Letter Cite This: Org. Lett. 2017, 19, 5565-5568
pubs.acs.org/OrgLett
Hydroboration Catalyzed by 1,2,4,3-Triazaphospholenes Chieh-Hung Tien,† Matt R. Adams,† Michael J. Ferguson,‡ Erin R. Johnson,*,† and Alexander W. H. Speed*,† †
Department of Chemistry, Dalhousie University, 6274 Coburg Road, P.O. Box 15000, Halifax, Nova Scotia, Canada B3H 4R2 X-ray Crystallography Laboratory, Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
‡
S Supporting Information *
ABSTRACT: The synthesis and study of the catalytic activity of 1,2,4,3-triazaphospholenes (TAPs) is reported. TAPs represent a more modular scaffold than previously reported diazaphospholenes. TAP halides were shown to catalyze the 1,2 hydroboration of 19 imines, and three α,β unsaturated aldehydes with pinacolborane, including examples that did not undergo hydroboration by previously reported diazaphospholene systems. DFT calculations support a mechanism where a triazaphospholene cation interacts with the substrate, a mechanism distinct from diazaphospholene catalyzed hydroborations.
M
pholenes with groups other than aryl and tert-butyl has proven challenging in our hands: low molecular weight diimines that are potential precursors for less sterically hindered diazaphospholenes are lachrymatory,13 rendering their exploration an unattractive prospect. Additionally in our hands, diimines with smaller substituents than tert-butyl, such as cyclohexyl, do not give clean cyclizations.14 Triazolium carbenes represent a privileged structure in catalysis and a modular scaffold for modifications.15 We sought to explore phosphorus-based analogues of triazolium carbenes, based on an extension of the notion that diazaphospholenes are analogous to Nheterocyclic carbenes (Figure 1).16 Only a handful of references to triazaphospholenes are known to us, and no examples are employed in catalysis.17 We envisioned formation of triazaphospholenes by the reaction of an amidrazone with a phosphorus trihalide in the presence of an acid scavenger. A variety of amidrazones are known, but many are only reported as intermediates, and not isolated.18 In our initial explorations, we chose to react bulky amidrazone 1, isolable as a free base, with phosphorus tribromide in the presence of triethylamine.19 This reaction cleanly provided triazaphospholene bromide 2a, the structure of which was verified by a single crystal X-ray crystallography experiment (Scheme 1). We next explored the formation of triazaphospholene hydrides. Bromide 2a could be transformed to alkoxide 3 by treatment with sodium benzyloxide in toluene. While exposure of alkoxytriazaphospholene 3 to HB(pin) in CH3CN did not result in a reaction, exposure to the more reactive HB(cat) resulted in the formation of a P−H bond, as evidenced by the
etal-free reductions of unsaturated organic molecules represent a burgeoning field. This is both due to increasing environmental, economic, and toxicological concerns associated with the use of transition metals in catalysis1 and, perhaps more crucially, because main-group-element based catalysts may provide differing reactivity profiles to transition metal catalysts.2 Frustrated Lewis pairs, most frequently containing boron Lewis acids, are preeminent catalysts for metal-free hydrogenation of imines.3 The use of terminal reductants other than hydrogen is often attractive for work on smaller scales. Until the past decade, hydroboration of imines has received little attention since seminal reports by Baker and co-workers involving the use of coinage metal catalysts.4 Imine hydroboration catalyzed by borenium cations was reported by Crudden and co-workers in 2012.5 Melen, Oestreich, and coworkers have recently reported imine hydroboration using specially tailored neutral Lewis acids.6 Diazaphospholenes represent an emerging class of reduction catalysts. Gudat and co-workers disclosed seminal reports of stoichiometric reduction reactions.7 Development of conditions for catalytic reduction was pioneered by Kinjo and co-workers, employing various terminal reductants for diazenes, carbonyl compounds, and carbon dioxide.8 Our group recently reported the convenient synthesis of diazaphospholene precatalysts from symmetrical diimines and demonstrated their utility in the reduction of imines and conjugate acceptors.9 Radosevich and co-workers have also reported imine reduction using the diazaphospholene motif.10 Kinjo and co-workers recently reported catalytic conjugate reduction of unsaturated esters.11 Despite the convenience of our reported precatalyst, we wished to explore more elaborate structures. The synthesis of nonsymmetrical diimines represents a significant challenge, limiting opportunities to explore nonsymmetrical diazaphospholene architecture.12 In addition, the synthesis of diazaphos© 2017 American Chemical Society
Received: August 30, 2017 Published: October 10, 2017 5565
DOI: 10.1021/acs.orglett.7b02695 Org. Lett. 2017, 19, 5565−5568
Letter
Organic Letters
Table 1. Reduction of an Imine Employing TAP Halides
Figure 1. Analogy of N-heterocyclic carbenes and diazaphospholenes with triazolium carbenes and triazaphospholenes.
