Synthesis of Nitriles from Primary Amides or Aldoximes under

Note Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

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Synthesis of Nitriles from Primary Amides or Aldoximes under Conditions of a Catalytic Swern Oxidation Rui Ding, Yongguo Liu, Mengru Han, Wenyi Jiao, Jiaqi Li, Hongyu Tian,* and Baoguo Sun* Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Key Laboratory of Flavor Chemistry, Beijing Technology and Business University, Beijing 100048, China

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ABSTRACT: The preparation of nitriles from primary amides or aldoximes was achieved by using oxalyl chloride with a catalytic amount of dimethyl sulfoxide in the presence of Et3N. The reactions were complete within 1 h after addition at room temperature. A diverse range of cyano compounds were obtained in good to excellent yields, including aromatic, heteroaromatic, cyclic, and acyclic aliphatic species.

N

sulfenllactonization10 and chlorolactonization of alkenoic acids,11 bromination of alkenes, alkynes, and ketones,12 and preparation of α,β-unsaturated γ-lactones.13 We noticed that primary amides could be dehydrated to afford nitriles under Swern oxidation conditions; however, DMSO and (COCl)2 were used in stoichiometric amounts and the reactions needed to be carried out at −78 °C.9 Obviously, it is very inconvenient to run reactions at such a low temperature. The work of Malkov and Rubtsov6b inspired us to investigate if the dehydration of amides or aldoximes may be achieved under conditions of a catalytic Swern oxidation at room temperature. Herein, we report the successful results of the dehydration of amides or aldoximes to afford nitriles with (COCl)2 and a catalytic amount of DMSO in the presence of Et3N at room temperature (Scheme 1).

itriles are important organic compounds either as versatile precursors in synthesis or as valuable end products. The cyano group can be easily converted to other functional groups, such as carboxyl derivatives, amines, ketones, and various heterocycles.1 Many cyanated compounds display attractive applications as pharmaceuticals, agrochemicals, or fragrances.2 A plethora of methods for the synthesis of nitriles has been developed over the past century, which can be divided into two classes, one involving introduction of a cyano group with inorganic or organic cyanating reagents3 and the other involving creation of a cyano group by chemical transformation of other functional groups.4 The dehydration of amides or aldoximes is the most commonly used approach for the creation of a cyano group by far. A wide variety of reagents have been described for the transformation of primary amides or aldoximes to nitriles.5 However, many of these existing methods suffer from drawbacks such as drastic reaction conditions, limited substrate scope, not readily available reagents, poor yields, and long reaction time. Several attractive methods have been reported recently in which the dehydration of primary amides or aldoximes could be achieved via catalysis under mild conditions.6 It is worth highlighting that a highly efficient catalytic Appel-type dehydration of amides to nitriles has been developed by Malkov and Rubtsov using oxalyl chloride and triethylamine along with triphenylphosphine oxide as a catalyst.6b The combination of DMSO and oxalyl chloride has been used widely in the oxidation of primary and secondary alcohols since Swern first reported this method in 1978.7 In addition, it was also very efficient for other transformations, such as methylthiomethyl esterification of carboxylic acids8 and dehydration of primary amides.9 In our recent work, novel application of the combined reagents of R2SO (R = Me or Ph) and (COX)2 (X = Cl or Br) has been developed, such as © XXXX American Chemical Society

Scheme 1. Dehydration of Amides or Aldoximes to Nitriles by a Catalytic Swern Oxidation

The investigation began by employing benzamide (1a) as a model substrate (Table 1). First, the experiment was carried out under conditions mimicking those in the protocol from amides to nitriles developed by Malkov and Rubtsov,6b in which 2 equiv of oxalyl chloride in anhydrous MeCN was added dropwise to the solution of 1a, 1 mol % of DMSO, and Received: August 24, 2018 Published: September 21, 2018 A

DOI: 10.1021/acs.joc.8b02190 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Table 1. Optimization of the Reaction Conditions of Dehydration of Amides

entry

DMSO (equiv)

(COCl)2 (equiv)

base (equiv)

1 2 3 4 5 6 7

0.01 0.01 0.01 0.01 0 0.01 0.01

2.0 2.0 2.0 1.2 1.2 1.2 1.2

Et3N (3.0) 0 Et3N (3.0) Et3N (2.5) Et3N (2.5) DBU (2.5) NMM (2.5)

time 10 24 24 40 24 24 24

min h h min h h h

Table 2. Dehydration of Amides to Nitriles under the Conditions of a Catalytic Swern Oxidation

yield (%) 92a 1b 1b,c 90a 0b 0b 58b

a

Isolation yield after chromatographic purification. bDetermined by GCMS. cThe only difference against the conditions of entry 1 was that Et3N was added last.

