Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Metal-free intermolecular formal cycloadditions enable an orthogonal access to nitrogen heterocycles


Nitrogen-containing heteroaromatic cores are ubiquitous building blocks in organic chemistry. Herein, we present a family of metal-free intermolecular formal cycloaddition reactions that enable highly selective and orthogonal access to isoquinolines and pyrimidines at will. Applications of the products are complemented by a density functional theory mechanistic analysis that pinpoints the crucial factors responsible for the selectivity observed, including stoichiometry and the nature of the heteroalkyne.


Heteroarenes constitute one of the privileged core structural motifs in organic chemistry1. Among them, isoquinolines and pyrimidines represent two big families in pharmaceutical agents, natural products and functional materials2,3,4,5,6,7,8,9. Therefore, continued effort is devoted to the exploration of new and efficient synthetic strategies for these backbones.

The classical strategies to prepare isoquinolines (Fig. 1a) generally focus on the crucial textbook disconnections C1-C8a (Bischler-Napieralski and Pictet-Spengler syntheses) or C4-C4a (Pomeranz-Fritsch synthesis). Recently developed routes centred on the bond-forming events N2–C3 or N2–C3/C4–C4a, employing electrophile-triggered annulation and transition metal-catalysed C–H or C–halogen bond activation, respectively1,10,11,12,13,14,15,16,17. A strategy relying on the simultaneous formation of N2–C3/C1–C8a is much less documented18.

Figure 1: Synthetic disconnections.

(a) Known synthetic disconnections for the isoquinoline and pyrimidine backbone. (b) Proposed direct disconnections through intermolecular metal-free alkyne/nitrile cycloadditions.

Conversely, most of the known avenues towards pyrimidine synthesis rely on the condensation of N–C–N subunits (mostly amidines or guanidines) with 1,3-dicarbonyl derivatives or the stoichiometric activation of carbonyl moieties with triflic anhydride (Fig. 1a) (refs 19, 20, 21, 22, 23). Ynamides have recently shown to be suitable candidates for regioselective cycloaddition with nitriles in the presence of a gold catalyst, leading to 4-aminopyrimidine cores24. Although the reactivity of ynamides has received considerable recent attention25,26,27,28,29,30,31,32,33, analogous investigation of the potential enclosed in the triple bond of thioalkynes is surprisingly rare34,35,36,37, even though the resulting sulfide is a useful38 and versatile substituent39,40,41,42.

Herein we report a family of reactions that enable a high yielding, orthogonal access to either isoquinolines or pyrimidines at will (Fig. 1b), by Brønsted acid-mediated regioselective formal cycloaddition of ynamides and thioalkynes with nitriles (for a review of transition-metal mediated [2+2+2] cycloadditions) (ref. 43). Mechanistic studies reveal the subtle differences that are responsible for selectivity.



Initial experiments involving the reaction of ynamide 1a with various Brønsted acids in the presence of varying amounts of acetonitrile led to moderate yields of isoquinoline 3aa. After optimization of conditions (see Supplementary Table 1 for details), we found that essentially equimolar amounts of 1a, 2a and TfOH in dichloroethane as solvent sufficed to enable preparation of 3aa in 89% yield (for a discussion of stoichiometry in these reactions, vide infra).

Holding suitable conditions in hand, we then examined several nitriles 2a-j under the optimized conditions. As shown in Fig. 2a, this direct formal cycloaddition is applicable to a broad range of substrates, generally affording good to excellent yields of isoquinoline products. Remarkably, alkyl nitriles bearing functional groups such as an ester (2c), aryl rings (2h and 2i) or C–C double bonds (2j) are compatible with the reaction conditions. It is worth mentioning that the isolated double bond in product 3aj does not migrate into conjugation with the isoquinoline ring under these conditions. Aryl nitriles (2dg) and α,β-unsaturated nitrile 2f are also viable partners delivering the corresponding substituted isoquinoline products in good to very good yields.

Figure 2: Scope of isoquinoline synthesis.

(a) Scope of nitriles and (b) Scope of ynamides for the synthesis of isoquinolines. Yields are for isolated products.

