Selective Phthalimido-N-oxyl (PINO)-Catalyzed C–H Cyanation of Adamantane Derivatives

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

We present a new method for the selective C(sp³)–H cyanation of adamantane derivatives with PINO as the hydrogen abstracting reagent. A cyano radical is thereby transferred from p -toluenesulfonyl cyanide, allowing the cyanation of adamantane derivatives in up to 71% yield. The protocol presents a novel way to orthogonally functionalized adamantanes that are otherwise difficult to prepare. Mechanistic studies support the hypothesis of a radical pathway.

Key words

adamantane - C–H activation - cyanation - N-hydroxyphthalimide - NHPI - PINO

Adamantane exhibits fascinating properties, such as rigidity, lipophilicity, steric bulkiness, electron richness, and chemical inertness.[1] By virtue of these desirable features diamondoids, i.e., diamond-like, nanometer-sized aliphatic cage hydrocarbons, for which adamantane is the parent, are used as catalyst backbones,[2] dispersion energy donors,[3] or molecular rectifiers.[4] Adamantane is an attractive moiety in the design of drugs, e.g., memantine and saxagliptin (both belonging to the top 200 drugs by worldwide sales 2016),[5] favorably affecting administration, distribution, metabolism, and excretion (ADME) properties.[6] The selective functionalization of diamondoids is essential for their application, and this presents a formidable challenge in selective sp³-C–H bond functionalization. Usually hydroxylation, bromination, or amination (via Ritter reaction) are used as the first step.[1] The resulting compounds can then readily be functionalized further. However, due to the chemical inertness of unactivated aliphatic C–H-bonds, functionalization requires harsh conditions, making the synthesis of orthogonally disubstituted adamantanes challenging (Scheme [1]). A mild direct C(sp³)–H functionalization of monosubstituted adamantanes would greatly streamline the synthesis of these diamondoids and facilitate their use even more. The incorporation of nitriles is particularly desirable, as they are widely present as key functional groups in a variety of natural products and pharmaceuticals.[7] They can readily be converted into carboxylic acids, esters, amines, or amides. Furthermore, they can be used in [3+2] cycloadditions affording heterocycles such as tetrazoles and oxadiazolines (Scheme [1]).[8]

Scheme 1 Orthogonally bifunctionalized adamantane derivatives

Due to the versatility of nitriles, a variety of cyanation methods were developed. While C(sp²)–H cyanations are well established,[9] C(sp³)–H cyanations remain challenging. They are often limited to the synthesis of pre-functionalized precursors such as alkyl iodides,[10] allylic compounds,[11] or enolates.[12] Recently, two photocatalytic systems for C(sp³) cyanation were reported utilizing alkyltrifluoroborates[13] and carboxylates[14] as precursors. Additionally, Sun and coworkers reported an oxidative or free radical C(sp³)–H cyanation for alkanes, ethers, and tertiary amines.[15] Moreover, cyanations of activated C(sp³)–H bonds, such as α-heteroatoms[16] and an enantioselective benzylic C–H cyanation[17] have been established. Although some of these methods tolerate a broad range of functional groups, their use is restricted due to elaborate precursor synthesis. Direct cyanations of unactivated C(sp³)–H bonds are rare. Only a few direct cyanations exist, including the pioneering studies by Müller and Huber in 1963, who introduced an unselective cyanation with cyanogen chloride[18] and a photoexcited benzophenone mediated C(sp³)–H cyanation.[19] While the latter approach is applicable to benzylic and aliphatic C–H bonds, the differentiation of these bonds is only modest, due to the use of benzophenone as the hydrogen atom transfer (HAT) reagent. Furthermore, aliphatic substrates often require the use of excess of substrate.

