Synthesis and reactivity of 1-sulfonylcyclooctatriazoles

Abstract

Strained eight-membered cyclic alkynes undergo rapid inverse electron demand cycloaddition with sulfonyl azides to give the corresponding 1-sulfonylcyclooctatriazoles in excellent yield. Treatment of these sulfonyltriazoles with a chiral rhodium(II) carboxylate catalyst prompted transannular C–H bond insertion in good yield and with excellent ee, or 1,2-H shift.

---

1-Sulfonyl-1,2,3-triazoles (1-STs) have emerged as valuable building blocks for organic synthesis.¹ The combination of nitrogen-rich heteroaromatic and electron-poor sulfonyl group means these compounds have on-demand access to powerful carbene reactivity. In the presence of a catalyst, typically a rhodium(II) carboxylate, the 1,2,3-triazole (3) undergoes denitrogenation to make a metal–carbene complex (4). The route to metal carbenes from 1-STs offers not only complementary reactivity to established carbene methodology but has allowed novel applications and this strategy has been applied to create value-added products, bioactive compounds and natural products. A small selection of 1-ST denitrogenation methodology includes (Scheme 1): functionalising C–H bonds with high yield and excellent selectivity (5),² heterocycle synthesis (6, 10)³ and 1,2-H shift (11).⁴

Scheme 1 Overview of sulfonyl triazole synthesis and examples of reactivity.

A key consideration in maximising the application of 1-ST methodology is facile access to these valuable heterocycles (Scheme 1). Most commonly, 1-STs with 4-substitution 3 are synthesised by Cu(I) thiophene carboxylate (CuTC) catalysed reaction between an alkyne and sulfonyl azide.⁵ 5-Substituted and 1,4-disubstituted 1-STs 9 have also been synthesised but are less common. These 1-STs 9 can be accessed by anionic methods (using nBuLi),⁶ Wittig-type reaction (e.g. with 7),⁷ or others⁸ but these methods have drawbacks including limited applicability, low yield and poor atom economy. Using a reaction between an electronically matched azide and alkyne pair can also give an efficient route to triazoles. For sulfonyl azides 2, which are very electron-poor, electron-rich alkynes (such as azoalkynes 8) react very rapidly and selectively to form 1-STs.^4,9

Increased rate of reaction is observed in the strain-promoted cycloaddition between azides 13 and cyclic alkynes 12 (SPAAC). This “explosive” reactivity was first noted by Blomquist and Liu¹⁰ and characterised by Wittig and Krebs.¹¹ Later, Bertozzi realised this cycloaddition would by compatible in vivo and it has become a very popular technique for marking and imaging biological processes.¹² However, SPAAC has not been considered in the context of 1-ST synthesis.

Here, the cycloaddition between cyclic alkynes 12 and sulfonyl azides 2 is explored as a route to the less-exploited class of 4,5-disubstituted 1-ST and described computationally. The reactivity of two types of the resulting trisubstituted triazole products 15 has been developed into an enantioselective transannular C–H insertion (16) and 1,2-H shift (17) depending on the cyclic alkyne.

A range of sulfonyl azides 2 was considered in the cycloaddition with cyclooctyne 18 (Fig. 1). Cyclooctyne was readily prepared in three steps from (Z)-cylcooctene¹³ and it was an important consideration that cyclooctyne decomposes upon storage (over days under argon at −20 °C). An equimolar mixture of cyclooctyne 18 and sulfonyl azide 2 was stirred in dichloromethane and the cycloaddition was complete by 30 min. The cycloadduct 1-ST 20 could be isolated directly from the reaction or following facile purification. For operational convenience, cyclooctyne could also be used in excess to ensure complete conversion and any unreacted excess could be removed in vacuo. The reaction was quantitative to give methanesulfonyl 20a, p-toluenesulfonyl 20b, p-nitrobenzenesulfonyl 20c and p-methoxybenzenesulfonyl 20d triazoles, showing excellent tolerance for across a range of electron-rich to electron-poor sulfonyl azides. The process also gave a very high yield of the triazole with the bulky triisopropylbenzenesulfonyl group 20e as well as polyaromatic sulfonyl triazoles with a p-biphenyl 20f or dimethylaminonaphthyl 20g substituent. Bicyclo[6.1.0]non-4-ynes (BCNs) are a popular class of cyclic alkyne, having a functional handle on the cyclopropyl ring, plus the bicyclic system brings an increase in reactivity through increased strain.¹⁴ A silicon protected BCN 19 was prepared in short order. The more functionalised cyclooctyne 19 also gave excellent yields of triazole 21 when reacting with a selection of different alkyl and aryl sulfonyl azides 21a–d.