Subsequently, a broad range of ynamides were submitted to this protocol (Fig. 2b). In the event, both electron-donating (1bd) and -withdrawing (1f) substituents were tolerated on the ynamide partner, leading to smooth isoquinoline assembly in good yields. Halogenated ynamides (1ef) were also amenable to this reaction, delivering isoquinoline products ripe for subsequent divergent functionalization. Thienopyridine skeletons could be obtained in reasonable yields (3ga and 3gh). Interestingly, N-tosyl-N-benzyl ynamide (1j) directly generated the corresponding debenzylated product: the tosyl-protected, pharmacologically relevant 3-aminoisoquinoline (3ja) (refs 44, 45). Moreover, the use of an alkenyl-substituted ynamide (1k) led to the annulated pyridine product (3ke).

After this initial success, we hypothesized that other heteroatom-substituted alkynes might prove amenable to a similar modular assembly of isoquinolines. In particular, we were drawn to the use of thioalkynes such as 4b, with the expectation of obtaining an (alkylthio)-isoquinoline 6ba where the sulfur residue could serve as a useful synthetic handle (Fig. 3a).

Figure 3: Synthesis of pyrimidine.

(a) Unexpected synthesis of pyrimidine 5ba. (b) Scope of nitriles in the synthesis of pyrimidines 5.

Much to our surprise, treatment of 4b with acetonitrile 2a under conditions identical to those employed previously led exclusively to the pyrimidine 5ba in 52% yield (Fig. 3a). Remarkably, product 5ba is the result of a formal, regioselective cycloaddition of one molecule of 4b with two molecules of 2a. This dramatic shift in product selectivity between ynamides and thioalkynes eventually presented us with a versatile cycloaddition route towards pyrimidines. Reaction optimization showed that this transformation proceeds most effectively at room temperature in the presence of an excess of acetonitrile (see Supplementary Table 2 for details).

Figure 3b depicts the full scope of nitriles 2bv compatible with this metal-free pyrimidine synthesis. Secondary aliphatic (2k) and alicyclic (2m-2p) carbonitriles smoothly coupled with thioalkyne 4a under the reaction conditions. This formal cycloaddition was also tolerant of nitriles bearing triple (2q) and double bonds (2j), including conjugated olefins (2f). Both electron-rich (2d and 2s) and electron-deficient (2t and 2u) substituted benzonitriles could be employed, providing the desired pyrimidine products in good to excellent yields. It is worth noting that heteroarylnitriles such as 3-cyanothiophene (2r) were also tolerated. The possibility of using dimethylcyanamide (2v), delivering an aminated pyrimidine in excellent yield, further highlights the generality of this synthetic method. Pyrimidine 5ae yielded crystals suitable for X-ray diffraction analysis, unambiguously confirming its structure (see Supplementary Fig. 64 and Supplementary Tables 4 and 5 for details).

Further studies focused on the scope of heteroalkynes for this pyrimidine synthesis (Fig. 4a). We were pleased to find that a cyclopropyl substituent (4c) was tolerated, as a cyclopropyl appended to a pyrimidine ring is a common feature in drug-like, biologically active cores46,47,48. Both electron-rich (4e and 4g) and electron-poor (4d and 4f) arylalkynes afforded the corresponding pyrimidine products in good yields. Furthermore, considerable flexibility can be exerted, concerning the location of substituents on the aryl ring (4dg).

Figure 4: Scope and orthogonality of heterocycles.

(a) Scope of heteroalkynes for the synthesis of pyrimidines 5 or 7. (b) Orthogonality in the synthesis of isoquinolines or pyrimidines from ynamides. See Supplementary Figs 62 and 63 for details.

Strikingly, we found that 4-aminosubstituted pyrimidines can also be obtained by exposing ynamides (1l, 1a and 1m) to the standard conditions developed for pyrimidine synthesis. A distal nitrile group carried by the ynamide partner could be successfully introduced into the pyrimidine product (7ma). Remarkably, when phenyl-substituted ynamide 1a was submitted to these conditions, a 4-amino-5-aryl pyrimidine product (7aa) was obtained in good yield (Fig. 4b). Together with the reactions described previously (cf. Figures 2–3), these results offer an entirely new orthogonal access to either isoquinoline or pyrimidine motifs at will, while unifying this novel, powerful family of formal cycloaddition reactions.