In continuation of our work with phthalimido-N-oxyl (PINO),[20] we envisioned a selective C(sp³)–H cyanation of adamantanes using N-hydroxyphthalimide (NHPI).[21] To the best of our knowledge, PINO has never been used in aliphatic C–H bond cyanations.[22] We envisioned a three-step process, consisting of the formation of PINO from its precursor NHPI, followed by HAT from adamantane 1 to PINO, generating an adamantyl radical 1^• , which is trapped by p-toluenesulfonyl cyanide (TsCN), thereby affording the desired cyanated product 2 (Scheme [2]).

Scheme 2 PINO-catalyzed C(sp³)–H cyanation concept

We commenced our studies with 1 as a model substrate and p-toluenesulfonyl cyanide (TsCN) as the electrophilic cyanide source[23] (Table [1]). At first we performed an initial screening to elaborate suitable reaction conditions for the generation of PINO. Systems such as α,α′-azobisisobutyronitrile (AIBN), cobalt (II/III) salts/O₂, and cerium(IV) ammonium sulfate (CAS) afforded only low yields of 1-cyano adamantane 2 [24] and significant amounts of starting material 1 remained. However, cerium(IV) nitrate (CAN)[25] was shown to be superior, resulting in 42% yield of 2. On the other hand, the use of CAN also led to the formation of significant amounts of 1-nitro adamantane 3 [26] (13%). This side product forms by reduction of Ce(IV) → Ce(III), thus generating HNO₃.[22] HNO₃ itself is capable to generate PINO, thereby releasing ^•NO₂ that recombines with the intermittently formed 1-adamantyl radical.[27] This pathway was confirmed with the use of 1 equiv HNO₃, affording 15% of 1-nitro adamantane 3.

Table 1 Screening of Systems for the PINO-Catalyzed Cyanation^a

SET reagent	2 (%)b
AIBNc	5
Co(acac)3 d	7
Co(OAc)2 d	8
CANe	42
CASe	9
HNO3 e	47

^a Reaction conditions: 0.5 mmol scale, ratio of1/NHPI/TsCN (1:0.1:2), 5 mL 1,2-dichloroethane, 16 h, 75 °C.

^b Yields determined by GC with hexadecane as internal standard.

^c 3 mol% AIBN.

^d 1 mol% of the corresponding metal salt, 1 atm air.

^e 1 equiv.

We envisioned to suppress the formation of 3 by capturing the released HNO₃ (Table [2]). Initial screening of bases including MgO, acetates, and carbonates, showed that carbonates performed best. The use of Cs₂CO₃ afforded no product, while Ag₂CO₃, Na₂CO₃, and Li₂CO₃ led to an increase of the yield with up to 77% for Li₂CO₃. In general, the yield increased with decreasing cation radius; 1 equiv ­Li₂CO₃ worked best. Furthermore, we tested Co(acac)₃, a known cocatalyst[28] for PINO, but it was ineffective under the chosen conditions. Importantly, the cyanation selectively proceeds at the tertiary C–H position, thus indicating that PINO performs a chemoselective hydrogen abstraction due to its polarity.[21b]

Table 2 Influence of Inorganic Bases^a

Base (1 equiv)	2 (%)b	3 (%)b
Cs2CO3	0	0
Ag2CO3	56	<5
Na2CO3	73	7
Li2CO3	77	5
Li2CO3 (1.5 equiv)	47	<5
Li2CO3 (0.5 equiv)	51	11
Na2CO3 c	71	8
Na2CO3 c,d	60	14

^a Reaction conditions: 0.5 mmol scale, ratio of 1/NHPI/CAN/TsCN/base (1:0.2:1:2:1), 5 mL 1,2-dichloroethane, 16 h, 75 °C.

^b Yields determined by GC with hexadecane as internal standard.

^c 0.1 equiv NHPI.

^d 1 mol% Co(acac)₃.

