Palladium-Catalyzed Carbonylation of Aryl Bromides with N-Substituted Cyanamides

Abstract

The palladium(0)-catalyzed three-component coupling reaction of aryl bromides, carbon monoxide, and N-alkyl cyan­amides has been developed employing a two-chamber system with ex situ generation of carbon monoxide from a silacarboxylic acid. The reactions proceeded well and were complete with a reaction time of only five hours leading to the corresponding N-alkyl cyanamides in good yields. The methodology was further extended to ¹³C isotope labeling of the carbonyl group through the use of a ¹³CO produced from the corresponding ¹³C-labeled version of the sila­carboxylic acid.

Cyanamides occupy a special place in organic chemistry as they are present attractive N–C–N building blocks, the reactivity of which can be further enhanced by installing an acyl group next to the amine nitrogen.[1] Cyanamides are widely used in the synthesis of amidines, quinazolinones, and some N-acyl cyclic guanidines.[2] In addition, there is an increased attention to cyanamides because of their applications as potent inhibitors of aldehyde dehydrogenase (A1DH)[3a] [b] [c] and their occurrence in biologically interesting molecules (Figure [1]).[3d,e] As a consequence of this, there is a continued interest in the development of new methodologies for their synthesis.

Since the first example reported by Heck and co-workers in 1974,[4] the three-component carbonylative coupling of an aryl halide, carbon monoxide, and a nucleophile has been expanded to the synthesis of a series of aromatic acyl derivatives including ketones,[5] esters,[6] amides,[7] aldehydes,[8] anhydrides,[9] acid chlorides,[10] and so on.[11] Despite the considerable attention for the application of nitrogen nucleophiles in carbonylative reactions, there are no examples for the employment of N-substituted cyanamides. In 2012, the group of Louie developed a palladium(0)-catalyzed cross-coupling of N-alkyl cyanamides with aryl halides.[12] And just recently, while our work was in progress, Larhed and co-workers disclosed that the parent cyanamide is also a competent nucleophile for the carbonylative coupling leading to synthesis of nonsubstituted N-acyl cyanamides.[13] Besides providing access to a larger functional diversity, N-alkylation blocks deprotonation of the base-labile cyanamide functionality. Correctly chosen, this would in turn allow the N-alkyl substituent to act as a cyanamide-protecting group.

Over the last three years, our group has developed and explored a connected two-chamber system for a number of palladium-catalyzed carbonylative reactions[14] of aryl halides and triflates using ex situ generation of CO gas from solid CO precursors, such as COgen and SilaCOgen.[15] During this work we became interested in applying alkylated cyanamides as nucleophiles in carbonylation reactions with stoichiometric CO. In this manuscript we wish to report on the development of the multicomponent reaction for performing a palladium-catalyzed carbonylative reaction providing direct access to N-substituted acyl cyanamides from aryl bromides (Scheme [1]). The developed method tolerates different N-alkylated cyanamides and performs with the inherent high functional-group tolerance of palladium catalysis. Finally, the method was extrapolated to include ¹³C labeling using ¹³CO obtained by simple exchange of the CO precurser for the ¹³C-labeled silacarboxylic acid derivative in the two-chamber system.

The initial investigation focused on the reaction of 2-bromonaphthalene (1a, 1.0 equiv) and N-benzyl cyanamide (2a, 1.2 equiv) in the presence of [Pd(cinnamyl)Cl]₂ (5 mol%), Ph₃P (10 mol%), K₃PO₄ (1.5 equiv), and CO (2.5 equiv) generated from methyldiphenylsilacarboxylic acid (SilaCOgen) in butyronitrile (0.1 M) as shown in Table [1].[16] We found that the desired product 3a was obtained in a 33% yield after five hours at 90 °C (Table [1], entry 1).