3 equiv of Et3N in anhydrous MeCN at rt (entry 1). The reaction was complete in 10 min to produce benzonitrile (2a) almost quantitatively. A reaction was also carried out in the absence of Et3N, in which only a trace of benzonitrile (2a) was detected by GCMS even after 24 h of stirring at rt (entry 2). Another experiment was performed under conditions similar to those in entry 1 except that 3 equiv of Et3N was added to the reaction mixture at last (entry 3). The conversion of benzonitrile (2a) was only 1% after 24 h of stirring at rt, which was similar to that in entry 2. These results indicated that it was feasible that the dehydration of an amide was carried out under the conditions of a catalytic Swern oxidation at rt, in which Et3N was needed to be added to the reaction mixture in advance. One more experiment was carried out to optimize the amounts of (COCl)2 and Et3N, in which they were reduced to 1.2 and 2.5 equiv, respectively (entry 4). It was observed that the reaction proceeded slightly slower than that in entry 1 but produced the desired nitrile 2a in a very close yield. The reaction was also attempted in the absence of DMSO, but no product was detected (entry 5). This result indicated that DMSO is indispensable for the reaction, which is consistent with that reported by Nakajima and Ubukata.9 In addition, two more bases were examined to see if they could promote this reaction. No product was obtained in the presence of DBU (entry 6), whereas the reaction gave the desired nitrile in 58% yield in the presence of NMM (entry 7). In comparison, Et3N is the most effective base for this conversion. The dehydration of more amides was explored under the same conditions as those in entry 4 of Table 1. The results are shown in Table 2. Three benzamides with substituted groups on the phenyl ring (1b−d) were converted to the corresponding benzonitriles (2b−d) in good to excellent yields, regardless of whether they bore electron-withdrawing group (2b, 2d) or electron-donating group (2c). Among the aromatic amides, 1d with two electron-withdrawing nitro groups on the phenyl ring afforded the nitrile in the lowest yield of 80%. Two heterocyclic amides 1e and 1f were then investigated. 2-Cyanothiophene 2e and 3-cyanopyridine 2f were obtained in 89% and 90% yields, respectively. The dehydration of 2-naphthamide 1h gave 2-cyanonaphthalene 2h in a high yield of 96%. Likewise, the unsaturated cinnamamide 1g was also converted smoothly to the nitrile 2g in 92% yield.

In addition, aliphatic linear (1i, 1j, 1k), cyclic (1l), and branched (1m, 1n) amides were dehydrated to produce the corresponding nitriles 2i−n in 80−87% yields, which were slightly lower than those from the above unsaturated amides. Phenyl-protected α-hydroxy amide 1k was also a compatible substrate, which gave the desired nitrile 2k in 80% yield. The same protocol also was applied to the two α-amino amides 1o and 1p with Boc and Cbz protective groups, respectively, and the corresponding nitriles 2o and 2p were obtained in 83% and 76% yields, respectively, with the protective groups intact. Moreover, the specific rotation values of the products indicated that no racemization occurred during the dehydration process. Most of the substrates included in Table 2 were also investigated in the work of Malkov and Rubtsov.6b For these substrates, the yields obtained in our work are comparable with those obtained via a catalytic Appel reaction. In addition, an acid-sensitive Boc-protected substrate 1o was converted to the corresponding nitrile in a good yield in our work, whereas it was mentioned that Boc-protected amino acids could not be converted to the desired nitriles under the conditions of a catalytic Appel reaction.6b Among the substrates mentioned above, some were also examined by Nakajima and Ubukata9 under Swern oxidation conditions with stoichiometric use of DMSO, including 1c, 1d, 1g, 1h, 1l, and 1p. Except for p-methoxybenzamide 1c with a similar yield and 3,5-dinitrobenzamide 1d with a lower yield, the other amides were converted to the corresponding nitriles in higher yields in our work. In the work of Nakajima and Ubukata,9 all of the reactions were carried out at −78 or −78 °C to rt with the combination of stoichiometric amounts of (COCl)2, DMSO, and Et3N, in which the addition of Et3N could be done either with (COCl)2 at the same time or at last without any effect on yields. In contrast, the reactions were able to be performed at rt mildly due to the usage of catalytic amount of DMSO in our present work. It was noteworthy that B