With the optimized conditions in hand, we focused on the cyanation of various substrates (Scheme [3]). Common C–H activation procedures require excess of the starting material, in order to suppress a second C–H activation of the product. Under our conditions, the cyanation requires only 1 equiv starting material, thereby affording, e.g., 1-cyano adamantane 2 in 69% yield without formation of the dicyanated product. The strong electron-withdrawing cyano group deactivates the cage, thus suppressing subsequent cyanation. This was illustrated by utilizing 2, affording 1,3-dicyano adamantane 4 [29] in only 20% yield. Hence, only 1 equiv substrate is necessary in the cyanation. Methyl adamantane (5)[30] was isolated in 71% yield, while dimethyl 6 [31] and trimethyl 7 [32] substituted adamantanes were isolated in 33% and 28% yield, respectively. The same reactivity trend for the corresponding halogenated derivatives was observed by Olah and coworkers in a Lewis acid catalyzed cyanation.[33] The di- and trisubstituted adamantanes were cyanated in comparable yields to the corresponding methyl derivatives, affording cyanated products 8 [34] and 9.[35] The cyanation of 1-bromo adamantane afforded product 10 [36] in 25% yield, with traces of N-tosyloxyphthalimide S1,[37] formally a product of the radical recombination of tosylsulfonyl and a PINO radical. Upon addition of 20 mol% NHPI after 6 h the yield of 10 increased to 34%. 1-Cyano-3-phenyl adamantane 11 [38] was obtained in 47% and the alkynyl derivative 12 [39] in 41% yield. Notably, 12 represents an orthogonal building block, containing a triple bond, which is otherwise not easily accessible. Adamantane carboxylic acid methyl ester was cyanated in 50% yield (13).[40] Silyl-protected alcohols can be also used under the chosen conditions, affording 39% (14a).[41] Use of phthalimides, acetamides, and azides in the cyanation results in the formation of γ-amino acid derivatives 15–17.[42] Note that the use of 17 results in another orthogonally difunctionalized building block readily available for ‘click-reactions’. Furthermore, diamantane can be cyanated in 60% yield, affording 18 [43] in a ratio of 4.3:1 in favor of the medial position. The cyanation of 4-diamantane carboxylic acid methyl ester afforded 35% yield in a ratio of 1:1.1 (19_m1 :19_m2 ).[44] Particular the syntheses of these cyanated products 19 would require considerably more steps in comparison to established methods.

Scheme 3 Substrate scope of the PINO-catalyzed C(sp³)–H cyanations. Yields of isolated, pure products are given. Reaction conditions: 0.5 mmol starting material, ratio of SM/NHPI/CAN/TsCN/base (1:0.2:1:2:1), 5 mL 1,2-dichloroethane, 16 h, 75 °C. ^a 20 mol% NHPI added after 6 h. ^b Ratio determined by GC-MS.

Table 3 Mechanistic Investigations^a

Conditions	2 (%)b
NaCN (2 equiv), TBACN (0.15 equiv)	traces (< 1%)
I2 (1 equiv)	0
0 mol% NHPI	10
dark	40
365 nm	37

^a Reaction conditions: 0.5 mmol scale, ratio of 1/NHPI/CAN/TsCN/base (1:0.2:1:2:1), 5 mL 1,2-dichloroethane, 16 h, 75 °C.

^b Yields determined by GC with hexadecane as internal standard.

In order to support our initial mechanistic hypothesis of a radical pathway, several tests were performed (Table [3]). In the presence of a radical scavenger such as I₂, no product formed. The isolation of traces of N-tosyloxyphthalimide S1, a result of a radical recombination, supports this hypothesis. By performing a control experiment with the optimized conditions (1 equiv TsCN, 1 equiv Li₂CO₃, 0.2 equiv NHPI, 75 °C, 16 h) the formation of S1 by a nucleophilic substitution could be excluded. In addition, the absence of NHPI afforded only 10% of the cyanated product. This underscores that PINO indeed is the catalytically active species. The exclusion of light decreased the yield to 40% yield. CAN is known to produce nitroxyl radicals upon UV irradiation, while Ce^IV is reduced to Ce^III.[45] However, irradiation of the reaction mixture at 365 nm afforded only 37% yield of 2. This result may indicate that low concentrations of nitroxyl radicals facilitate the cyanation, while a higher concentration of ^•NO₃ leads to a higher probability of termination events, consequently lowering the yield. Furthermore, CAN is reduced upon UV irradiation, thus it is not available for the generation of PINO and finally affording a lower yield. Moreover, the oxidation of the adamantyl radical 1^• to the cation[25] [46] could be excluded by the use of a CN⁻ source (NaCN) in combination with a phase-transfer catalyst (TBACN), affording less than 1% yield.