Table 1 Selected Entries for the Optimization of the Carbonylative Coupling of 2-Bromonaphthalene (1a) with N-Benzyl Cyanamide (2a)^a

Entry	Ligand	Base	Solvent	Yield (%)b
1	Ph3P	K3PO4	butyronitrile	33
2	L1	K3PO4	butyronitrile	83 (81)
3	DPPP	K3PO4	butyronitrile	75
4	L2	K3PO4	butyronitrile	11
5	L3	K3PO4	butyronitrile	35
6c	L1	K3PO4	butyronitrile	37
7d	L1	K3PO4	butyronitrile	80
8	L1	K2CO3	butyronitrile	74
9	L1	Cy2NMe	butyronitrile	77
10	L1	DIPEA	butyronitrile	74
11	L1	K3PO4	dioxane	65
12	L1	K3PO4	toluene	42

^a Chamber 1: ArBr (0.20 mmol), N-benzyl cyanamide (0.24 mmol), [Pd(cinnamyl)Cl]₂ (5 mol%), ligands (monodentate ligands 10 mol%, bidentate ligands 5 mol%), K₃PO₄ (1.5 equiv), and solvent (2.0 mL); chamber 2: methyldiphenylsilacarboxylic acid (0.50 mmol), KF (0.50 mmol), and butyronitrile (2.0 mL).

^b Yield was determined by ¹H NMR spectroscopic data of crude products using 1,3,5-trimethoxybenzene as an internal standard. Isolated yield is given in parenthesis.

^c Conditions: 5 mol% CataCXium A (L1) was employed.

^d Conditions: 20 mol% CataCXium A (L1) was employed.

Applying the more electron-rich and sterically demanding monodentate phosphine ligand, CataCXium A (L1, Figure [2]), improved the yield of 3a significantly to 83% (Table [1], entry 2). On the other hand, employing bidentate phosphine ligands such as dppp, DPEPhos (L2), and XantPhos (L3) led to a reduced efficiency of the coupling reaction (Table [1], entries 3–5). Varying the amount of CataCXium A did not improve the yield of 3a (Table [1], entries 6 and 7), while exchange of K₃PO₄ as the base for K₂CO₃, Cy₂NMe, or DIPEA only led to a slight reduction of the coupling yield (Table [1], entries 8–10). Replacement of the solvent butyronitrile with toluene or dioxane also led to a deterioration of the coupling yield to 3a (Table [1], entries 11 and 12).

Having identified optimal reaction conditions for the preparation of an N-substituted acyl cyanamide, we next set out to examine the substrate scope of this palladium-catalyzed carbonylative reaction with various aryl bromides (Scheme [2]). All reactions proceeded smoothly with N-benzyl cyanamide and were complete in five hours generating the corresponding acyl cyanamides in yields ranging from 42–86%. Both aryl bromides with electron-withdrawing and electron-donating substituents proved to be compatible with the coupling conditions. Substrates displaying an ortho substituent proved reactive, albeit providing reduced yields as exemplified with acyl cyanamide 3g. On the other hand, substituents in the para or meta position did not have a significant influence on the coupling efficiency. It is interesting to note that the thioester containing product 3n could be prepared although with some deterioration of the yield most likely due to competing amination at the thioester bond. For successful coupling with the more electron-deficient aryl bromides containing a 4-nitro or a 4-cyano substituent as in 3q and 3r, it was necessary to reduce the reaction temperature to 80 °C, as well as increasing the loading of the catalytic system in order to promote a reasonable conversion.

Next, a few other N-alkyl-substituted cyanamides were evaluated as coupling partners with 2-naphthyl bromide (1a, Scheme [3]). Not too surprisingly, the alkyl substituent on the cyanamide did indeed influence the reactivity of this particular nucleophile, however, the three examples 3s–u could all be secured in acceptable yields after column chromatography.

Finally, we examined the possibility for ¹³C isotope labeling applying ¹³CO generated from ¹³C-labeled methyldiphenylsilacarboxylic acid (Scheme [1]). As illustrated in Scheme [4], starting from 2-bromonaphthalene, the corresponding N-acyl cyanamide ¹³C-3a was obtained in an 80% yield (Scheme [4]).[16] Repeating the sequence in the coupling with 4-bromobiphenyl afforded ¹³C-3e in the yield of 77%, whereas with the n-hexyl-substituted cyanamide ¹³C-3t was generated in a yield of 62%.