Density functional theory study

We approached the mechanistic study of this reaction performing density functional theory (DFT) calculations of two reaction manifolds: the first leading to isoquinoline products (by modelling the entire pathway introducing a single acetonitrile molecule, see Fig. 5a) and the second leading to pyrimidine adducts (by computing the mechanism with two acetonitrile molecules, see Fig. 5b). The first question that arises is what occurs when all these species are in the presence of the TfOH promoter, as there are many potential protonation sites. DFT calculations (see Computational details in the Supplementary Figs 65–67) show that protonation would take place preferably on the heteroalkyne partner. Indeed, calculated transition states for the oxazolidinone (+7.6 and +6.0) and methylthio (+5.3 and +10.7) derivatives (in the presence of either one or two acetonitrile molecules, IIi and IIp, respectively) are much lower than the acetonitrile protonation (+17.0 Kcal mol−1). Furthermore, we confirmed that this protonation takes place regioselectively β- to the heteroatom as anticipated, leading to either a keteniminium IIIi or ketenethionium IIIp species, as the TfO anion is stabilized by acetonitrile (which in these reactions coincides with the nucleophilic species). In the second mechanistic step, a nucleophilic attack by acetonitrile takes place stereoselectively from the face opposite to the β-proton due to shielding by TfO (see IVi and IVp in Fig. 5). In fact, in both cases the introduction of acetonitrile, giving respectively Vi and Vp, is more stable than the corresponding TfO bonded derivative by 6.1 and 7.7 Kcal mol−1 for the oxazolidinone and methylthio derivatives, respectively. Interestingly, and very important for the reaction outcome, in the absence of acetonitrile the TfO species readily adds to the positively charged intermediate effectively blocking further reaction with acetonitrile. Moreover, we verified that nucleophilic attack by acetonitrile can only take place after the first protonation event as the highest occupied molecular orbital of acetonitrile (−0.3264 H) and the neutral ynamide’s lowest unoccupied molecular orbital (−0.0242 H) are energetically too far apart. The protonation process, however, results in an alkyne-centred lowest unoccupied molecular orbital turned by 90° at −0.2443 H, whereas the highest occupied molecular orbital of the TfO counteranion lies at −0.0742 H (see Supplementary Figs 65 in the Computational details section of the Supplementary Information). A similar trend is observed for the methylthio derivative. These two first processes (protonation+nucleophilic attack of acetonitrile) are common to both pathways. At this juncture, we can separately analyse the mechanisms leading to the isoquinoline and the pyrimidine scaffolds.

Figure 5: Energy profiles.

Isoquinoline (a, up, i subscript in roman numerals) and pyrimidine (b, down, p subscript in roman numerals) formation for the oxazolidinone (blue) and methylthio (red) derivatives. The corresponding three-dimensional structure sequence is exemplified for the methylthio derivative, for both a and b pathways, in Supplementary Figs 66 and 67, respectively

Isoquinoline formation

Following the addition of acetonitrile, the TfO anion immediately adds to the resulting carbocation (as the former lost its prior stabilization by acetonitrile) delivering a neutral and highly stable imino-triflate Vi. The last step consists of a Friedel–Crafts-like cyclization, VIIi, with further elimination of TfOH giving rise to the isoquinoline skeleton (VIIIi). This final addition process is characterized by high energy-transition states: +30.6 and +34.5 Kcal mol−1, respectively, for the oxazolidinone and methylthio derivatives (VIi; Fig. 5a). This is why heating is necessary in this case. The higher enthalpic barrier for the methylthio derivative stands in agreement with the experimental findings, as no isoquinoline product is observed for this derivative. In addition, nuclear magnetic resonance studies carried out with the starting heteroalkynes in the presence of TfOH suggest that the thermal stability of the methylthio-derivative is notably low. This could be a determining factor towards the experimental observations.

Pyrimidine formation

In this case, with two acetonitrile molecules (used for simplicity of the model, although the experimentally optimized molar ratio is higher), a different situation arises as a second addition becomes a more probable event. In fact, this process takes place through low energy-transition states (+6.5 and +7.1 Kcal mol−1, respectively, for the oxazolidinone and methylthio derivatives), VIp, giving rise to rather stable intermediates (VIIp; see Fig. 5b). Once the second molecule is added, the system could conceivably undergo a polymerization process with continued further addition of more acetonitrile molecules to the newly generated carbocationic species (+0.546 and +0.529 e, respectively, for the oxazolidinone and methylthio derivatives). Instead, the negatively charged (–0.208 and –0.210 e, for the oxazolidinone and methylthio derivatives, respectively) β-carbon atom can attack (VIIIp) the newly generated carbocation to form an entropically favoured, six-membered pyrimidine ring (after a very exothermic re-aromatization promoted by TfO, IXpXp). This is the driving force for pyrimidine formation.