In summary, we report a novel direct C(sp³)–H cyanation of adamantane and two diamantane derivatives, utilizing only 1 equiv of substrate.[47] The method allows the efficient synthesis of substituted cyano adamantanes. A variety of these valuable compounds was synthesized for the first time. Mechanistic experiments support a radical mechanism.

Acknowledgment

J.-P. Berndt and F. R. Erb contributed equally to this work. We thank Prof. A. A. Fokin for fruitful discussions.

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• 30 1-Cyano-3-methyladamantane (5) Yield 0.062 g (0.359 mmol, 71%). R_f = 0.40 (n-hexane/EtOAc, 15:1). HRMS (ESI): m/z calcd for C₁₂H₁₇NNa⁺: 198.1253; found: 198.1254 [M + Na⁺]⁺. IR (ATR): 2906, 2850, 2232, 1532, 1456, 1360, 1343, 1162, 1112, 974, 923, 756, 692 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.09–2.02 (m, 2 H), 2.00–1.87 (m, 4 H), 1.73 (s, 2 H), 1.64–1.57 (m, 2 H), 1.49–1.41 (m, 4 H), 0.84 (s, 3 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 125.2 (C), 46.4 (C), 42.9 (CH₂), 39.4 (2 CH₂), 35.1 (2 CH₂), 31.0 (CH₂), 30.5 (C), 29.8 (CH₃), 27.9 (2 CH) ppm.
• 31 1-Cyano-3,5-dimethylcyanoadamantane (6) Yield 0.031 g (0.164 mmol, 33%). R_f = 0.43 (n-hexane/EtOAc, 15:1). HRMS (ESI): m/z calcd for C₁₃H₁₉NNa⁺: 212.1410; found: 212.1412 [M + Na⁺]⁺. IR (ATR): 2902, 2848, 2235, 1455, 1378, 1359, 1342, 1232, 1144, 965, 934, 912, 772, 733 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.11 (hept, J = 3.1 Hz, 1 H), 1.86–1.83 (m, 2 H), 1.70–1.59 (m, 4 H), 1.41–1.31 (m, 4 H), 1.17 (s, 2 H), 0.85 (s, 6 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 125.1 (C), 50.1 (CH₂), 45.9 (2 CH₂), 42.2 (2 CH₂), 38.7 (CH₂), 31.8 (C), 30.6 (C), 30.1 (2 CH₃), 28.5 (2 CH) ppm.
• 32 1-Cyano-3,5,7-trimethyladamantane (7) Yield 0.028 g (0.138 mmol, 28%). R_f = 0.71 (n-hexane/EtOAc, 5:1). HRMS (ESI): m/z calcd for C₁₄H₂₁NNa⁺ m/z = 226.1566; found: 226.1563 [M + Na⁺]⁺. IR (ATR): 2948, 2918, 2865, 2843, 2230, 1455, 1377, 1358, 1257, 1233, 912, 788 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.58 (s, 6 H), 1.16–1.02 (m, 6 H), 0.86 (s, 9 H) ppm.¹³C NMR (101 MHz, CDCl₃): δ = 125.0 (C), 49.5 (3 CH₂), 45.3 (3 CH₂), 32.5 (C), 31.5 (3 C), 29.7 (3 CH₃) ppm.
• 33 Olah GA, Farooq O, Surya Prakash GK. Synthesis 1985; 1140