In summary, a protocol for the direct transformation of a variety of aryl bromides into N-acyl cyanamides via a palladium-catalyzed carbonylative protocol has been developed using our previously described two-chamber system with a slight excess of ex situ generated carbon monoxide. Both electron-deficient and electron-rich aryl bromides could be transformed into the desired product, and furthermore, the process tolerates a wide variety of functional groups while an example with an ortho substituent provide slightly reduced yields. Lastly, isotope labeling with ¹³CO proved the corresponding ¹³C-labeled N-acyl cyanamides.

Acknowledgment

We are deeply appreciative of generous financial support from the Danish National Research Foundation (grant no. DNRF59), the Villum Foundation, the Danish Council for Independent Research: Technology and Production Sciences, the Lundbeck Foundation, the Carlsberg Foundation, and Aarhus University for generous financial support of this work. Furthermore, we thank the Chinese Scholarship Council for a grant to Z.L.

• References and Notes

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  Thieme ConnectSearch in Google Scholar
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  CrossrefSearch in Google Scholar
• 2e Hu Z, Li S.-d, Hong P.-Z. ARKICOV 2010; (ix): 171
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• 3a Guay D, Beaulieu C, Percival MD. Curr. Top. Med. Chem. 2010; 10: 708
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• 3b Shirota FN, Stevens JM, DeMaster EG, Nagasawa HT. J. Med. Chem. 1997; 40: 1870
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• 3e Larraufie M.-H, Maestri G, Malacria M, Ollivier C, Fensterbank L, Lacôte E. Synthesis 2012; 44: 1279
  Thieme ConnectSearch in Google Scholar
• 4a Schoenberg A, Bartoletti I, Heck RF. J. Org. Chem. 1974; 39: 3318
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• 4b Schoenberg A, Heck RF. J. Org. Chem. 1974; 39: 3327
  CrossrefSearch in Google Scholar
• 5a Ahmed MS. M, Mori A. Org. Lett. 2003; 5: 3057
  CrossrefSearch in Google Scholar
• 5b Ishiyama T, Kizaki H, Hayashi T, Suzuki A, Miyaura N. J. Org. Chem. 1998; 63: 4726
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• 6a Albaneze J, Bazaral C, Leavey T, Dormer PG, Murry JA. Org. Lett. 2004; 6: 2097
  CrossrefSearch in Google Scholar
• 6b Munday RH, Martinelli JR, Buchwald SL. J. Am. Chem. Soc. 2008; 130: 2754
  CrossrefSearch in Google Scholar
• 6c Hu Y, Liu J, Lu Z, Luo X, Zhang H, Lan Y, Lei A. J. Am. Chem. Soc. 2010; 132: 3153
  CrossrefPubMedSearch in Google Scholar
• 6d Lapidus AL, Eliseev OL, Bondarenko TN, Sizan OE, Ostapenko AG, Beletskaya IP. Synthesis 2002; 317
• 7a Kumar K, Zapf A, Michalik D, Tillack A, Heinrich T, Arlt M, Beller M. Org. Lett. 2004; 6: 7
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• 7b Liang D, Hu Z, Peng J, Huang J, Zhu Q. Chem. Commun. 2013; 173
• 7c Xie P, Xia C, Huang H. Org. Lett. 2013; 15: 3370
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• 7d Fang W, Deng Q, Xu M, Tu T. Org. Lett. 2013; 15: 3678
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• 7e Iizuka M, Kondo Y. Chem. Commun. 2006; 16: 1739
  Search in Google Scholar
• 7f Nielsen DU, Taaning R, Lindhardt A, Gøgsig TM, Skrydstrup T. Org. Lett. 2011; 13: 4454
  CrossrefPubMedSearch in Google Scholar
• 8 Klaus S, Neumann H, Zapf A, Almena J, Riermeier T, Groâ P, Sarich M, Krahnert W.-R, Rossen K, Beller M. Angew. Chem. Int. Ed. 2006; 45: 154
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• 9 Pri-Bar I, Alper H. J. Org. Chem. 1989; 54: 36
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• 10 Quesnel JS, Arndtsen BA. J. Am. Chem. Soc. 2013; 135: 16841
  CrossrefPubMedSearch in Google Scholar