Fig. 1 Cycloaddition between MsN₃2 and cyclooctynes 18, 19. Isolated yield.

The increased reactivity of cyclooctynes is attributed to the alkyne they contain being distorted from its ideal 180° angle. Bickelhaupt and Houk have formalised a distortion–interaction transition state theory for reactions¹⁵ that is particularly suited to describe the reactions of strained molecules and has been applied to cyclooctynes.¹⁶ In this model, the activation energy required for a reaction between molecules (ΔE^‡) is a combination of the energy required for the individual components to distort to their transition state geometries (ΔE^‡_dist) offset by stabilising orbital interactions between those two components (ΔE^‡_int = ΔE^‡ − ΔE^‡_dist). The transition states for the cycloaddition between mesyl azide and each of cyclooctyne TS1 BCN TS2 and acetylene TS3 were considered (Table 1) in the framework of Houk's previous work in this area.^16a Calculations were performed on the PSI4 program:¹⁷ geometry optimisation and thermochemistry analysis was performed using B3LYP/6-31G(d); and orbital energies were calculated using HF/6-311++G(2d,p) at the B3LYP/6-31g(d) geometries.

Table 1 Transition structures for the cycloaddition between MsN₃ and cyclooctyne TS1, BCN TS2 and acetylene TS3

	TS1	TS2	TS3
Calculations at B3LYP/6-31g(d) except orbital energies at HF/6-311++G(2d,p)//B3LYP/6-31g(d). See ESI.
ΔE	8.4	7.1	16.1	kcal mol^−1
ΔE^‡dist (alkyne)	1.7	1.2	5.4	kcal mol^−1
ΔE^‡dist (azide)	17.7	16.0	21.6	kcal mol^−1
ΔE^‡int	−11.0	−10.1	−10.9	kcal mol^−1
ΔG^‡	20.6	19.2	28.2	kcal mol^−1
HOMOalkyne–LUMOazide	10.5	10.6	12.1	eV
HOMOazide–LUMOalkyne	13.0	12.9	13.0	eV

---

In each of the three transition structures, the cycloaddition was concerted, and asynchronous: with shorter C–N distances at the unsubstituted azide N3 terminus. The azide required significant distortion to reach its reacting geometry: the 175° ∠N–N–N bond angle in MsN₃ ground state¹⁸ being reduced by over 35° in the three transition structures. This distortion corresponded to a 17.7, 16.0 and 21.6 kcal mol⁻¹ increase in energy (ΔE^‡_dist) for the azide to attain these reactive geometries. For the cyclic alkynes, only a small deviation from the ground state¹⁹ alkyne bond angles was required and the associated change in energy was small (ΔE^‡_dist = 1.7 and 1.2 kcal mol⁻¹). In contrast, the 180° alkyne bond angles in acetylene were reduced considerably in its transition structure, with an associated ΔE^‡_dist of 5.4 kcal mol⁻¹. The interaction energy, was very similar across the three reactions (ΔE^‡_int: −11.0, −8.7; −10.9 kcal mol⁻¹) suggesting that each of the three reactions has similar electrostatic, charge transfer and repulsion interactions. Overall, the for the cycloaddition of MsN₃ with the cyclic alkynes was significantly lower than calculated for acetylene and this analysis suggests that this is due to the strained alkyne being preorganised towards its transition state geometry.

Examination of frontier molecular orbital energies revealed that for each of the transition structures, the HOMO_alkyne–LUMO_azide gap was lower than the HOMO_azide–LUMO_alkyne counterpart. This constitutes an inverse electron-demand (IED) mechanism:^16c usually for SPAAC the dominant orbital interactions are between the azide HOMO and alkyne LUMO—that can be explained by the very electron withdrawing nature of the sulfonyl group.