A comparative analysis of both calculated mechanisms reveals at a glance that those involving the oxazolidinone derivative proceed generally with lower energies than the thioalkyne one. The main reason for that is the greater stabilization of the positive charge in the former case. In addition, although pathways for formation of either heterocycle could exist for both heteroalkynes, the pathway for isoquinoline formation through the thioalkyne derivative (Fig. 5a) has a prohibitive energy barrier when considering the addition of a single acetonitrile molecule. This barrier is much lower in the case of pyrimidine formation (Fig. 5b). This is due to the fact that in the latter case, there is a significant stabilization of the corresponding transition state introduced by the presence of the second acetonitrile molecule. Yet, the transition state for the first acetonitrile attack is 5.2 Kcal mol−1 higher in the case of isoquinoline formation. In this value, 3.2 Kcal mol−1 are purely due to the stabilization offered by the second acetonitrile molecule, as calculations made considering cationic structures (namely just the substrate and the acetonitrile molecule(s) without the TfO species) show this same energy difference. Therefore, the remaining 2 Kcal mol−1 should derive from stabilization by the counteranion (which is present in our mechanistic studies) through cooperative cyclic δ+·δ interactions between the different molecular units (see Fig. 6). In fact, we expect this transition state to be very low-lying, taking into account more solvent molecules. The preceding mechanistic analysis also permits a rationalization of why isoquinoline synthesis (formal [4+2]; (refs 49, 50, 51, 52)) requires high temperatures (highest energy barriers), whereas pyrimidine formation (formal [2+2+2]) typically occurs at room temperature.

Figure 6: Transition states for the first acetonitrile addition.

Isoquinoline (left) and pyrimidine (right) pathways, the latter presenting additional cyclic, electrostatic stabilizing interactions.

In both cases, stoichiometry plays a crucial role and imposes the final result, as both pathways are irreversible. In the presence of several molecules of acetonitrile (Fig. 5b), the corresponding transition state for a real [2+2+2] approximation is either transition state IVp or VIp, depending on the initial geometry conditions. These transition state also appear in a sequential pathway (as described in Fig. 5), thus indicating a natural direction for this molecular set. In the case of isoquinoline formation (Fig. 5a), the reaction of the unique acetonitrile molecule (imposed by stoichiometry) creates a positive charge that is readily neutralized by the negatively charged triflate present in the surrounding (as a remnant from the initial protonation event). The latter reaction should be faster than the time required for another acetonitrile molecule to approach, to follow pathway B. Once triflate blocks this position, a quite stable intermediate (Vi) is formed and no additional acetonitrile molecules can be added.

It is noteworthy that although all the computed reaction pathways would only require a catalytic amount of TfOH to proceed (owing to its regeneration on aromatization, vide supra), the most stable final product in either pathway is the corresponding nitrogen-protonated heterocycle (readily converted into the experimentally isolated products following basic workup). This neatly accommodates the experimental need for stoichiometric amounts of acid, to obtain high yields.

Further studies

Given the prevalence of isoquinoline motifs in the core of bioactive molecules53,54,55, we were eager to showcase the synthetic utility of our products (Fig. 7). The tetramethoxy adduct 3di, carrying two electronically differentiated fused rings in its isoquinoline system, could be hydrogenated in acetic acid to deliver (±)-norlaudanosine 8 (Fig. 7a). Removal of the oxazolidinone takes place under these conditions analogously to previous work by Glorius et al.56 on related pyridines and quinolones57. It is noteworthy that the use of a chiral 2-oxazolidone analogue, as in 3hi, enabled the hydrogenation to proceed with some level of asymmetric induction (55% e.e.). See Supplementary Fig. 60 for more detail.

Figure 7: Synthetic application and modification.

(a) Preparation of norlaudanosine 8 by hydrogenation of 3di. (b) Transformations of compound 5ba. (c) Reductive desulfurization of compound 5aa. (d) Pyrimidine 7aa can be prepared in gram scale.