DOI: 10.1021/acs.joc.8b02190 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry it was necessary to add Et3N to the reaction mixture in advance of our protocol, which indicatd that Et3N acted as base to eliminate the intermediates to release DMSO required for the next reaction cycle. The possible mechanistic pathway for the dehydration of amides under catalytic Swern oxidation conditions was proposed as follows (Scheme 2). DMSO (A)

Table 3. Optimization of the Reaction Conditions of Dehydration of Aldoximes

Scheme 2. Possible Mechanistic Pathway for the Dehydration of Amides under Catalytic Swern Oxidation Conditions

entry

DMSO (equiv)

(COCl)2 (equiv)

base (equiv)

time

yield (%)

1 2 3 4 5 6 7

0 0.01 0.05 0.05 0.01 0.01 0.01

1.5 1.2 1.5 1.5 1.2 1.2 1.2

0 0 0 TEA (3.0) TEA (2.5) DBU (2.5) NMM (2.5)

24 h 30 min 24 h 20 min 1h 24 h 2h

0a 2a 100a 100a 93b 0a 100a

a Determined by HNMR. purification.

b

Isolation yield after chromatographic

and 1.5 equiv of (COCl)2 in the absence of base (entry 3). The addition of Et3N (3.0 equiv) reduced the reaction time from 24 h to 20 min (entry 4). The amounts of reagents were optimized further. The reaction was complete in 1 h an produced 2a in 93% isolated yield in the presence of 0.01 equiv of DMSO, 1.2 equiv of (COCl)2, and 2.5 equiv of Et3N (entry 5). DBU and NMM were also used in attempts to replace Et3N to promote the dehydration of 3a. No nitrile was obtained in the presence of DBU (entry 6). In contrast, the nitrile was obtained in the presence of NMM in a yield comparable to that with Et3N but over a longer reaction time of 2 h (entry 7). These results were similar to those obtained from the dehydration of amides. Five other aldoximes underwent dehydration under the above optimized conditions: o-bromobenzaldehyde oxime 3b, thiophene-2-carbaldehyde oxime 3e, trans-cinnamaldehyde oxime 3g, cyclohexanecarboxaldehyde oxime 3l, and 3phenylpropanal oxime 3q. The results are shown in Table 4. All of these substrates were converted to the corresponding nitriles in high yields, and the reactions were complete in 1 h. Yadav et al. reported that bromodimethylsulfonium bromide was used to convert aldoximes and primary amides to nitriles,5a in which it was claimed that the presence of a base slowed the

reacted with (COCl)2 to produce the intermediate chlorodimethylsulfonium chloride (B), which was attacked by the oxygen of an amide through a nucleophilic substitution in the presence of Et3N to give the intermediate C. It was then deprotonated by Et3N to generate the intermediate D, which underwent elimination to afford the corresponding nitrile and release DMSO (A) to enter the next cycle. No product was obtained when Et3N was replaced by DBU, which might be due to the reaction between DBU and (COCl)2.14 In contrast, NMM gave the desired product in a lower yield for a longer reaction time than Et3N, which indicated that the elimination of the intermediate C to the nitrile is the rate-limiting step influenced by the basicity of the amine. There is an alternative possible pathway for the transformation of the intermediate C to nitrile; i.e., the deprotonation may occur on the methyl group to give the intermediate E, which undergoes a retro-heteroene reaction to generate nitrile. In order to clarify the mechanism, DMSO-d6 was used for the dehydration of benzamide (1a), and the reaction mixture was analyzed by GC−EIMS after the reaction was complete. Compared with the mass spectrum of DMSOd6, the major fragment ion peaks in the spectrum of DMSO in the reaction mixture are similar to those of the standard DMSO-d6. However, two additional minor peaks at m/z 83 and 63 both with an intensity of 2.6% appear in the mass spectrum of DMSO in the reaction mixture, which indicates that a small amount of DMSO-d6 was converted into DMSOd5 after the reaction. These results indicate that the transformation of the intermediate C to nitrile occurs mainly by an E2 mechanism but do not exclude a retro-heteroene mechanism to some extent. The application scope of the present method was further explored by transforming aldoximes to the nitriles. The dehydration of benzaldehyde oxime (3a) was investigated under different conditions in order to optimize reaction conditions (Table 3). The reaction failed to produce benzonitrile (2a) in the presence of (COCl)2 only if without DMSO (entry 1). Compound 3a was converted into 2a thoroughly after 24 h by treatment with 0.05 equiv of DMSO