For recent carbonylative reaction review, see:
• 11a Wu XF, Neumann H, Beller M. Chem. Rev. 2013; 113: 1
  CrossrefPubMedSearch in Google Scholar
• 11b Wu XF, Neumann H, Beller M. Chem. Soc. Rev. 2011; 40: 4986
  CrossrefPubMedSearch in Google Scholar
• 11c Magano J, Dunetz JR. Chem. Rev. 2011; 111: 2177
  Search in Google Scholar
• 11d Grigg R, Mutton SP. Tetrahedron 2010; 66: 5515
  CrossrefSearch in Google Scholar
• 11e Brennfuhrer AH, Neumann H, Beller M. Angew. Chem. Int. Ed. 2009; 48: 4114
  CrossrefSearch in Google Scholar
• 12 Stolley RM, Guo W.-X, Louie J. Org. Lett. 2012; 14: 322
  Search in Google Scholar
• 13 Mane RS, Nordeman P, Odell LR, Larhed M. Tetrahedron Lett. 2013; 54: 6912
  CrossrefSearch in Google Scholar
• 14a Hermange P, Lindhardt A, Taaning R, Bjerglund K, Lupp D, Skrydstrup T. J. Am. Chem. Soc. 2011; 133: 6061
  CrossrefPubMedSearch in Google Scholar
• 14b Hermange P, Gøgsig T, Lindhardt A, Taaning R, Skrydstrup T. Org. Lett. 2011; 13: 2444
  CrossrefSearch in Google Scholar
• 14c Xin Z, Gøgsig T, Lindhardt A, Skrydstrup T. Org. Lett. 2012; 14: 284
  CrossrefSearch in Google Scholar
• 14d Nielsen DU, Neumann K, Taaning R, Lindhardt A, Modvig A, Skrydstrup T. J. Org. Chem. 2012; 77: 6155
  CrossrefSearch in Google Scholar
• 14e Bjerglund K, Lindhardt A, Skrydstrup T. J. Org. Chem. 2012; 77: 3793
  CrossrefPubMedSearch in Google Scholar
• 14f Burhardt M, Taaning R, Skrydstrup T. Org. Lett. 2013; 15: 948
  CrossrefPubMedSearch in Google Scholar
• 15a Friis S, Taaning R, Lindhardt A, Skrydstrup T. J. Am. Chem. Soc. 2011; 133: 18114
  CrossrefPubMedSearch in Google Scholar
• 15b Friis S, Andersen TL, Skrydstrup T. Org. Lett. 2013; 15: 1378
  CrossrefSearch in Google Scholar
• 16 General Procedure for the Synthesis of N-Benzyl-N-cyano-2-naphthamide (3a) In an argon-filled glovebox to chamber 1 of the two-chamber system was added 2-bromonaphthalene (42 mg, 0.20 mmol), [Pd(cinnamyl)Cl]₂ (5.0 mg, 0.01 mmol), CataCXium A (8.0 mg, 0.02 mmol), K₃PO₄ (65 mg, 0.3 mmol), and butyronitrile (1.0 mL) in that order. The chamber was closed with a screwcap fitted with a Teflon seal. To chamber 2 of the two-chamber system was added methyldiphenylsila-carboxylic acid (122 mg, 0.50 mmol) and KF (30 mg, 0.50 mmol). The chamber was closed with a screwcap fitted with a Teflon seal. The loaded two-chamber system was removed from the glovebox and heated to 30 °C for 15 min. Then N-benzyl cyanamide (31 mg, 0.24 mmol) in butyronitrile (1.0 mL) was added to chamber 1. Lastly butyronitrile (2.0 mL) was added to chamber 2. This reaction was stirred at 90 °C for 5 h and was then cooled to r.t. The solids were filtrated off, and the reaction was concentrated under vacuum. The crude residue was subjected to flash chromatography using pentane–EtOAc (10:1) as eluent. This resulted in 46 mg (81%) of 3a as white solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.43 (s, 1 H), 7.94–7.98 (m, 2 H), 7.91 (d, J = 8.4 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.44–7.84 (m, 7 H), 4.98 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.1, 135.3, 133.8, 131.9, 130.0, 129.2, 129.1 (2 C), 129.0 (2 C), 128.8, 128.7, 128.6, 127.9, 127.8, 127.2, 124.3, 111.1, 51.4. HRMS: m/z calcd for C₁₉H₁₅N₂O [M + H]⁺: 287.1184; found: 287.1178. ¹³C-Labeled N-Benzyl-N-cyano-2-naphthamide (¹³C-3a) According to the general procedure. Flash chromatography using pentane–EtOAc (10:1) as eluent resulted in 46 mg (80% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.40 (d, J = 4.4 Hz, 1 H), 7.81–7.96 (m, 4 H), 7.41–7.64 (m, 7 H), 4.96 (d, J = 2.8 Hz, 2 H). ¹³C NMR (0100 MHz, CDCl₃): δ = 168.1 (¹³C-enriched), 135.4, 133.9, 132.0 (d, J = 5.1 Hz), 130.1 (d, J = 2.2 Hz), 129.3 (2 C), 129.1 (d, J = 2.9 Hz, 2 C), 128.8, 128.7, 128.6, 128.4, 127.9, 127.7, 127.3, 124.3 (d, J = 2.2 Hz), 111.1 (d, J = 3.6 Hz), 51.5. HRMS: m/z calcd for C₁₈ ¹³CH₁₅N₂O [M + H]⁺: 288.1218; found: 288.1213.