The (methylthio)pyrimidine 5ba could be easily oxidized to the corresponding methylsulfonyl derivative 9, in which the methylsulfonyl group is available for substitution. As shown in Fig. 7b, this can be achieved by the action of alcohols, amines or Grignard reagents, delivering substituted pyrimidines 10–12 in very good to excellent yields.

In addition, Raney-Ni-mediated hydrogenation of 5aa smoothly excises the sulfide residue to afford the 2,5,6-trisubstituted pyrimidine 13 in 87% yield (Fig. 7c). These simple transformations outline the versatility and usefulness of the methods reported herein. Moreover, the reaction can be readily carried out in gram scale (Fig. 7d).


A family of reactions selectively leading to isoquinoline and pyrimidine motifs has been developed, by Brønsted acid-promoted regioselective merger of alkynes and nitriles. These methodologies benefit from the strategic use of readily available nitriles as the C–N sources. Most importantly, the orthogonality of the methods enables the preparation of either family of heterocycles from the same starting materials. The practicality of these metal-free formal cycloadditions is illustrated by the large scope of alkynes and nitriles that can be employed. DFT calculations reveal the crucial role of TfOH and the reaction stoichiometry in these processes. With one equivalent of acetonitrile, the preferred pathway leads to isoquinoline products through a Friedel–Crafts-like process; with larger amounts of nitrile, a second addition is allowed en route to the formation of a pyrimidine derivative. Furthermore, subtle differences between the classes of heteroalkynes employed control which products can be formed. We believe that the simple yet powerful heterocycle syntheses presented here will be eagerly adopted into the repertoire of synthetic chemistry.


Full experimental details, characterization of compounds, Cartesian coordinates and energies of all the structures appearing in Supplementary Figs 66 and 67, and computational details can be found in the Supplementary Information (Supplementary Figs 1–67 and Supplementary Methods).

Additional information

Accession codes: The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 1423496. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via

How to cite this article: Xie, L.-G. et al. Metal-free intermolecular formal cycloadditions enable an orthogonal access to nitrogen heterocycles. Nat. Commun. 7:10914 doi: 10.1038/ncomms10914 (2016).


  1. 1

    Joule, J. A. & Mills, K. Heterocyclic Chemistry 5th edn 194–200John Wiley & Sons, Ltd (2010) .

  2. 2

    Iranshahy, M., Quinn, R. J. & Iranshahi, M. Biologically active isoquinoline alkaloids with drug-like properties from the genus Corydalis. RSC Adv. 4, 15900–15913 (2014) .

    CAS  Article  Google Scholar 

  3. 3

    Bentley, K. W. β-Phenylethylamines and the isoquinoline alkaloids. Nat. Prod. Rep. 23, 444–463 (2006) .

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Su, Y. J. et al. Highly efficient red electrophosphorescent devices based on iridium isoquinoline complexes: remarkable external quantum efficiency over a wide range of current. Adv. Mater. 15, 884–888 (2003) .

    CAS  Article  Google Scholar 

  5. 5

    Ho, C.-L. et al. Red-light-emitting iridium complexes with hole-transportingn 9-arylcarbazole moieties for electrophosphorescence efficiency/color purity trade-off optimization. Adv. Funct. Mater. 18, 319–331 (2008) .

    CAS  Article  Google Scholar 

  6. 6

    Walker, S. R., Carter, E. J., Huff, B. C. & Morris, J. C. Variolins and related alkaloids. Chem. Rev. 109, 3080–3098 (2009) .

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Lagoja, I. M. Pyrimidine as constituent of natural biologically active compounds. Chem. Biodivers. 2, 1–50 (2005) .

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Köytepe, S., Paşahan, A., Ekinci, E. & Seçkin, T. Synthesis, characterization and H2O2-sensing properties of pyrimidine-based hyperbranched polyimides. Eur. Polym. J. 41, 121–127 (2005) .

    Article  Google Scholar 

  9. 9

    Gompper, R., Mair, H.-J. & Polborn, K. Synthesis of oligo(diazaphenyls). Tailor-made fluorescent heteroaromatics and pathways to nanostructures. Synthesis (Mass) 696–718 (1997) .

  10. 10

    He, R., Huang, Z.-T., Zheng, Q.-Y. & Wang, C. Isoquinoline skeleton synthesis via chelation-assisted C-H activation. Tetrahedron Lett. 55, 5705–5713 (2014) .