• 34 1-Cyanoadamantane-3,5-acetic Acid Methyl Ester (8) Yield 0.054 g (0.177 mmol, 35%). R_f = 0.23 (n-hexane/EtOAc, 3:1). HRMS (ESI): m/z calcd for C₁₇H₂₃NNaO₄ ⁺: 328.1519; found: 328.1516 [M + Na⁺]⁺. IR (ATR): = 2910, 2857, 2235, 1731, 1438, 1330, 1242, 1162, 1128, 1057, 1022, 851 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 3.65 (s, 6 H), 2.21–2.17 (m, 1 H), 2.16 (s, 4 H), 1.93–1.87 (m, 4 H), 1.87–1.80 (m, 2 H), 1.62–1.55 (m, 2 H), 1.55–1.46 (m, 4 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 171.2 (2 C), 124.2 (C), 51.5 (2 CH₃), 47.1 (2 CH₂), 45.6 (CH₂), 43.4 (2 CH₂), 39.8 (2 CH₂), 38.5 (CH₂), 33.1 (2 C), 31.6 (C), 28.0 (CH) ppm.
• 35 1-Cyanoadamantane-3-acetic Acid Methyl Ester (9) Yield 0.039 g (0.149 mmol, 30%). R_f = 0.08 (n-pentane/Et₂O, 10:1). HRMS (ESI): m/z calcd for C₁₆H₂₃NNaO₂ ⁺: 284.1621; found: 284.1623 [M + Na⁺]⁺. IR (ATR): 2950, 2924, 2900, 2866, 2849, 2232, 1735, 1456, 1356, 1312, 1231, 1192, 1147, 1087, 1012 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 3.66 (s, 3 H), 2.16 (s, 2 H), 1.76 (s, 2 H), 1.62 (s, 4 H), 1.33–1.20 (m, 4 H), 1.20–1.10 (m, 2 H), 0.88 (s, 6 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 171.5 (C), 124.5 (C), 51.5 (CH₃), 49.4 (CH₂), 47.2 (2 CH₂), 47.0 (CH₂), 45.2 (2 CH₂), 43.0 (CH₂), 34.06 (C), 32.37 (C), 31.4 (2 C), 29.7 (2 CH₃) ppm.
• 36 1-Cyano-3-bromoadamantane (10) Yield 0.040 g (0.167 mmol, 34%). R_f = 0.16 (n-pentane/Et₂O, 20:1). HRMS (ESI): m/z calcd for C₁₁H₁₄BrNNa⁺: 262.0202; 262.0204 [M + Na⁺]⁺. IR (ATR): 2948, 2925, 2862, 2228, 1455, 1344, 1330, 1311, 1245, 1121, 1097, 966, 990, 822, 726, 677, 457 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.58 (s, 2 H), 2.35–2.26 (m, 4 H), 2.25–2.17 (m, 2 H), 2.04 (d, J = 2.9 Hz, 4 H), 1.75–1.69 (m, 2 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 123.2 (C), 59.6 (C), 50.1 (CH₂), 47.4 (2 CH₂), 38.4 (2 CH₂), 33.9 (CH₂), 33.5 (C), 31.0 (2 CH) ppm.
• 37 Chanmiya Sheikh M, Takagi S, Ogasawara A, Ohira M, Miyatake R, Abe H, Yoshimura T, Morita H. Tetrahedron 2010; 66: 2132
• 38 1-Cyano-3-phenyladamantane (11) Yield 0.056 g (0.236 mmol, 47%). R_f = 0.23 (n-pentane/Et₂O, 20:1). HRMS (ESI): m/z calcd for C₁₇H₁₉NNa⁺: 260.1410; 260.1411 [M + Na⁺]⁺. IR (ATR): = 2926, 2853, 2234, 1599, 1498, 1447, 1343, 1261, 1106, 1080, 1031, 978, 758, 700, 532 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.39–7.31 (m, 4 H), 7.25–7.20 (m, 1 H), 2.27–2.23 (m, 2 H), 2.20 (s, 2 H), 2.12–2.04 (m, 4 H), 1.95–1.89 (m, 4 H), 1.80–1.73 (m, 2 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 148.6 (C), 128.6 (2 CH), 126.5 (CH), 125.0 (CN), 124.7 (2 CH), 45.1 (CH₂), 41.6 (2 CH₂), 39.3 (2 CH₂), 36.0 (C), 35.1 (CH₂), 31.5 (C), 28.1 (2 CH) ppm.