• References and Notes

• 1 Larraufie M.-H, Maestri G, Malacria M, Ollivier C, Fensterbank L, Lacôte E. Synthesis 2012; 44: 1279
  Thieme ConnectSearch in Google Scholar
• 2a Nekrasov DD. Russ. J. Org. Chem. 2004; 40: 1387
  CrossrefSearch in Google Scholar
• 2b Nekrasov DD. Chem. Heterocycl. Compd. 2004; 40: 1107
  CrossrefSearch in Google Scholar
• 2c Maestri G, Larraufie MH, Ollivier C, Malacria M, Fensterbank L, Lacôte E. Org. Lett. 2012; 14: 5538
  CrossrefSearch in Google Scholar
• 2d Larraufie M.-H, Courillon C, Ollivier C, Lacôte E, Malacria M, Fensterbank L. J. Am. Chem. Soc. 2010; 132: 4381
  CrossrefSearch in Google Scholar
• 2e Hu Z, Li S.-d, Hong P.-Z. ARKICOV 2010; (ix): 171
  Search in Google Scholar
• 3a Guay D, Beaulieu C, Percival MD. Curr. Top. Med. Chem. 2010; 10: 708
  CrossrefSearch in Google Scholar
• 3b Shirota FN, Stevens JM, DeMaster EG, Nagasawa HT. J. Med. Chem. 1997; 40: 1870
  CrossrefSearch in Google Scholar
• 3c Kwon C.-H, Nagasawa HT, De Master EG, Shirota NF. J. Med. Chem. 1986; 29: 1922
  CrossrefSearch in Google Scholar
• 3d Ronn R, Gossas T, Sabnis YA, Daoud H, Akerblom E, Danielson UH, Sandstrom A. Bioorg. Med. Chem. 2007; 15: 4057
  CrossrefPubMedSearch in Google Scholar
• 3e Larraufie M.-H, Maestri G, Malacria M, Ollivier C, Fensterbank L, Lacôte E. Synthesis 2012; 44: 1279
  Thieme ConnectSearch in Google Scholar
• 4a Schoenberg A, Bartoletti I, Heck RF. J. Org. Chem. 1974; 39: 3318
  CrossrefSearch in Google Scholar
• 4b Schoenberg A, Heck RF. J. Org. Chem. 1974; 39: 3327
  CrossrefSearch in Google Scholar
• 5a Ahmed MS. M, Mori A. Org. Lett. 2003; 5: 3057
  CrossrefSearch in Google Scholar
• 5b Ishiyama T, Kizaki H, Hayashi T, Suzuki A, Miyaura N. J. Org. Chem. 1998; 63: 4726
  CrossrefSearch in Google Scholar
• 6a Albaneze J, Bazaral C, Leavey T, Dormer PG, Murry JA. Org. Lett. 2004; 6: 2097
  CrossrefSearch in Google Scholar
• 6b Munday RH, Martinelli JR, Buchwald SL. J. Am. Chem. Soc. 2008; 130: 2754
  CrossrefSearch in Google Scholar
• 6c Hu Y, Liu J, Lu Z, Luo X, Zhang H, Lan Y, Lei A. J. Am. Chem. Soc. 2010; 132: 3153
  CrossrefPubMedSearch in Google Scholar
• 6d Lapidus AL, Eliseev OL, Bondarenko TN, Sizan OE, Ostapenko AG, Beletskaya IP. Synthesis 2002; 317
• 7a Kumar K, Zapf A, Michalik D, Tillack A, Heinrich T, Arlt M, Beller M. Org. Lett. 2004; 6: 7
  CrossrefSearch in Google Scholar
• 7b Liang D, Hu Z, Peng J, Huang J, Zhu Q. Chem. Commun. 2013; 173
• 7c Xie P, Xia C, Huang H. Org. Lett. 2013; 15: 3370
  CrossrefSearch in Google Scholar
• 7d Fang W, Deng Q, Xu M, Tu T. Org. Lett. 2013; 15: 3678
  CrossrefSearch in Google Scholar
• 7e Iizuka M, Kondo Y. Chem. Commun. 2006; 16: 1739
  Search in Google Scholar
• 7f Nielsen DU, Taaning R, Lindhardt A, Gøgsig TM, Skrydstrup T. Org. Lett. 2011; 13: 4454
  CrossrefPubMedSearch in Google Scholar
• 8 Klaus S, Neumann H, Zapf A, Almena J, Riermeier T, Groâ P, Sarich M, Krahnert W.-R, Rossen K, Beller M. Angew. Chem. Int. Ed. 2006; 45: 154
  CrossrefSearch in Google Scholar
• 9 Pri-Bar I, Alper H. J. Org. Chem. 1989; 54: 36
  CrossrefSearch in Google Scholar
• 10 Quesnel JS, Arndtsen BA. J. Am. Chem. Soc. 2013; 135: 16841
  CrossrefPubMedSearch in Google Scholar