Table 4. Dehydration of Aldoximes to Nitriles under the Conditions of a Catalytic Swern Oxidation

C

DOI: 10.1021/acs.joc.8b02190 J. Org. Chem. XXXX, XXX, XXX−XXX

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with a catalytic amount of DMSO. This approach has several advantages, such as simple operation, mild conditions, high yields, and short reaction time. It offers a practical alternative for the preparation of nitriles by the dehydration of primary amides or aldoximes. The investigation about the generality of this method is still ongoing in our laboratory.

dehydration of aldoximes. In contrast, it was observed that the reactions of all the aldoximes in our work were very slow in the absence of Et3N and completed in 5−48 h. The possible mechanistic pathway for the dehydration of aldoximes is shown in Scheme 3, which is similar to the catalytic cycle above for

■

Scheme 3. Possible Mechanistic Pathway for the Dehydration of Aldoximes under Catalytic Swern Oxidation Conditions

EXPERIMENTAL SECTION

General Information. NMR spectra were obtained on a Bruker AV 300 spectrometer (1H NMR at 300 MHz, 13C NMR at 75 MHz) in CDCl3 using TMS as an internal standard. Chemical shifts (δ) are given in ppm and coupling constants (J) in hertz. GC−MS data were obtained on an Agilent 7890B-5977A under the following conditions: capillary column HP-5MS 5% Phenyl Methyl Silox (30 m × 0.25 mm × 0.25 um); oven temperature programmed from 50 to 150 °C at a rate of 15 °C/min, then 10 to 280 °C at a rate of 10 °C/min; carrier gas, helium; flow rate, 1.2 mL/min; electron ionization, 70 eV; ion source temperature, 230 °C. TLC was performed with precoated TLC plates, silica gel 60F-254, layer thickness 0.25 mm. Flash chromatography separations were performed on 200−300 mesh silica gel. Reagents and solvents are commercial grade and were used as supplied. Amides (1a−p) and aldoximes (3a, 3b, 3e, and 3g) are commercially available and were purchased from Innochem; the other aldoximes (3l and 3q) were synthesized in our laboratory. General Procedure for Dehydration of Primary Amides or Aldoximes to Nitriles. Amide 1 (3 mmol, 1.0 equiv) or aldoxime 3 (3 mmol, 1.0 equiv) was dissolved in 10 mL of anhydrous acetonitrile, followed by addition of DMSO (2.5 mg, 0.03 mmol, 0.01 equiv) and Et3N (1.04 mL, 7.5 mmol, 2.5 equiv). Oxalyl chloride (0.31 mL, 3.6 mmol, 1.2 equiv) in anhydrous acetonitrile (5 mL) was added dropwise at 20 °C and stirred at room temperature. After completion of reaction as indicated by TLC or GCMS, the mixture was filtered and concentrated in vacuo. Distilled water (15 mL) was added, the mixture was extracted with EtOAc (3 × 10 mL), and combined extracts were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (silica gel, petroleum ether/ethyl acetate = 9:1) afforded the corresponding nitrile 2. General Procedure for Synthesis of Aldoximes from Aldehydes. To a mixture of an aldehyde (10 mmol, 1.0 equiv) and hydroxylamine hydrochloride (1.38 g, 20 mmol, 2.0 equiv) in anhydrous dichloromethane (30 mL) was added pyridine (3.22 mL, 40 mmol, 4.0 equiv). The mixture was stirred for 24 h at room temperature. HCl (aq 2.0 M, 30 mL) was added to the reaction mixture, and the solution was extracted with dichloromethane (3 × 30 mL). The combined extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum to give the corresponding aldoxime 3. Analytical Data. Benzonitrile (2a).6b Colorless oil, 285 mg, 92% yield. 