• 39 1-Cyano-3-ethynyladamantane (12) Yield 0.038 g (0.204 mmol, 41%). R_f = 0.56 (n-hexane/EtOAc, 1:1). HRMS (ESI): m/z calcd for C₁₃H₁₅NNa⁺: 208.1097; 208.1095 [M + Na⁺]⁺. IR (ATR): 3261, 2917, 2857, 2236, 2110, 1726, 1579, 1451, 1345, 1260, 1088, 1014, 869, 795, 688, 50 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.15 (s, 1 H), 2.14 (s, 2 H), 2.13–2.09 (m, 2 H), 1.99 (d, J = 3.0 Hz, 4 H), 1.89–1.84 (m, 4 H), 1.70–1.66 (m, 2 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 124.3 (C), 90.2 (C), 68.5 (CH), 44.4 (CH₂), 41.3 (2 CH₂), 39.0 (2 CH₂), 34.6 (CH₂), 30.5 (C), 29.2(C), 27.2 (2 CH).
• 40 ​3-Cyanoadamantane-1-​carboxylic Acid Methyl Ester (13) Yield 0.055 g (0.250 mmol, 50%). R_f = 0.47 (n-hexane/EtOAc, 3:1). HRMS (ESI): m/z calcd for C₁₃H₁₇NNaO₂ ⁺: 242.1152; 242.1149 [M + Na⁺]⁺. IR (ATR): 2952, 2915, 2859, 2229, 1720, 1480, 1446, 1346, 1323, 1265, 1240, 1192, 1151, 1125, 1106, 1029, 952, 866, 777, 747, 728, 570, 481, 445 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 3.67 (s, 3 H), 2.19–2.13 (m, 4 H), 2.04–1.96 (m, 4 H), 1.93–1.80 (m, 4 H), 1.70 (s, 2 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 176.2 (C), 124.4 (C), 52.1 (CH₃), 40.7 (CH₂), 40.3 (C), 39.1 (2 CH₂), 37.5 (2 CH₂), 34.8 (CH₂), 30.6 (C), 27.2 (2 CH).
• 41 1-O-(tert-Butyldiphenylsilyl)-3-cyanoadamantanol (14a) Yield 0.080 g (0.193 mmol, 39%). R_f = 0.39 (n-hexane/EtOAc, 15:1). HRMS (ESI): m/z calcd for C₂₇H₃₃NNaOSi⁺: 438.2224; found: 438.2226 [M + Na⁺]⁺. IR (ATR): 3071, 2931, 2858, 2235, 1590, 1472, 1455, 1428 1357, 1337, 1316, 1155, 1143, 1110, 1068, 975, 903, 821, 740, 702, 610, 503 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.74–7.70 (m, 4 H), 7.45–7.36 (m, 6 H), 2.09 (s, 2 H), 1.99 (s, 2 H), 1.84–1.73 (m, 4 H), 1.70–1.64 (m, 4 H), 1.50–1.37 (m, 2 H), 1.02 (s, 9 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 136.1 (4 CH), 135.7 (2 C), 129.7 (2 CH), 127.6 (4 CH), 124.2 (C), 71.0 (C), 47.5 (CH₂), 44.3 (2 CH₂), 38.8 (2 CH₂), 34.4 (CH₂), 33.0 (C), 29.9 (3 CH₃), 27.1 (2 CH), 19.3 (C) ppm.