As a novel class of 1-ST, the reactivity of the cyclooctatriazoles was probed (Scheme 2). The 1-ST 20b derived from cyclooctyne and TsN₃ was treated with rhodium(II) acetate as catalyst in the presence of 2,5-dimethylfuran,^3c,i,j styrene,²⁰ triethylsilane,²¹ or benzonitrile,²² all of which have been demonstrated to be excellent partners for transformations with 4-substituted sulfonyl triazoles. Once the starting material was consumed, THF and lithium aluminium hydride were added to convert any sulfonyl imine into the corresponding amide. In each case the same outcome was observed, a new product was formed that did not incorporate any reacting partner. Analysis by NMR revealed that the product was a [3.3.0]-bicyclic sulfonamide 22b and that it had been formed with complete diastereocontrol (>20 : 1 dr by ¹H NMR). The eight-membered ring is well known to have close transannular interactions²³ so this reaction is proposed to involve 1,5-insertion of the rhodium carbene into the transannular C–H bond.^24,25 The same outcome was observed for all the different sulfonyl groups evaluated (22a–g). The stereochemistry was confirmed by comparison with known bicyclic sulfonamide 22b that was accessed by anionic transannular aziridine opening and whose structure was validated by independent synthesis and crystallography.²⁶

Scheme 2 Transannular C–H insertion reaction.

The generation of stereocentres prompted an investigation into creating an enantioselective variant of the reaction (Table 2 and ESI†). There are many chiral rhodium(II) carboxylate catalysts that have been demonstrated to impart good enantioselectivity using 1-STs. A brief screen showed that Rh₂(S-NTTL)₄ catalyst²⁷ was significantly more effective at controlling stereoselectivity in the reaction than Rh₂DOSP₄ or Rh₂PTAD₄. Interestingly, the selectivity was also complementary between these ligands. Lowering the temperature from 90 to 50 °C gave better enantioselectivity (29% ee) but at ambient temperature the reaction did not proceed. Varying the solvent gave another step towards enantioselectivity with toluene (68% ee) and perfluorobenzene (91% ee) giving further improvement. Finally, the sulfonyl group was considered. Enantiomeric excess was determined by HPLC analysis following LiAlH₄ reduction; or the intermediate sulfonyl imine was hydrolysed to the ketone 23 using basic Al₂O₃ and converted to the tertiary alcohol 24 by nucleophilic addition of PhMgBr (>20 : 1 dr by ¹H NMR, Scheme 2). Accessing known ketone 23²⁸ allowed further confirmation of the absolute stereochemistry. The second workup was essential in cases where the sulfonamide enantiomers 22 could not be separated by HPLC or functionality was incompatible with LiAlH₄ reduction (i.e. Ns, R = pNO₂C₆H₄). Electron donating aromatic sulfonyl groups gave their bicyclic product in lower ee compared with electron withdrawing ones. The Ns group gave higher enantioselectivity and accelerated the reaction rate. Combining these outcomes: treating the N–Ns cyclooctatriazole product with Rh₂(S-NTTL)₄ in perfluorobenzene at 50 °C followed by the hydrolysis and Grignard addition resulted in clean conversion to the bicyclic product in 94% ee and with 78% yield over the two steps.

Table 2 Optimisation highlights for enantiomeric excess of transannular C–H insertion

Entry	R	Solvent	T	Workup	Yield (%)	ee (%)
NTTL = 2-(1,3-dioxobenzo[de]isoquinolin-2-yl)-3,3-dimethyl-butanoate.
1	pTol	CH2Cl2	50	LiAlH4	36	29
2	pTol	PhMe	50	LiAlH4	43	68
3	pTol	C 6 F 6	50	LiAlH4	72	91
4	pMeOC6H4	PhMe	50	LiAlH4	36	24
5	pNO2C6H4	PhMe	50	Al2O3/PhMgBr	57	69
6	pNO2C6H4	C6F6	50	Al2O3/PhMgBr	78	94