1H NMR (300 MHz, CDCl3): δ 7.68−7.64 (m, 2H, H-ophenyl), 7.64−7.58 (m, 1H, H-p-phenyl), 7.50−7.44 (m, 2H, H-mphenyl). 13C NMR (75 MHz, CDCl3): δ 132.9 (C-p-phenyl), 132.3 (C-o-phenyl), 129.2 (C-m-phenyl), 119.0 (C−CN), 112.6 (C1phenyl). 2-Bromobenzonitrile (2b).15 White solid, 516 mg, 95% yield. 1H NMR (300 MHz, CDCl3): δ 7.70−7.64 (m, 2H, H−C3-phenyl and H−C6-phenyl), 7.49−7.39 (m, 2H, H−C4-phenyl and H−C5phenyl). 13C NMR (75 MHz, CDCl3): δ 134.4 (C6-phenyl), 134.0 (C4-phenyl), 133.3 (C3-phenyl), 127.8 (C5-phenyl), 125.4 (C2phenyl), 117.2 (C−CN), 116.0 (C1-phenyl). The NMR peak assignments were confirmed by the HMQC and HMBC spectra. 4-Methoxybenzonitrile (2c).6b White solid, 380 mg, 95% yield. 1H NMR (300 MHz, CDCl3): δ 7.61−7.56 (m, 2H, H-o-phenyl), 6.97− 6.93 (d, 2H, H-m-phenyl), 3.86 (s, 3H, H−OCH3). 13C NMR (75 MHz, CDCl3): δ 163.0 (C-p-phenyl), 134.1 (C-o-phenyl), 119.4 (C− CN), 114.9 (C-m-phenyl), 104.2 (C1-phenyl), 55.7 (C-OCH3). 3,5-Dinitrobenzonitrile (2d). White solid, 463 mg, 80% yield. 1H NMR (300 MHz, CDCl3): δ 9.27 (t, J = 2.1 Hz, 1H, H-p-phenyl), 8.85 (d, J = 2.1 Hz, 2H, H-o-phenyl). 13C NMR (75 MHz, CDCl3): δ

the dehydration of amides. The presence of Et3N is crucial for the regeneration of DMSO, which is necessary for the next reaction cycle. In work of Denton et al. about the dehydration of oximes using oxalyl chloride in combination with 5 mol % of Ph3PO, a catalytic cycle was proposed involving the activated mono oxime ester generated from the reaction of oxime and oxalyl chloride as intermediate, which was then converted to nitrile by Ph3PO or chlorophosphonium salt. In order to explore the possibility of the similar pathway, two more experiments were carried out, in which benzamide 1a or benzaldehyde oxime 3a reacted with 1.5 equiv of oxalyl chloride first for 5 h at room temperature, and then 0.05 equiv of DMSO was added. In the case of benzamide 1a, no product was detected after 24 h. In contrast, benzaldehyde oxime 3a was converted to the desired nitrile in 90% yield after stirring for 6 h. These results indicated that for oximes, a catalytic cycle involving the activated mono oxime ester (G) was possible (Scheme 4). However, in the case of amides, the mechanism shown in Scheme 2 is more reasonable. In conclusion, a highly efficient preparation method of nitriles from primary amides or aldoximes has been developed using the combination of oxalyl chloride and triethylamine Scheme 4. Possible Mechanistic Pathway for the Dehydration of Aldoximes through the Activated Mono Oxime Ester

D

DOI: 10.1021/acs.joc.8b02190 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