• 42 1-Cyano-3-acetamidoadamantane (15) Yield 0.024 g (0.110 mmol, 22%). R_f = 0.46 (CH₂Cl₂/MeOH, 20:1). HRMS (ESI): m/z calcd for C₁₃H₁₈N₂NaO⁺: 241.1311; found: 241.1317 [M + Na⁺]⁺. IR (ATR): 3295, 3078, 2918, 2856, 2232, 1731, 1651, 1548, 1456, 1366, 1307, 1144, 1061, 1007, 702, 602, 541, 452 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.32 (s, 1 H), 2.35 (s, 2 H), 2.21 (s, 2 H), 2.11–2.06 (m, 2 H), 2.03–1.93 (m, 4 H), 1.92 (s, 3 H), 1.88–1.80 (m, 2 H), 1.67 (s, 2 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 169.8 (C), 124.1 (C), 51.0 (C), 42.9(CH₂), 40.3 (2 CH₂), 39.0 (2 CH₂), 34.8 (CH₂), 31.8 (C), 28.5 (2 CH), 24.6 (CH₃) ppm. 1-N-Adamantylphthalimide-3-cyano (16) Yield 0.033 g (0.108 mmol, 22%). R_f = 0.28 (n-hexane/EtOAc, 3:1). HRMS (ESI): m/z calcd for C₁₉H₁₈N₂NaO₂ ⁺: 329.1261; found: 329.1262 [M + Na⁺]⁺. IR (ATR): 2926, 2863, 2226, 1768, 1703, 1611, 1468, 1361, 1341, 1313, 1155, 1111, 1070, 999, 980, 969, 870, 790, 715, 643, 532, 407 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.79–7.74 (m, 2 H), 7.72–7.66 (m, 2 H), 2.80 (s, 2 H), 2.58–2.46 (m, 4 H), 2.30 (s, 2 H), 2.14–1.98 (m, 4 H), 1.82–1.66 (m, 2 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 169.5 (2 C), 134.1 (2 CH), 131.8 (2 C), 124.01 (C), 123.0 (2 CH), 58.6 (C), 41.8 (CH₂), 38.9 (2 CH₂), 38.9 (2 CH₂), 34.6 (CH₂), 32.3 (C), 28.8 (2 CH) ppm. 1-Azido-3-cyano-adamantane (17) Yield 0.027 g (0.133 mmol, 27%). R_f = 0.13 (n-pentane/Et₂O, 20:1). HRMS (ESI): m/z calcd for C₁₁H₁₄N₄Na⁺: 225.1114; found: 225.1111 [M + Na⁺]⁺. IR (ATR): 2919, 2861, 2230, 2087, 1456, 1360, 1339, 1318, 1244, 1130, 1108, 997, 925, 872, 836, 714, 678, 561, 489 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.33–2.27 (m, 2 H), 2.04 (s, 2 H), 2.02–1.93 (m, 4 H), 1.84–1.76 (m, 4 H), 1.69–1.63 (m, 2 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 123.6 (C), 57.3 (C), 43.7 (CH₂), 40.1 (2 CH₂), 38.8 (2 CH₂), 34.3 (CH₂), 32.2 (C), 28.9 (2 CH) ppm.
• 43 4-Cyanodiamantane (18a) R_f = 0.23 (n-pentane/Et₂O, 10:1). HRMS (ESI): m/z calcd for C₁₅H₁₉NNa⁺: 236.1410; found: 236.1411 [M + Na⁺]⁺. IR (ATR): 2908, 2884, 2847, 2228, 1440, 1377, 1358, 1314, 1258, 1126, 1090, 1047, 984, 902, 799, 572, 545, 462 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.03–1.97 (m, 6 H), 1.85 (s, 3 H), 1.83–1.79 (m, 1 H), 1.77–1.74 (m, 3 H), 1.73–1.69 (m, 6 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 125.5 (C), 40.9 (3 CH₂), 37.6 (3 CH₂), 36.4 (3 CH), 36.1 (3 CH), 28.8 (C), 25.4 (CH) ppm. 1-Cyanodiamantane (18m) R_f = 0.27 (n-pentane/Et₂O, 10:1). HRMS (ESI): m/z calcd for C₁₅H₁₉NNa⁺: 236.1410; found: 236.1408 [M + Na⁺]⁺. IR (KBR): 2918, 2889, 2850, 2227, 1636, 1460, 1443, 1340, 1314, 1260, 1057, 1048, 984, 800, 615 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.23–2.15 (m, 2 H), 2.05–2.00 (m, 2 H), 2.00–1.92 (m, 3 H), 1.87 (s, 3 H), 1.71 (s, 9 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 124.6 (C), 41.4 (CH₂), 39.0 (2 CH), 38.1 (C), 37.7 (CH₂), 37.1 (2 CH₂), 36.6 (2 CH), 36.3 (CH), 35.1 (2 CH₂), 25.6 (CH), 25.0 (CH) ppm.
• 44 1-Cyano-3-diamantane Carboxylic Acid Methyl Ester (19_m1) R_f = 0.13 (n-hexane/EtOAc, 10:1). HRMS (ESI): m/z calcd for C₁₇H₂₁NnaO₂ ⁺: 294.1465; found: 294.1467 [M + Na⁺]⁺. IR (ATR): 2909, 2890, 2858, 2227, 1726, 1463, 1433, 1280, 1254, 1228, 1215, 1133, 1115, 1068, 1033, 985, 889, 846, 790, 767, 739, 709, 632, 507 433, 422 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 3.68 (s, 3 H), 2.22 (s, 1 H), 2.20–2.16 (m, 3 H), 2.01–1.98 (m, 2 H), 1.97–1.94 (m, 2 H), 1.92–1.83 (m, 6 H), 1.77–1.73 (m, 4 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 176.5 (C), 123.6 (C), 52.1 (CH₃), 42.1 (CH₂), 39.1 (C), 38.8 (2 CH₂), 38.5 (C), 38.2 (2 CH), 37.1 (CH₂), 36.5 (2 CH), 35.3 (CH), 34.3 (2 CH₂), 24.7 (CH) ppm. 1-Cyano-4-diamantane Carboxylic Acid Methyl Ester (19_m2) R_f = 0.13 (n-hexane/EtOAc, 10:1). HRMS (ESI): m/z calcd for C₁₇H₂₁NnaO₂ ⁺: 294.1465; found: 294.1462 [M + Na⁺]⁺. IR (ATR): 2906, 2881, 2853, 2224, 1714, 1466, 1444, 1427, 1341, 1321, 1283, 1247, 1221, 1142, 1123, 1091, 1072, 1060, 1045, 1012, 980, 949, 883, 860, 814, 787, 758, 744, 698, 628, 566, 543, 519, 490, 427 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 3.67 (s, 3 H), 2.34 (s, 1 H), 2.31 (s, 1 H), 2.10–2.03 (m, 4 H), 1.96 (q, J = 3.1 Hz, 1 H), 1.92–1.90 (m, 1 H), 1.89–1.82 (m, 6 H), 1.77–1.72 (m, 4 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 177.1 (C), 123.9 (C), 52.0 (CH₃), 40.8 (CH₂), 39.4 (CH₂), 38.9 (2 CH), 38.4 (C), 37.3 (C), 36.5 (2 CH₂), 36.5 (2 CH₂), 36.1 (CH), 35.6 (2 CH), 25.3 (CH) ppm.
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• 47 PINO-Catalyzed Cyanations of Adamantane Derivatives – General Procedure 1 equiv substrate, 2 equiv TsCN, 1 equiv CAN, 1 equiv Li₂CO₃, 0.2 equiv NHPI and 5 mL DCE were stirred for 16 h at 75 °C. The reactions mixture was allowed to cool down to room temperature and filtered over silica gel (50 mL EtOAc, 50 mL MeCN, 50 mL EtOAc).