    CAS  Article  Google Scholar 

  11. 11

    Shi, Z., Koester, D. C., Boultadakis-Arapinis, M. & Glorius, F. Rh(III)-catalyzed synthesis of multisubstituted isoquinoline and pyridine N-oxides from oximes and diazo compounds. J. Am. Chem. Soc. 135, 12204–12207 (2013) .

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Zhao, D., Lied, F. & Glorius, F. Rh(III)-catalyzed C–H functionalization/aromatization cascade with 1,3-dienes: a redoxneutral and regioselective access to isoquinolines. Chem. Sci. 5, 2869–2873 (2014) .

    CAS  Article  Google Scholar 

  13. 13

    Roesch, K. R., Zhang, H. & Larock, R. C. Synthesis of isoquinolines and pyridines by the palladium-catalyzed iminoannulation of internal alkynes. J. Org. Chem. 66, 8042–8051 (2001) .

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Fischer, D. et al. Iodine-mediated electrophilic cyclization of 2-alkynyl-1-methylene azide aromatics leading to highly substituted isoquinolines and its application to the synthesis of Norchelerythrine. J. Am. Chem. Soc. 130, 15720–15725 (2008) and references therein .

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Gilmore, C. D., Allan, K. M. & Stoltz, B. M. Orthogonal synthesis of indolines and isoquinolines via aryne annulation. J. Am. Chem. Soc. 130, 1558–1559 (2008) .

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Castillo, J.-C., Quiroga, J., Abonia, R., Rodriguez, J. & Coquerel, Y. The aryne aza-Diels–Alder reaction: flexible syntheses of isoquinolines. Org. Lett. 17, 3374–3377 (2015) .

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Coppola, A., Sucunza, D., Burgos, C. & Vaquero, J. J. Isoquinoline synthesis by heterocyclization of tosylmethyl isocyanide derivatives: total synthesis of mansouramycin B. Org. Lett. 17, 78–81 (2015) .

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Mrtínez, A. G., Fernández, A. H., Vilchez, D. M., Gutiérrez, M. L. L. & Subramanian, L. R. A new easy one-step synthesis of isoquinoline derivatives from substituted phenylacetic esters. Synlett. 1993, 229–230 (1993) .

    Article  Google Scholar 

  19. 19

    Hill, M. D. & Movassaghi, M. New strategies for the synthesis of pyrimidine derivatives. Chem. Eur. J. 14, 6836–6844 (2008) and references therein .

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Movassaghi, M. & Hill, M. D. Single-step synthesis of pyrimidine derivatives. J. Am. Chem. Soc. 128, 14254–14255 (2006) .

    CAS  Article  PubMed  Google Scholar 

  21. 21

    Martínez, A. G. et al. On the mechanism of the reaction between ketones and trifluoromethanesulfonic anhydride. An improved and convenient method for the preparation of pyrimidines and condensed pyrimidines. J. Org. Chem. 57, 1627–1630 (1992) and references therein .

    Article  Google Scholar 

  22. 22

    Herrera, A., Martínez-Álvarez, R., Chioua, M., Chioua, R. & Sánchez, Á. On the regioselectivity in the reaction of aliphatic ketones and aromatic nitriles. Regiospecific synthesis of alkylarylpyrimidines. Tetrahedron 58, 10053–10058 (2002) .

    CAS  Article  Google Scholar 

  23. 23

    Martínez, A. G. et al. Sterically hindered bases. Synthesis of 2,4,6-trisubstituted pyrimidine. Synthesis (Mass) 881–882 (1990) and references therein .

    Article  Google Scholar 

  24. 24

    Karad, S. N. & Liu, R.-S. Regiocontrolled gold-catalyzed [2+2+2] cycloadditions of ynamides with two discrete nitriles to construct 4-aminopyrimidine cores. Angew. Chem. Int. Ed. 53, 9072–9076 (2014) .

    CAS  Article  Google Scholar 

  25. 25

    Evano, G., Coste, A. & Jouvin, K. Ynamides: versatile tools in organic synthesis. Angew. Chem. Int. Ed. 49, 2840–2859 (2010) .

    CAS  Article  Google Scholar 

  26. 26

    DeKorver, K. A. et al. Ynamides: a modern functional group for the new millennium. Chem. Rev. 110, 5064–5106 (2010) .

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Wang, X.-N. et al. Ynamides in ring forming transformations. Acc. Chem. Res. 47, 560–578 (2014) .