CH(CH3)2). 13C NMR (75 MHz, CDCl3) δ 154.7 (CO), 118.1 (CN), 80.7 (C−OC(CH3)3), 48.4 (C-CHCN), 31.7 (C-CH(CH3)2), 28.1 (C-OC(CH3)3), 18.4 (C−CH(CH3)2), 17.9 (C−CH(CH3)2). The NMR peak assignments were confirmed by the HMQC spectrum. [α]23D = −66.3 (c 1.41, MeOH). (S)-Benzyl 1-Cyano-2-methylpropylcarbamate (2p).19 White solid, 530 mg, 76% yield. 1H NMR (300 MHz, CDCl3, 40 °C): δ 7.41−7.28 (m, 5H, H-phenyl), 5.29 (br d, J = 8.4 Hz, 1H, H-NH), 5.15 (s, 2H, H−CH2Ph), 4.49 (br s, 1H, H−CHCN), 2.11−1.96 (m, 1H, H−CH(CH3)2), 1.08 (d, J = 6.6 Hz, 3H, H−CH(CH3)2), 1.06 (d, J = 6.9 Hz, 3H, H−CH(CH3)2).13C NMR (75 MHz, CDCl3): δ 155.4 (CO), 135.7 (C1-phenyl), 128.7, 128.6, 128.3 (C2−C6phenyl), 117.8 (CN), 67.8 (C-CH2Ph), 49.1 (C-CHCN), 31.8 (CCH(CH3)2), 18.6 (C−CH(CH3)2), 18.0 (C−CH(CH3)2). The NMR peak assignments were confirmed by the HMQC spectrum. [α]23D = −53.8 (c 1.05, CH2Cl2). 3-Phenylpropanenitrile (2q).20 Colorless oil, 355 mg, 90% yield. 1 H NMR (300 MHz, CDCl3): δ 7.37−7.20 (m, 5H, H-phenyl), 2.94 (t, J = 7.5 Hz, 2H, H−C-3), 2.60 (t, J = 7.5 Hz, 2H, H−C-2). 13C NMR (75 MHz, CDCl3): δ 138.1 (C1-phenyl), 128.9 (C-m-phenyl), 128.3 (C-o-phenyl), 127.3 (C-p-phenyl), 119.2 (C−CN), 31.6 (C-3), 19.4 (C-2). The NMR peak assignments were confirmed by the HMQC and HMBC spectra. Cyclohexanecarbaldehyde Oxime (3l).21 Colorless oil, 1.05 g, 83% yield. 1H NMR (300 MHz, CDCl3): δ 8.94 (br s, 1H, H−OH, major and minor), 7.32 (d, J = 6.0 Hz, 1H, H−CHN, major), 6.53 (d, J = 7.2 Hz, 1H, H−CHN, minor), 3.02−2.90 (m, 1H, H−C1cyclohexane, minor), 3.26−2.15 (m, 1H, H−C1-cyclohexane, major), 1.85−1.09 (m, 10H, H-5CH2, major and minor). 13C NMR (75 MHz, CDCl3): δ 156.6 (C−CHN, minor), 156.1 (C−CHN, major), 38.6 (C1-cyclohexane, major), 33.9 (C1-cyclohexane, minor), 30.3 (C2- and C6-cyclohexane, major), 29.5 (C2- and C6-cyclohexane, minor), 26.01 (C4-cyclohexane, minor), 25.96 (C4-cyclohexane, major), 25.5 (C3- and C5-cyclohexane, major), 25.3 (C3- and C5cyclohexane, minor). The NMR peak assignments were confirmed by the HMQC spectrum. 3-Phenylpropanal Oxime (3q).21 White solid, 1.19 g, 80% yield. 1 H NMR (300 MHz, CDCl3) δ 8.80 (br s, 1H, H−OH, major and minor), 7.38 (t, J = 6.0 Hz, 1H, H−CHN, minor), 7.24−7.09 (m, 5H, H-phenyl, major and minor), 6.67 (t, J = 5.1 Hz, 1H, H−CH N, major), 2.77−2.71 (m, 2H, H−C-3, major and minor), 2.67−2.59 (m, 2H, H−C-2, major), 2.48−2.41 (m, 2H, H−C-2, minor). 13C NMR (75 MHz, CDCl3) δ 151.8 (C−CHN, major), 151.5 (C− CHN, minor), 140.7 (C1-phenyl), 140.6 (C1-phenyl), 128.6, 128.5, 128.4, 126.4 (C2−C6-phenyl), 32.9 (C-3, minor), 32.0 (C-3, major), 31.3 (C-2, minor), 26.5 (C-2, major). The NMR peak assignments were confirmed by the HMQC spectrum.