Scheme 1. Synthesis and Reactivity of Triazaphospholene 2aa
entry
catalyst
solvent
conversion (%)
1 2 3 4 5 6 7 8 9 10
3 2h 2h 2a 2b 2c 2d 2e 2f 2g
THF THF MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN
0 44 >98 10 29 37 68 >98 74 64
Table 2. Hydroboration of Imine Substrate Scope Using 2ha
a
The thermal ellipsoids are scaled at the 30% probability level. Hydrogen atoms are omitted for clarity. Selected interatomic distances (Å): P1−Br1 2.4032(5), P1−N2 1.6810(14), P1−N3 1.6865(15).
a
Reaction performed in THF unless otherwise stated. bIsolated yield after column chromatography. cReaction performed in MeCN.
Figure 2. Synthesized triazaphospholene halides and alkoxide.
less hindered amidrazones.17,18,22 These were subsequently converted to the corresponding triazaphospholene halides (2b−2h, Figure 2) by cyclization with a phosphorus trihalide in the presence of triethylamine. Unfortunately, attempts to convert these compounds to benzyloxides did not give clean product mixtures. We then explored catalytic imine reductions in THF with HB(pin) as the terminal reductant using imine 5a as the substrate (Table 1). Due to the paucity of alkoxytriazaphospholenes, we decided to investigate the ability of the triazaphospholene halides shown in Figure 2 to serve directly as catalysts for reduction. As might be expected from the lack of reactivity with pinacolborane in a stoichiometric experiment, compound 3 was not a competent catalyst for reduction in an initial attempt (entry 1).
appearance of a diagnostic doublet (J = 154.0 Hz) at 67.4 ppm in a proton coupled 31P NMR experiment. While compound 4 was not isolated, this diagnostic doublet is at a comparable chemical shift range to a dimesityl diazaphospholene P−H signal (64.6 ppm).20 HB(cat) is not an ideal reductant for catalyst controlled imine reductions due to a significant background reaction with imines.21 We attributed the inability of HB(pin) to convert the alkoxytriazaphospholene to the corresponding hydride to the high steric hindrance around the phosphorus atom in triazaphospholene 3. Regardless of this result, the syntheses of 2a, 3, and 4 establish spectroscopic parameters for observing more reactive triazaphospholenes by NMR. Accordingly, we prepared several 5566
DOI: 10.1021/acs.orglett.7b02695 Org. Lett. 2017, 19, 5565−5568
Letter
Organic Letters Scheme 2. Additional Hydroboration Substrate Scope Using 2b to 2h (Bolded Bonds Indicate Former Unsaturation Position except for 10 and 11, Where They Indicate Absolute Stereochemistry)
Scheme 3. Proposed Catalytic Cycle and Enthalpies Calculated by DFTa
a
Reaction performed using 2e as catalyst. bReaction performed using 2h as catalyst. cProduct could not be isolated from sm by column chromatography; bracket indicates conversion (%). a
We chose compound 2h to investigate the activity of triazaphospholene halides. Gratifyingly, the combination of imine 5a, HB(pin), and 10 mol % of 2h in THF resulted in 44% conversion of the imine to amine 6a (entry 2). We subsequently observed quantitative conversion to 6a in acetonitrile (entry 3). Unlike alkoxide 3, triazaphospholene halide 2a did allow formation of some reduced product; however, conversion was poor, presumably due to its steric bulk (entry 4). We observed a clear trend where TAPs derived from more electron-rich hydrazines gave the highest conversion (entries 5−8). It should be noted that imine 5a was not hydroborated by our previously reported diazaphospholene precatalyst.9 We investigated the scope of imines for the reduction reaction (Table 2). Even though 2h and 2e afforded comparable reactivity, we chose 2h as the main catalyst for our scope study due to the ease of isolation of the corresponding amidrazone. Either THF or MeCN were acceptable solvents for reductions of alkyl imines 7b−7p to corresponding amines, while MeCN was the optimal solvent choice for reduction of aniline derived imine 5a, and the orthosubstituted imine 7a. Other ortho-substituted imines such as 7i, 7o, and 7p underwent clean reduction in THF. Alkyl amine derived imines all gave high conversions regardless of the ketone counterpart. Heterocycles such as pyridine and furan do not interfere with the reduction of imines 7m and 7n. A more hindered isobutyrophenone-derived imine 7c was also well tolerated. Cyclopropyl and alkyne groups were not affected during the reaction by ring-opening or hydroboration, respectively (entries 5 and 16). Two members of our substrate table are pharmaceuticals, fendiline (8h, entry 9) and rasagiline (8o,
Energies given in kcal/mol relative to starting materials.