---

The reactivity of the novel N-sulfonylBCNs 21 was also investigated (Scheme 3). In the case of these 1-STs, there was no transannular reaction. Switching to much more forcing conditions was required to see any reaction, namely toluene as solvent, Rh₂(OAc)₄ as catalyst and 120 °C (sealed vial). At this temperature, the rhodium(II) complex catalysed a denitrogenation and 1,2-H shift to give an α,β-unsaturated intermediate 17; that was hydrolysed to the corresponding ketone 25. The same outcome was observed for a number of different sulfonyl group each of which delivered the enone in good yield. The 1,2-H shift is well-documented in metallocarbenes with an adjacent C–H bond, including those derived from 1-STs.⁴ It is proposed that the difference in reactivity compared to the cyclooctyne derived 1-STs was that the resulting polycyclic product 26 would be highly strained.

Scheme 3 1,2-H Shift.

In summary, strain-promoted inverse electron demand cycloaddition is an effective route to highly substituted 1-STs. These can undergo transannular C–H insertion with very high enantioselectivity or 1,2-H shift.

Conflicts of interest

There are no conflicts to declare.

Notes and references

1. (a) T. Miura and M. Murakami, Rhodium Catal. Org. Synth., 2019, 449–470; (b) H. M. L. Davies and J. S. Alford, Chem. Soc. Rev., 2014, 43, 5151–5162; (c) P. Anbarasan, D. Yadagiri and S. Rajasekar, Synthesis, 2014, 3004–3023.
2. (a) S. Chuprakov, J. A. Malik, M. Zibinsky and V. V. Fokin, J. Am. Chem. Soc., 2011, 133, 10352–10355; (b) L. Li, X.-H. Xia, Y. Wang, P. P. Bora and Q. Kang, Adv. Synth. Catal., 2015, 357, 2089–2097; (c) V. N. G. Lindsay, H. M. F. Viart and R. Sarpong, J. Am. Chem. Soc., 2015, 137, 8368–8371; (d) X. Ma, F. Wu, X. Yi, H. Wang and W. Chen, Chem. Commun., 2015, 51, 6862–6865; (e) M.-H. Shen, Y.-P. Pan, Z.-H. Jia, X.-T. Ren, P. Zhang and H.-D. Xu, Org. Biomol. Chem., 2015, 13, 4851–4854; (f) M. Senoo, A. Furukawa, T. Hata and H. Urabe, Chem. – Eur. J., 2016, 22, 890–895; (g) H. Shen, J. Fu, H. Yuan, J. Gong and Z. Yang, J. Org. Chem., 2016, 81, 10180–10192; (h) Z. J. Garlets and H. M. L. Davies, Org. Lett., 2018, 20, 2168–2171; (i) J. Vaitla, Y. T. Boni and H. M. L. Davies, Angew. Chem., Int. Ed., 2020, 59, 7397–7402; (j) K. Pal and C. M. R. Volla, Chem. Rec., 2021, 21, 4032–4058.
3. (a) B. Chattopadhyay and V. Gevorgyan, Angew. Chem., Int. Ed., 2012, 51, 862–872; (b) T. Miura, K. Hiraga, T. Biyajima, T. Nakamuro and M. Murakami, Org. Lett., 2013, 15, 3298–3301; (c) B. T. Parr, S. A. Green and H. M. L. Davies, J. Am. Chem. Soc., 2013, 135, 4716–4718; (d) E. E. Schultz and R. Sarpong, J. Am. Chem. Soc., 2013, 135, 4696–4699; (e) J. E. Spangler and H. M. L. Davies, J. Am. Chem. Soc., 2013, 135, 6802–6805; (f) S. W. Kwok, L. Zhang, N. P. Grimster and V. V. Fokin, Angew. Chem., Int. Ed., 