBH4 was used instead of NaBH4. 2085

DOI: 10.1021/acs.orglett.8b00626 Org. Lett. 2018, 20, 2084−2087

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Organic Letters In contrast, 1-adamantane-carbonitrile 1m afforded adamantane 2m in 45% yield (Table 2, entry 12). Interestingly, the reaction of 1l in the absence of catalyst 3b and with Bu4NBH4, which has a higher solubility than NaBH4, and in place of NaBH4 gave adamantane in 80% yield (Table 2, entry 13). Though we reinvestigated Bu4NBH4-mediated decyanation of other nitriles (e.g., 1a) in the presence of thiols or disulfides, we could not obtain better results due to the formation of aryl butyl sulfides in situ. Since the dehydration or detosylation19 proceeded, βhydroxy nitriles or nitrile bearing tosylamides are not suitable for the present decyanation. Ethylation is an important transformation in organic synthesis.20 Radical addition to ethene (ethylene) is an attractive route to ethylated products that is rarely reported.21 This is because rate constants for addition of alkyl radicals to ethene are low. High concentrations of ethene are needed, and polymerization competes. In contrast, acrylonitrile reacts with alkyl radicals selectively and with high rate constants.22 We envisioned that a one-pot reaction from an alkyl iodide and acrylonitrile via borohydride-mediated reductive radical addition reaction,23 followed by reductive decyanation reaction would afford an ethylation product. In this reaction, acrylonitrile behaves as an ethene equivalent. To demonstrate this principle, a room temperature t-BuOH solution of 1-iodododecane (3a), acrylonitrile, NaBH3CN, and 2,2′-azobis(2-methylpropionitrile) (AIBN) was photoirradiated with two black lights to form adduct 1a (Scheme 2). Then,

Scheme 3. Proposed Mechanism for Reductive Decyanation Reaction

The formation of radical cyclization product 2c′ supports the intermediacy of alkyl radicals C. In addition, the inertness of 3°nitrile 1k (Table 2, entry 11) suggests that the borohydride radical anion A adds to the carbon atom of the nitrile (to give B) rather than to the nitrogen atom. This addition is subject to steric hindrance. Finally, the presence of an aryl nitrile suppresses the reaction because radical A can add to aryl nitriles in competition with (and perhaps faster than) addition to alkyl nitriles. However, the resulting adduct [ArC(N•)BH3−] does not fragment because aryl radicals are less stable than alkyl radicals. In essence, aryl nitriles inhibit the chain reaction. Indeed, when 1napthonitrile was added to a standard reduction with 1a, hardly any 2a was formed with recovery of 1a and 1-napthonitrile. In summary, we have discovered that primary and secondary alkyl nitriles can be reductively decyanated with inexpensive NaBH4 in the presence of a thiol and t-BuOOt-Bu (an initiator). The reaction proceeds via an iminyl radical intermediate, which then fragments to an alkyl radical. The thiol acts on this radical as a polarity reversal catalyst. We also achieved one-pot radical ethylation by reductive addition, followed by reductive decyanation. Here, the common radical acceptor acrylonitrile acts as an ethene equivalent.

Scheme 2. One-Pot Synthesis of Alkane from 1-Iododecane (3a) and Acrylonitrile

NaBH4, methyl thiosalicylate 3b, and t-BuOOt-Bu were directly added to the reaction mixture, which was heated for 48 h. Reductive ethylation product 2a was generated in 60% yield, which was determined by GC-MS using decane as an internal standard. A plausible radical chain mechanism for the reductive decyanation reaction is shown in Scheme 3. Initiation occurs by homolytic cleavage of t-BuOOt-Bu to produce a tert-butoxy radical, which abstracts a hydride hydrogen from borohydride anion to give borane radical anion A (and tert-butylalcohol).24 A adds to the nitrile carbon of 1 to form an iminyl radical B, followed by β-fragmentation to give cyanoborohydride anion and an alkyl radical C.24 The radical C can potentially abstract a hydrogen atom from borohydride anion to form 2, but this reaction is sluggish due to polarity mismatching.16,23 Instead, hydrogen transfer from the thiol (ArSH) to C predominates, forming 2 and ArS•. The chain cycle is closed by reaction of ArS• with BH4− to give back the thiol and the radical anion A of borohydride. An alternative mechanism is also illustrated in Scheme 3. The generating thiyl radicals dimerize to from a disulfide, which is reduced by NaBH4 to give thiol. Thus, an excess amount of initiator is possibly needed.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00626. Experimental procedures, compound characterization data, and copies of NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Takuji Kawamoto: 0000-0002-1845-4700 Dennis P. Curran: 0000-0001-9644-7728 Akio Kamimura: 0000-0002-3060-4265 Notes

The authors declare no competing financial interest. 2086

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Organic Letters

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this needed five steps. See: Wipf, P.; Spencer, S. R. J. Am. Chem. Soc. 2005, 127, 225−235. (21) Jaynes, B. S.; Hill, C. L. J. Am. Chem. Soc. 1993, 115, 12212− 12213. (22) Zytowski, T.; Fischer, H. J. Am. Chem. Soc. 1997, 119, 12869− 12878. (23) (a) Ryu, I.; Uehara, S.; Hirao, H.; Fukuyama, T. Org. Lett. 2008, 10, 1005−1008. (b) Fukuyama, T.; Kawamoto, T.; Kobayashi, M.; Ryu, I. Beilstein J. Org. Chem. 2013, 9, 1791−1796. (c) Kawamoto, T.; Uehara, S.; Hirao, H.; Fukuyama, T.; Matsubara, H.; Ryu, I. J. Org. Chem. 2014, 79, 3999−4007. (24) (a) Giles, J. R. M.; Roberts, B. P. J. Chem. Soc., Perkin Trans. 2 1983, 2, 743−755. (b) Giles, J. R. M.; Roberts, B. P. J. Chem. Soc., Chem. Commun. 1981, 360−361.

ACKNOWLEDGMENTS This work was partially supported by a JSPS Grant-in-Aid for Young Scientists (B) (16K17869), the Tokuyama Science Foundation, the Naito Foundation, the YU project for formation of the core research center (Yamaguchi University), the Yazaki Memorial Foundation for Science and Technology, the Inamori Foundation, and the Yamaguchi University Foundation. D.P.C. thanks the US National Science Foundation for support.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b00626 Org. Lett. 2018, 20, 2084−2087