For recent carbonylative reaction review, see:
• 11a Wu XF, Neumann H, Beller M. Chem. Rev. 2013; 113: 1
  CrossrefPubMedSearch in Google Scholar
• 11b Wu XF, Neumann H, Beller M. Chem. Soc. Rev. 2011; 40: 4986
  CrossrefPubMedSearch in Google Scholar
• 11c Magano J, Dunetz JR. Chem. Rev. 2011; 111: 2177
  Search in Google Scholar
• 11d Grigg R, Mutton SP. Tetrahedron 2010; 66: 5515
  CrossrefSearch in Google Scholar
• 11e Brennfuhrer AH, Neumann H, Beller M. Angew. Chem. Int. Ed. 2009; 48: 4114
  CrossrefSearch in Google Scholar
• 12 Stolley RM, Guo W.-X, Louie J. Org. Lett. 2012; 14: 322
  Search in Google Scholar
• 13 Mane RS, Nordeman P, Odell LR, Larhed M. Tetrahedron Lett. 2013; 54: 6912
  CrossrefSearch in Google Scholar
• 14a Hermange P, Lindhardt A, Taaning R, Bjerglund K, Lupp D, Skrydstrup T. J. Am. Chem. Soc. 2011; 133: 6061
  CrossrefPubMedSearch in Google Scholar
• 14b Hermange P, Gøgsig T, Lindhardt A, Taaning R, Skrydstrup T. Org. Lett. 2011; 13: 2444
  CrossrefSearch in Google Scholar
• 14c Xin Z, Gøgsig T, Lindhardt A, Skrydstrup T. Org. Lett. 2012; 14: 284
  CrossrefSearch in Google Scholar
• 14d Nielsen DU, Neumann K, Taaning R, Lindhardt A, Modvig A, Skrydstrup T. J. Org. Chem. 2012; 77: 6155
  CrossrefSearch in Google Scholar
• 14e Bjerglund K, Lindhardt A, Skrydstrup T. J. Org. Chem. 2012; 77: 3793
  CrossrefPubMedSearch in Google Scholar
• 14f Burhardt M, Taaning R, Skrydstrup T. Org. Lett. 2013; 15: 948
  CrossrefPubMedSearch in Google Scholar
• 15a Friis S, Taaning R, Lindhardt A, Skrydstrup T. J. Am. Chem. Soc. 2011; 133: 18114
  CrossrefPubMedSearch in Google Scholar
• 15b Friis S, Andersen TL, Skrydstrup T. Org. Lett. 2013; 15: 1378
  CrossrefSearch in Google Scholar