2014, 53, 3452–3456; (g) T. Miura, Y. Funakoshi and M. Murakami, J. Am. Chem. Soc., 2014, 136, 2272–2275; (h) H. Shang, Y. Wang, Y. Tian, J. Feng and Y. Tang, Angew. Chem., Int. Ed., 2014, 53, 5662–5666; (i) Y. Funakoshi, T. Miura and M. Murakami, Org. Lett., 2016, 18, 6284–6287; (j) A. S. Makarov, M. G. Uchuskin and A. S. K. Hashmi, Chem. Sci., 2019, 10, 8583–8588; (k) M. B. Williams and A. Boyer, J. Org. Chem., 2022 DOI:10.1021/acs.joc.2c00434.
4. M. L. Martin and A. Boyer, Eur. J. Org. Chem., 2021, 5857–5861.
5. (a) J. Raushel and V. V. Fokin, Org. Lett., 2010, 12, 4952–4955; (b) E. J. Yoo, M. Ahlquist, S. H. Kim, I. Bae, V. V. Fokin, K. B. Sharpless and S. Chang, Angew. Chem., Int. Ed., 2007, 46, 1730–1733.
6. (a) M. E. Meza-Aviña, M. K. Patel and M. P. Croatt, Tetrahedron, 2013, 69, 7840–7846; (b) M. E. Meza-Aviña, M. K. Patel, C. B. Lee, T. J. Dietz and M. P. Croatt, Org. Lett., 2011, 13, 2984–2987; (c) J. Boyer, C. Mack, N. Goebel and J. L. Morgan, J. Org. Chem., 2003, 23, 1051–1053.
7. G. R. Harvey, J. Org. Chem., 1958, 31, 1587–1590.
8. (a) S. Rajasekar and P. Anbarasan, Chem. – Asian J., 2019, 14, 4563–4567; (b) J. John, J. Thomas and W. Dehaen, Chem. Commun., 2015, 51, 10797–10806; (c) Y. Y. Morzherin, Y. A. Rozin, E. A. Vorob'eva and V. A. Bakulev, Chem. Heterocycl. Compd., 2001, 37, 560–566.
9. (a) R. E. Harmon, F. Stanley, S. K. Gupta and J. Johnson, J. Org. Chem., 1970, 35, 3444–3448; (b) M. Regitz and G. Himbert, Tetrahedron Lett., 1970, 11, 2823–2826; (c) N. Selander and V. V. Fokin, J. Am. Chem. Soc., 2012, 134, 2477–2480.
10. A. T. Blomquist and L. H. Liu, J. Am. Chem. Soc., 1953, 75, 2153–2154.
11. G. Wittig and A. Krebs, Chem. Ber., 1961, 94, 3260–3275.
12. (a) J. M. Baskin, J. A. Prescher, S. T. Laughlin, N. J. Agard, P. V. Chang, I. A. Miller, A. Lo, J. A. Codelli and C. R. Bertozzi, Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 16793–16797; (b) J. M. Baskin and C. R. Bertozzi, QSAR Comb. Sci., 2007, 26, 1211–1219; (c) N. J. Agard, J. A. Prescher and C. R. Bertozzi, J. Am. Chem. Soc., 2004, 126, 15046–15047.
13. L. Brandsma and H. D. Verkruijsse, Synthesis, 1978, 290.
14. (a) J. G. K. O’Brien, S. R. Chintala and J. M. Fox, J. Org. Chem., 2017, 83, 7500–7503; (b) J. Dommerholt, S. Schmidt, R. Temming, L. J. A. Hendriks, F. P. J. T. Rutjes, J. C. M. van Hest, D. J. Lefeber, P. Friedl and F. L. van Delft, Angew. Chem., Int. Ed., 2010, 49, 9422–9425.
15. (a) F. M. Bickelhaupt, J. Comput. Chem., 1999, 20, 114–128; (b) D. H. Ess and K. N. Houk, J. Am. Chem. Soc., 2007, 129, 10646–10647; (c) W.-J. van Zeist and F. M. Bickelhaupt, Org. Biomol. Chem., 2010, 8, 3118–3127; (d) F. M. Bickelhaupt and K. N. Houk, Angew. Chem., Int. Ed., 2017, 56, 10070–10086.