149.0 (C-m-phenyl), 132.1 (C-o-phenyl), 122.8 (C-p-phenyl), 116.0 (C−CN), 114.7 (C1-phenyl). Thiophene-2-carbonitrile (2e).6b Colorless oil, 292 mg, 89% yield. 1 H NMR (300 MHz, CDCl3): δ 7.65−7.63 (m, 1H, H−C-3), 7.61 (dd, J = 5.1, 1.2 Hz, 1H, H−C-5), 7.14 (dd, J = 5.1, 3.6 Hz, 1H, H− C-4). 13C NMR (75 MHz, CDCl3): δ 137.5 (C-3), 132.7 (C-5), 127.7 (C-4), 114.3 (C−CN), 110.0 (C-2). The NMR peak assignments were confirmed by the HMQC and HMBC spectra. Nicotinonitrile (2f).6b White solid, 281 mg, 90% yield. 1H NMR (300 MHz, CDCl3): δ 8.89 (d, J = 1.2 Hz, 1H, H−C-2), 8.82 (dd, J = 4.8, 1.8 Hz, 1H, H−C-6), 7.96 (dt, J = 7.8, 1.8 Hz, 1H, H−C-4), 7.44 (ddd, J = 7.8, 4.8, 0.9 Hz, 1H, H−C-5). 13C NMR (75 MHz, CDCl3): δ 153.1 (C-6), 152.6 (C-2), 139.3 (C-4), 123.7 (C-5), 116.6 (C− CN), 110.3 (C-3). The NMR peak assignments were confirmed by the HMQC spectrum. Cinnamonitrile (2g).6b Colorless oil, 357 mg, 92% yield. 1H NMR (300 MHz, CDCl3): δ 7.48−7.37 (m, 6H, H-phenyl and H−CHPh), 5.88 (d, J = 16.8 Hz, 1H, H−CHCN). 13C NMR (75 MHz, CDCl3): δ 150.7 (C-CHPh), 133.6 (C1-phenyl), 131.3 (C-p-phenyl), 129.2 (C-m-phenyl), 127.4 (C-o-phenyl), 118.2 (C−CN), 96.4 (C-CHCN). 2-Naphthonitrile (2h).15 White solid, 441 mg, 96% yield. 1H NMR (300 MHz, CDCl3): δ 8.24 (s, 1H, H−C-1), 7.94−7.88 (m, 3H, H− C-4, H−C-5 and H−C-8), 7.69−7.57 (m, 3H, H−C-3, H−C-6 and H−C-7). 13C NMR (75 MHz, CDCl3): δ 134.8 (C-4a), 134.3 (C-1), 132.4 (C-8a), 129.3, 129.2, 128.6, 128.2, 127.8, 126.5 (C-3, C-4, C-5, C-6, C-7 and C-8), 119.4 (C−CN), 109.6 (C-2). Hexanenitrile (2i).16 Colorless oil, 233 mg, 80% yield. 1H NMR (300 MHz, CDCl3): δ 2.33 (t, J = 7.2 Hz, 2H, H−C-2), 1.71−1.62 (m, 2H, H−C-3), 1.49−1.32 (m, 4H, H−C-4 and H−C-5), 0.92 (t, J = 7.2 Hz, 3H, H−C-6). 13C NMR (75 MHz, CDCl3): δ 120.0 (C− CN), 30.9 (C-4), 25.2 (C-3), 22.0 (C-5), 17.2 (C-2), 13.8 (C-6). The NMR peak assignments were confirmed by the HMQC spectrum. 2-Phenylacetonitrile (2j).6b Light yellow oil, 291 mg, 83% yield. 1 H NMR (300 MHz, CDCl3): δ 7.42−7.31 (m, 5H, H-phenyl), 3.75 (s, 2H, H−CH2). 13C NMR (75 MHz, CDCl3): δ 130.0 (C1-phenyl), 129.3 (C-o-phenyl), 128.2 (C-p-phenyl), 128.0 (C-m-phenyl), 118.0 (C−CN), 23.7 (C−CH2). 2-Phenoxyacetonitrile (2k).6b Colorless oil, 320 mg, 80% yield. 1H NMR (300 MHz, CDCl3): δ 7.40−7.33 (m, 2H, H-m-phenyl), 7.13− 7.07 (m, 1H, H-p-phenyl), 7.02−6.97 (m, 2H, H-o-phenyl), 4.77 (s, 2H, H−CH2). 13C NMR (75 MHz, CDCl3): δ 156.7 (C1-phenyl), 130.0 (C-m-phenyl), 123.3 (C-p-phenyl), 115.1 (C-o-phenyl and C− CN), 53.7 (C−CH2). Cyclohexanecarbonitrile (2l).17 Colorless oil, 285 mg, 87% yield. 