entry 16), showing the applicability of this reduction method toward commercially important compounds. We additionally screened 2e (Scheme 2) in several reduction reactions. We found this was also an excellent catalyst for reduction of aniline derived imines 5a−5c, and hindered benzyl imine 7a. Notably, reduction of 5c, which did not go to completion with catalyst 2h, did go to completion with 2e. We also screened reduction of α, β-unsaturated aldehydes and observed exclusive 1,2 reductions to allylic alcohols 9a−9c where the geometry of the alkenes also remained intact. This contrasts with our previously reported diazaphospholene chemistry, where conjugate acceptors underwent 1,4 reduction or decomposition rather than 1,2 reduction.9 We also examined reduction of chiral imine 10. While diastereoselectivity was modest, a dependence of selectivity on catalyst structure was observed, with bulky mesityl containing catalyst 2d providing the highest selectivity for meso product 11. We next considered the mechanism of the reaction. Mixtures of 2h, imine 7b, and HB(pin) in CD3CN showed no evidence of formation of a P−H bond by 31P NMR spectroscopy. A 1:1 mixture of 2h and imine 7b in CD3CN showed downfield shifts in the 1H spectrum of the imine (approximately 0.05 ppm for the methyl and benzylic signals) indicating a possible interaction between 2h and 7b (see Supporting Information for spectra). Compound 2h is likely ionized in CD3CN since the methylene signals on the backbone do not demonstrate diastereotopic character, indicating a likely planarization of the phosphorus center. We investigated a potential mechanism using DFT calculations with the LC-ωPBE functional,23 and the exchange-hole dipole moment (XDM) dispersion model 5567
DOI: 10.1021/acs.orglett.7b02695 Org. Lett. 2017, 19, 5565−5568
Organic Letters
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(Scheme 3).24,25 Starting with a complex of triazaphospholene cation with imine (I), an interaction suggested by the NMR experiment, formation of the van der Waals prereaction complex II, where HB(pin) interacts with the nitrogen bearing a tert-butyl group, is feasible. Subsequent hydride transfer through a six-membered transition state is exothermic, with an activation barrier of 23.0 kcal/mol above complex II, leading to complex III. We investigated interaction of HB(pin) with other Lewis basic sites on the molecule, but found subsequent barriers to elimination were prohibitive. Finally, regeneration of the triazaphospholene cation, by release of the borylated amine, is accomplished through B−N bond formation, followed by dissociation of the borylated amine, with a modest barrier of 11.7 kcal/mol for this step. The overall process is exothermic by −27.4 kcal/mol. This process resembles the reduction process proposed for Itsuno/CBS type boranes,26 with the distinction that phosphorus serves as the Lewis acid in this case. In conclusion, we have demonstrated that triazaphospholene halides can be employed to catalyze imine hydroborations, including imines derived from aniline, which did not undergo reaction with diazaphospholene catalysts. We are currently synthesizing nonracemic triazaphospholenes for the exploration of asymmetric catalysis and investigating nonreductive transformations employing this motif.
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REFERENCES