    CAS  Article  PubMed  Google Scholar 

  28. 28

    Li, L. et al. Zinc-catalyzed alkyne oxidation/C–H functionalization: highly site selective synthesis of versatile isoquinolones and β-carbolines. Angew. Chem. Int. Ed. 54, 8245–8249 (2015) .

    CAS  Article  Google Scholar 

  29. 29

    Shu, C. et al. Generation of α-imino gold carbenes through gold-catalyzed intermolecular reaction of azides with ynamides. J. Am. Chem. Soc. 137, 9567–9570 (2015) .

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Theunissen, C. et al. Keteniminium ion-initiated cascade cationic polycyclization. J. Am. Chem. Soc. 136, 12528–12531 (2014) .

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Peng, B., Huang, X., Xie, L.-G. & Maulide, N. A Brønsted acid-catalyzed redox arylation. Angew. Chem. Int. Ed. 53, 8718–8721 (2014) .

    CAS  Article  Google Scholar 

  32. 32

    Xin, Z., Kramer, S., Overgaard, J. & Skrydstrup, T. Access to 1,2-dihydroisoquinolines through gold-catalyzed formal [4+2] cycloaddition. Chem. Eur. J. 20, 7926–7930 (2014) .

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Minko, Y., Pasco, M., Lercher, L., Botoshansky, M. & Marek, I. Forming all-carbon quaternary stereogenic centres in acyclic systems from alkynes. Nature 490, 522–526 (2012) .

    ADS  CAS  Article  PubMed  Google Scholar 

  34. 34

    Ding, S. et al. Highly regio- and stereoselective hydrosilylation of internal thioalkynes under mild monditions. Angew. Chem. Int. Ed. 54, 5632–5635 (2015) .

    CAS  Article  Google Scholar 

  35. 35

    Ding, S., Jia, G. & Sun, J. Iridium-catalyzed intermolecular azide–alkyne cycloaddition of internal thioalkynes under mild conditions. Angew. Chem. Int. Ed. 53, 1877–1880 (2014) .

    CAS  Article  Google Scholar 

  36. 36

    Huang, K.-H. & Isobe, M. Highly regioselective hydrosilylation of unsymmetric alkynes using a phenylthio directing group. Eur. J. Org. Chem. 4733–4740 (2014) and references therein .

  37. 37

    Frei, R. et al. Fast and highly chemoselective alkynylation of thiols with hypervalent iodine reagents enabled through a low energy barrier concerted mechanism. J. Am. Chem. Soc. 136, 16563–16573 (2014) .

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Favre, A. & Fourrey, J.-L. Structural probing of small endonucleolytic ribozymes in solution using thio-substituted nucleobases as intrinsic photolabels. Acc. Chem. Res. 28, 375–382 (1995) .

    CAS  Article  Google Scholar 

  39. 39

    Dubbaka, S. R. & Vogel, P. Organosulfur compounds: electrophilic reagents in transition-metal-catalyzed carbon–carbon bond-forming reactions. Angew. Chem. Int. Ed. 44, 7674–7684 (2005) .

    CAS  Article  Google Scholar 

  40. 40

    Prokopcová, H. & Kappe, C. O. The Liebeskind–Srogl C–C cross-coupling reaction. Angew. Chem. Int. Ed. 48, 2276–2286 (2009) .

    Article  Google Scholar 

  41. 41

    Pan, F. & Shi, Z.-J. Recent advances in transition-metal-catalyzed C−S activation: from thioester to (hetero)aryl thioether. ACS Catal. 4, 280–288 (2014) .

    CAS  Article  Google Scholar 

  42. 42

    Melzig, L., Metzger, A. & Knochel, P. Pd- and Ni-catalyzed cross-coupling reactions of functionalized organozinc reagents with unsaturated thioethers. Chem. Eur. J. 17, 2948–2956 (2011) and references therein .

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Chopade, P. R. & Louie, J. [2+2+2] Cycloaddition reactions catalyzed by transition metal compleyes. Adv. Synth. Catal. 348, 2307–2327 (2006) .

    CAS  Article  Google Scholar 

  44. 44

    Suzuki, H. & Abe, H. A simple cyclization route to some 4-substituted 3-aminoisoquinolines. Synthesis (Mass) 763–765 (1995) and references therein .