1 H NMR (300 MHz, CDCl3): δ 2.61 (tt, J = 8.1, 3.9 Hz, 1H, H−C1), 1.89−1.80 (m, 2H, H−C-2 and H−C-6), 1.77−1.63 (m, 4H, H′− C-2 and H′−C-6, H−C-3 and H−C-5), 1.51−1.36 (m, 4H, H′−C-3 and H′−C-5, H−C-4). 13C NMR (75 MHz, CDCl3): δ 122.7 (C− CN), 29.6 (C-2 and C-6), 28.1 (C-1), 25.3 (C-4), 24.2 (C-3 and C5). The NMR peak assignments were confirmed by the HMQC spectrum. 2-Phenylbutanenitrile (2m).6b Yellow oil, 379 mg, 87% yield. 1H NMR (300 MHz, CDCl3): δ 7.42−7.29 (m, 5H, H-phenyl), 3.74 (t, J = 7.2 Hz, 1H, H−CHCN), 2.00−1.90 (m, 2H, H−CH2), 1.08 (t, J = 7.5 Hz, 3H, H−CH3). 13C NMR (75 MHz, CDCl3): δ 135.9 (C1phenyl), 129.1 (C-m-phenyl), 128.1 (C-p-phenyl), 127.4 (C-ophenyl), 120.9 (C−CN), 39.0 (H-CHCN), 29.3 (C−CH2), 11.6 (C−CH3). The NMR peak assignments were confirmed by the HMBC spectrum. Adamantane-1-carbonitrile (2n).15 White solid, 396 mg, 82% yield. 1H NMR (300 MHz, CDCl3): δ 2.04 (br, 9H, H−CH2−β-CN and H−CH-γ-CN), 1.77−1.68 (m, 6H, H−CH2−δ-CN). 13C NMR (75 MHz, CDCl3): δ 125.4 (C−CN), 40.0 (C-β-CN), 35.9 (C-δCN), 30.3 (C-α-CN), 27.2 (C-γ-CN). The NMR peak assignments were confirmed by the dept135 and HMQC spectra. (S)-tert-Butyl 1-Cyano-2-methylpropylcarbamate (2o).18 White solid, 493 mg, 83% yield. 1H NMR (300 MHz, CDCl3, 40 °C) δ 4.93 (br d, J = 8.7 Hz, 1H, H-NH), 4.42 (br s, 1H, H−CHCN), 2.01 (octet, J = 6.6 Hz, 1H, H−CH(CH3)2), 1.46 (s, 9H, H−OC(CH3)3), 1.08 (d, J = 6.6 Hz, 3H, H−CH(CH3)2), 1.06 (d, J = 6.3 Hz, 3H, H−

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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.joc.8b02190. 1 H and 13C NMR spectra of all the synthesized compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*Tel and Fax: +8610 68984545. E-mail: [email protected]. *Tel and Fax: +8610 68984545. E-mail: [email protected]. ORCID

Hongyu Tian: 0000-0002-7117-6420 Baoguo Sun: 0000-0003-4326-8237 Notes

The authors declare no competing financial interest. E

DOI: 10.1021/acs.joc.8b02190 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry

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ACKNOWLEDGMENTS Financial support from the National Key Research and Development Program (2016YFD0400801), the Beijing Postdoctoral Research Foundation (2017-22-011), and the Importation and Development of High-Caliber Talents Project of Beijing Municipal Institutions (CIT&TCD20140306) is gratefully acknowledged.

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DOI: 10.1021/acs.joc.8b02190 J. Org. Chem. XXXX, XXX, XXX−XXX