(1) Egorova, K. S.; Ananikov, V. P. Angew. Chem., Int. Ed. 2016, 55, 12150−12162. (2) Wilkins, L. C.; Melen, R. L. Coord. Chem. Rev. 2016, 324, 123− 139. (3) (a) Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W. Angew. Chem., Int. Ed. 2007, 46, 8050−8053. (b) Stephan, D. W. Science 2017, 354, 1248. (4) Baker, R. T.; Calabrese, J. C.; Westcott, S. A. J. Organomet. Chem. 1995, 498, 109−117. (5) Eisenberger, P.; Bailey, A. M.; Crudden, C. M. J. Am. Chem. Soc. 2012, 134, 17384−17387. (6) Yin, Q.; Soltani, Y.; Melen, R. L.; Oestreich, M. Organometallics 2017, 36, 2381−2384. (7) Gudat, D.; Haghverdi, A.; Nieger, M. Angew. Chem., Int. Ed. 2000, 39, 3084−3086. (8) (a) Reduction of diazene: Chong, C. C.; Hirao, H.; Kinjo, R. Angew. Chem., Int. Ed. 2014, 53, 3342−3346. (b) Carbonyl reduction: Chong, C. C.; Hirao, H.; Kinjo, R. Angew. Chem., Int. Ed. 2015, 54, 190−194. (9) Adams, M. R.; Tien, C.-H.; Huchenski, B. S. N.; Ferguson, M. J.; Speed, A. W. H. Angew. Chem., Int. Ed. 2017, 56, 6268−6271. (10) Lin, Y.-C.; Hatzakis, E.; McCarthy, S. M.; Reichl, K. D.; Lai, T.Y.; Yennawar, H. P.; Radosevich, A. T. J. Am. Chem. Soc. 2017, 139, 6008−6016. (11) Chong, C. C.; Rao, B.; Kinjo, R. ACS Catal. 2017, 7, 5814− 5819. (12) (a) Schmid, D.; Bubrin, D.; Förster, D.; Nieger, M.; Roeben, E.; Strobel, S.; Gudat, D. C. R. Chim. 2010, 13, 998−1005. (b) Hans, M.; Lorkowski, J.; Demonceau, A.; Delaude, L. Beilstein J. Org. Chem. 2015, 11, 2318−2325. (13) Kliegman, J. M.; Barnes, R. K. Tetrahedron 1970, 26, 2555− 2560. (14) Chang, Y.-C.; Lee, Y.-C.; Chang, M.-F.; Hong, F.-E. J. Organomet. Chem. 2016, 808, 23−33. (15) (a) Enders, D.; Breuer, K.; Raabe, G.; Runsink, J.; Teles, J. H.; Melder, J.-J.; Ebel, K.; Brode, S. Angew. Chem., Int. Ed. Engl. 1995, 34, 1021−1023. (b) Enders, D.; Breuer, K.; Kallfass, U.; Balensiefer, T. Synthesis 2003, 1292−1295. (16) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307−9387. (17) (a) Hormuth, v. P. B.; Becke-Goehring, M. Z. Anorg. Allg. Chem. 1970, 372, 280−284. (b) Zhang, J.; Cao, Z. Synthesis 1985, 1985, 1067−1069. (c) Rodi, Y. K.; Lopez, L.; Malavaud, C.; Boisdon, M.-T.; Fayet, J.-P. Can. J. Chem. 1993, 71, 1200−1205. (d) Smadhi, M.; Abderrahim, R. Phosphorus, Sulfur Silicon Relat. Elem. 2010, 185, 2229−2232. (18) (a) Neilson, D. G.; Roger, R.; Heatlie, J. W. M.; Newlands, L. R. Chem. Rev. 1970, 70, 151−170. (b) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70, 5725−5728. (19) Amidrazone 1 has previously been used in the synthesis of boron heterocycles by Kinjo and co-workers: Lu, W.; Hu, H.; Li, Y.; Ganguly, R.; Kinjo, R. J. Am. Chem. Soc. 2016, 138, 6650−6661. (20) Burck, S.; Gudat, D.; Nieger, M.; Du Mont, W.-W. J. Am. Chem. Soc. 2006, 128, 3946−3955. (21) Enders, D.; Rembiak, A.; Seppelt, M. Tetrahedron Lett. 2013, 54, 470−473. (22) Liew, S. K.; Holownia, A.; Tilley, A. J.; Carrera, E. I.; Seferos, D. S.; Yudin, A. K. J. Org. Chem. 2016, 81, 10444−10453. (23) Vydrov, O. A.; Scuseria, G. E. J. Chem. Phys. 2006, 125, 234109. (24) Otero-de-la Roza, A.; Johnson, E. R. J. Chem. Phys. 2013, 138, 204109. (25) Johnson, E. R. The Exchange-Hole Dipole Moment Dispersion Model. In Non-covalent Interactions in Quantum Chemistry and Physics; Otero-de-la-Roza, A., DiLabio, G. A., Eds.; Elsevier: Amsterdam, 2017; Chapter 5, pp 169−194. (26) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551−5553.
ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02695.
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Letter
Crystallographic data for 2a (CIF) General considerations, reagents, ORTEP drawing for 2a, Cartesian coordinates for DFT calculations, NMR spectra of TAPs and products, references (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Michael J. Ferguson: 0000-0002-5221-4401 Erin R. Johnson: 0000-0002-5651-468X Alexander W. H. Speed: 0000-0002-8997-3807 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from Dalhousie University (start-up funding), NSERC Discovery Grant (A.W.H.S. and E.R.J.), the Nova Scotia Innovation and Research Scholarship and Killam Foundation (C.-H.T.), and the Nova Scotia Black and First Nations Entrance Scholarship (M.R.A.) are gratefully acknowledged. Dr. Mike Lumsden and Mr. Xiao Feng (Dalhousie University) are thanked for assistance with NMR spectroscopy and mass spectrometry, respectively. Prof. Jean Burnell (Dalhousie University) is thanked for a helpful suggestion. Compute Canada (Westgrid) is thanked for computational resources. 5568
DOI: 10.1021/acs.orglett.7b02695 Org. Lett. 2017, 19, 5565−5568