16. (a) D. H. Ess, G. O. Jones and K. N. Houk, Org. Lett., 2008, 10, 1633–1636; (b) F. Schoenebeck, D. H. Ess, G. O. Jones and K. N. Houk, J. Am. Chem. Soc., 2009, 131, 8121–8133; (c) J. Dommerholt, O. van Rooijen, A. Borrmann, C. F. Guerra, F. M. Bickelhaupt and F. L. van Delft, Nat. Commun., 2014, 5, 5378.
17. J. M. Turney, A. C. Simmonett, R. M. Parrish, E. G. Hohenstein, F. A. Evangelista, J. T. Fermann, B. J. Mintz, L. A. Burns, J. J. Wilke, M. L. Abrams, N. J. Russ, M. L. Leininger, C. L. Janssen, E. T. Seidl, W. D. Allen, H. F. Schaefer, R. A. King, E. F. Valeev, C. D. Sherrill and T. D. Crawford, Wiley Interdiscip. Rev.: Comput. Mol. Sci., 2012, 2, 556–565.
18. G. Deng, D. Li, Z. Wu, H. Li, E. Bernhardt and X. Zeng, J. Phys. Chem. A, 2016, 120, 5590–5597.
19. I. Yavari, F. Nasiri, H. Djahaniani and A. Jabbari, Int. J. Quantum Chem., 2006, 106, 697–703.
20. (a) S. Chuprakov, S. W. Kwok, L. Zhang, L. Lercher and V. V. Fokin, J. Am. Chem. Soc., 2009, 131, 18034–18035; (b) T. Miura, T. Nakamuro, Y. Ishihara, Y. Nagata and M. Murakami, Angew. Chem., Int. Ed., 2020, 59, 20475–20479; (c) T. Miura, T. Nakamuro, H. Nikishima and M. Murakami, Chem. Lett., 2016, 45, 1003–1005; (d) Y. Xing, G. Sheng, J. Wang, P. Lu and Y. Wang, Org. Lett., 2014, 16, 1244–1247.
21. H. Wang, H. Qiao, H. Zhang, H. Yang, Y. Zhao and H. Fu, Eur. J. Org. Chem., 2015, 4471–4480.
22. T. Horneff, S. Chuprakov, N. Chernyak, V. Gevorgyan and V. V. Fokin, J. Am. Chem. Soc., 2008, 130, 14972–14974.
23. (a) A. C. Cope, H.-H. Lee and H. E. Petree, J. Am. Chem. Soc., 1958, 80, 2849–2852; (b) L. A. Paquette, Y. Miyahara and C. W. Doecke, J. Am. Chem. Soc., 1986, 108, 1716–1718.
24. (a) G. Engling, T. Emrick, J. Hellmann, E. McElroy, M. Brandt and I. D. Reingold, J. Org. Chem., 1994, 59, 1945; (b) P. Müller and E. Maîtrejean, Collect. Czech. Chem. Commun., 1999, 64, 1807–1826; (c) M. Regitz and J. Rüter, Chem. Ber., 1969, 102, 3877–3890.
25. (a) D. M. Hodgson, T. J. Buxton, I. D. Cameron, E. Gras and E. H. M. Kirton, Org. Biomol. Chem., 2003, 1, 4293–4301; (b) D. M. Hodgson and I. D. Cameron, Org. Lett., 2001, 3, 441–444; (c) P. Müller and P. Nury, Helv. Chim. Acta, 2001, 84, 662–677; (d) D. Stead, P. O'Brien and A. Sanderson, Org. Lett., 2008, 10, 1409–1412.
26. (a) P. Müller, D. Riegert and G. Bernardinelli, Helv. Chim. Acta, 2004, 87, 227–239; (b) P. O’Brien, C. M. Rosser and D. Caine, Tetrahedron Lett., 2003, 44, 6613–6615; (c) P. O'Brien, C. M. Rosser and D. Caine, Tetrahedron, 2003, 59, 9779–9791.
27. F. G. Adly, J. Maddalena and A. Ghanem, Chirality, 2014, 26, 764–774.
28. (a) D. C. Billington, W. J. Kerr, P. L. Pauson and C. F. Farnocchi, J. Organomet. Chem., 1988, 356, 213–219; (b) J. K. Whitesell, M. A. Minton and S. W. Felman, J. Org. Chem., 1983, 48, 2193–2195.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, NMR and HPLC data. See DOI: https://doi.org/10.1039/d2cc03648g

---