• 16 General Procedure for the Synthesis of N-Benzyl-N-cyano-2-naphthamide (3a) In an argon-filled glovebox to chamber 1 of the two-chamber system was added 2-bromonaphthalene (42 mg, 0.20 mmol), [Pd(cinnamyl)Cl]₂ (5.0 mg, 0.01 mmol), CataCXium A (8.0 mg, 0.02 mmol), K₃PO₄ (65 mg, 0.3 mmol), and butyronitrile (1.0 mL) in that order. The chamber was closed with a screwcap fitted with a Teflon seal. To chamber 2 of the two-chamber system was added methyldiphenylsila-carboxylic acid (122 mg, 0.50 mmol) and KF (30 mg, 0.50 mmol). The chamber was closed with a screwcap fitted with a Teflon seal. The loaded two-chamber system was removed from the glovebox and heated to 30 °C for 15 min. Then N-benzyl cyanamide (31 mg, 0.24 mmol) in butyronitrile (1.0 mL) was added to chamber 1. Lastly butyronitrile (2.0 mL) was added to chamber 2. This reaction was stirred at 90 °C for 5 h and was then cooled to r.t. The solids were filtrated off, and the reaction was concentrated under vacuum. The crude residue was subjected to flash chromatography using pentane–EtOAc (10:1) as eluent. This resulted in 46 mg (81%) of 3a as white solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.43 (s, 1 H), 7.94–7.98 (m, 2 H), 7.91 (d, J = 8.4 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.44–7.84 (m, 7 H), 4.98 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.1, 135.3, 133.8, 131.9, 130.0, 129.2, 129.1 (2 C), 129.0 (2 C), 128.8, 128.7, 128.6, 127.9, 127.8, 127.2, 124.3, 111.1, 51.4. HRMS: m/z calcd for C₁₉H₁₅N₂O [M + H]⁺: 287.1184; found: 287.1178. ¹³C-Labeled N-Benzyl-N-cyano-2-naphthamide (¹³C-3a) According to the general procedure. Flash chromatography using pentane–EtOAc (10:1) as eluent resulted in 46 mg (80% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.40 (d, J = 4.4 Hz, 1 H), 7.81–7.96 (m, 4 H), 7.41–7.64 (m, 7 H), 4.96 (d, J = 2.8 Hz, 2 H). ¹³C NMR (0100 MHz, CDCl₃): δ = 168.1 (¹³C-enriched), 135.4, 133.9, 132.0 (d, J = 5.1 Hz), 130.1 (d, J = 2.2 Hz), 129.3 (2 C), 129.1 (d, J = 2.9 Hz, 2 C), 128.8, 128.7, 128.6, 128.4, 127.9, 127.7, 127.3, 124.3 (d, J = 2.2 Hz), 111.1 (d, J = 3.6 Hz), 51.5. HRMS: m/z calcd for C₁₈ ¹³CH₁₅N₂O [M + H]⁺: 288.1218; found: 288.1213.

• Supplementary Material