  45. 45

    Neumeyer, J. L., Weinhardt, K. K., Carrano, R. A. & McCurdy, D. H. Isoquinolines 3. 3-aminoisoquinoline derivatives with central nervous system depressant activity. J. Med. Chem. 16, 808–813 (1973) .

    CAS  Article  PubMed  Google Scholar 

  46. 46

    Straub, A. et al. NO-independent stimulators of soluble guanylate cyclase. Bioorg. Med. Chem. Lett. 11, 781–784 (2001) .

    CAS  Article  PubMed  Google Scholar 

  47. 47

    Axon, J., Chakravarty, S., Dugar, S., Mcenroe, G. & Murphy, A. Inhibitors of TFGbeta. PCT Int. Appl WO 2004/024159 A1 (2004) .

  48. 48

    Mciver, E. G. et al. Pyrimidine derivatives capable of inhibiting one or more kinases. APCT Int. ppl WO 2009/122180 A1 (2009) .

  49. 49

    Barluenga, J., Fernández-Rodríguez, M. Á., García-García, P. & Aguilar, E. Gold-catalyzed intermolecular hetero-dehydro-diels−alder cycloaddition of captodative dienynes with nitriles: a new reaction and regioselective direct access to pyridines. J. Am. Chem. Soc. 130, 2764–2765 (2008) .

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Wessig, P. & Müller, G. The dehydro-diels−alder reaction. Chem. Rev. 108, 2051–2063 (2008) .

    CAS  Article  PubMed  Google Scholar 

  51. 51

    Fernández-García, J. M., Fernández-Rodríguez, M. Á. & Aguilar, E. Catalytic intermolecular hetero-dehydro-Diels–Alder cycloadditions: regio- and diasteroselective synthesis of 5,6-dihydropyridin-2-ones. Org. Lett. 13, 5172–5175 (2011) .

    Article  PubMed  Google Scholar 

  52. 52

    Hoye, T. R., Baire, B., Niu, D., Willoughby, P. H. & Woods, B. P. The hexadehydro-Diels–Alder reaction. Nature 490, 208–212 (2012) .

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Chrzanowska, M. & Rozwadowska, M. D. Asymmetric synthesis of isoquinoline alkaloids. Chem. Rev. 104, 3341–3370 (2004) .

    CAS  Article  PubMed  Google Scholar 

  54. 54

    Scott, J. D. & Williams, R. M. Chemistry and biology of the tetrahydroisoquinoline antitumor antibiotics. Chem. Rev. 102, 1669–1730 (2002) .

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Kartsev, V. G. Natural compounds in drug discovery. Biological activity and new trends in the chemistry of isoquinoline alkaloids. Med. Chem. Res. 13, 325–336 (2004) .

    CAS  Article  Google Scholar 

  56. 56

    Glorius, F., Spielkamp, N., Holle, S., Goddard, R. & Lehmann, C. W. Efficient asymmetric hydrogenation of pyridines. Angew. Chem. Int. Ed. 43, 2850–2852 (2004) .

    CAS  Article  Google Scholar 

  57. 57

    Heitbaum, M., Frchlich, R. & Glorius, F. Diastereoselective hydrogenation of substituted quinolines to enantiomerically pure decahydroquinolines. Adv. Synth. Catal. 352, 357–362 (2010) .

    CAS  Article  Google Scholar 

Download references


We are grateful to the European Research Council (ERC StG 278872 to N.M.) and the University of Vienna for support of this work. We acknowledge Dr Michael J. Fink and Professor Marko D. Mihovilovic (Vienna University of Technology) for hydrogenation reactions and helpful discussions. The computational results have been achieved in part using the Vienna Scientific Cluster (VSC).

Author information




L.-G.X. and N.M. planned the project. L.-G.X. and S.N. carried out the experiments and analysed the data. A.J.M. and L.G. carried out the DFT analysis. L.-G.X., A.J.M., S.N., L.G. and N.M. wrote the manuscript.

Corresponding author

Correspondence to Nuno Maulide.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information


Supplementary Figures 1-67, Supplementary Tables 1-5, Supplementary Methods and Supplementary References (PDF 8722 kb)

Rights and permissions

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Xie, LG., Niyomchon, S., Mota, A. et al. Metal-free intermolecular formal cycloadditions enable an orthogonal access to nitrogen heterocycles. Nat Commun 7, 10914 (2016).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing