Activation of the P–H bond by a frustrated Lewis pair and its application in catalytic Z-selective hydrophosphonylation of terminal ynones

Yizhen Liu, Xiaoting Fan, Zhen Hua Li* and Huadong Wang*
Department Shanghai Key Laboratory of Molecular Catalysis and Innovative Material, Department of Chemistry, Fudan University, Shanghai, 200433, China. E-mail: huadongwang@fudan.edu.cn

Received 29th June 2017 , Accepted 19th July 2017

First published on 19th July 2017


The frustrated Lewis pair (FLP) comprised of B(C6F5)3 and 1,2,2,6,6-pentamethylpiperidine (PMP) can efficiently catalyze Z-selective hydrophosphonylation of terminal ynones with a Z/E selectivity of up to 20[thin space (1/6-em)]:[thin space (1/6-em)]1. Mechanistic studies suggest that the trans arrangement of the phosphite nucleophilic attack and hydrogen bond formation on the alkyne moiety is responsible for the observed Z-selectivity.


Hydrophosphonylation reactions1 have emerged as a powerful tool for the synthesis of phosphonate compounds which are widely applied in organic synthesis,2 biochemistry3 and material sciences.4 One of the mostly applied hydrophosphonylation reagents is dialkyl phosphonate which often functions as a phosphorus nucleophile in the reaction process. As the equilibrium of phosphonate–phosphite tautomerization strongly favors the unreactive phosphonate form (eqn (1)), strong bases are usually required to shift the equilibrium to the more nucleophilic phosphite form.5 Despite the success of this strategy in hydrophosphonylation of aldehydes, ketones, imines and electron deficient olefins,1a,b there has been no report of base promoted hydrophosphonylation of alkynes, possibly due to the low electrophilicity of alkyne substrates. An alternative strategy pioneered by Han and Takada provided the solution for alkyne hydrophosphonylation by employing transition metal (such as Ni, Rh and Pd) complexes as catalysts.1c,d It is believed that the catalytic cycle starts with the oxidative addition of the P–H bond to the transition metal center followed by alkyne insertion and subsequent reductive elimination. As a result, only the E-selective hydrophosphonylation product can be obtained with terminal alkynes. More recently, photoinduced hydrophosphonylation of terminal alkynes was also reported, which affords 1[thin space (1/6-em)]:[thin space (1/6-em)]1 Z/E mixtures.6 The selective synthesis of less thermodynamically favored (Z)-vinylphosphonate through hydrophosphonylation still remains a challenge.7
 
image file: c7cc05028c-u1.tif(1)

The concept of frustrated Lewis pairs (FLPs), recently developed by Stephan and Erker groups, provides a conceptually different strategy for E–H bond (such as H–H, B–H, C–H, Si–H and N–H) activation and reduction of unsaturated organic substrates.8 Surprisingly, so far no FLP mediated P–H bond activation has been reported. We envisioned that the coordination of a Lewis acid to the P[double bond, length as m-dash]O moiety of dialkyl phosphonate would allow a relatively weak base to deprotonate the P–H bond (Scheme 1). The resulting cation could then interact with the alkyne moiety to increase its electrophilicity, thus facilitating the nucleophilic attack by the phosphite anion. We speculated that, if the base is bulky enough to disfavor the syn addition, Z-hydrophosphonylation products could be obtained.


image file: c7cc05028c-s1.tif
Scheme 1 Working hypothesis for FLP-catalyzed Z-selective alkyne hydrophosphonylation.

To begin our investigation, we first examined the stoichiometric reaction of diethylphosphonate with an FLP comprised of B(C6F5)3 and 1,2,2,6,6-pentamethylpiperidine (PMP) which was recently applied as the catalyst for Mannich-type and amination reactions by the Wasa group.9 Upon addition of 1 eq. of PMP to a CH2Cl2 solution of the known B(C6F5)3–(EtO)2P(O)H adduct (1)10 at room temperature, a new species 2 was immediately formed along with 0.5 eq. of unreacted PMP and free (EtO)2P(O)H remaining in the reaction mixture (Scheme 2). Subsequently, by decreasing the molar ratio of PMP to 1 to 1[thin space (1/6-em)]:[thin space (1/6-em)]2, compound 2 was isolated as a white solid in 65% yield after 5 minutes of stirring at room temperature. The 11B NMR spectrum of compound 2 features two distinct signals in a 1[thin space (1/6-em)]:[thin space (1/6-em)]1 ratio, one as a singlet at δ = −2.62 ppm and the other as a doublet at δ = −15.06 ppm (1JB–P = 175 Hz). The former was assigned to a B(C6F5)3 moiety coordinating to an oxygen atom, and the latter to another B(C6F5)3 moiety coordinating to the phosphorus atom. This was corroborated by the 31P NMR signal at δ = 53.75 ppm as a quartet with the same 1JB–P coupling constant. The identity of 2 was also confirmed by HRMS analysis. Compound 2 is not stable in the presence of PMP and (EtO)2P(O)H. After stirring 2 with equimolar amounts of PMP and (EtO)2P(O)H in CH2Cl2 at room temperature for 3 days, compound 2 can be quantitatively converted to compound 3 which can be isolated in 75% yield after recrystallization. Compound 3 can also be synthesized directly from equimolar amounts of PMP and 1 after 3 days of stirring in similar yield. Compound 3 is characterized by a 11B NMR doublet signal at δ = −16.59 ppm and a 31P NMR quartet signal at δ = 54.67 ppm (1JB–P = 179 Hz), in agreement with a direct B–P connection. The structure of compound 3 was confirmed by an X-ray crystal structure analysis (Fig. 1). In the solid state, both the boron and phosphorus atoms in compound 2 show tetrahedral coordination geometries. The distance of the P–B bond is 2.026(2) Å, typical for a B(C6F5)3-phosphine adduct.11 A N⋯H⋯O hydrogen bond was also observed between the cation and anion (d(N–H) = 0.87(2) Å, d(O⋯H) = 1.87(2) Å). Therefore, compound 3 can be considered as a rare example of borane/amine stabilized phosphite. A related BH3/NEt3 stabilized phosphite [HNEt3][(MeO)2P(OBH3)] is known, although it was synthesized from trimethylsilyl stabilized phosphite instead of directly from dialkyl phosphonate.12


image file: c7cc05028c-s2.tif
Scheme 2 Reaction between PMP and 1.

image file: c7cc05028c-f1.tif
Fig. 1 Molecular structure of 3 (thermal ellipsoids are shown with 30% probability). Hydrogen atoms except N–H are omitted for clarity.

The formation of compound 2 possibly starts with the deprotonation of compound 1 with PMP, which leads to the formation of intermediate 4, an isomer of compound 3. As the phosphorus atom in 4 is likely more basic than the P[double bond, length as m-dash]O moiety in (EtO)2P(O)H, one B(C6F5)3 molecule will transfer from compound 1 to compound 4, yielding compound 2 and free (EtO)2P(O)H. In order to observe compound 4 in solution, we decided to increase the amount of (EtO)2P(O)H to suppress the B(C6F5)3 transfer. After 10 eq. of (EtO)2P(O)H and 1 eq. of PMP were added to a CD2Cl2 solution of 1, besides the signal for 2, a new signal was observed at 133.2 ppm in the 31P NMR spectrum (Fig. S1, ESI). This signal gradually disappeared at room temperature along with the appearance of the signal for 3. As this low field resonance is comparable to those reported for phosphite species,13 this signal was assigned to intermediate 4. To confirm this assignment, density functional theory (M06-2X)14 with the GIAO method15 was employed to calculate the chemical shift of 4 in the 31P NMR spectrum and the calculated value (130.7 ppm) matches nicely with that observed experimentally. Calculations were also carried out to compare the stability of isomers 3 and 4. Compound 3 was found to be 4.2 kcal mol−1 more stable than compound 4 in free energy at 298 K. As the thermodynamically favored 3 lacks the required nucleophilicity for hydrophosphonylation reactions, a relatively electron-deficient alkyne would be necessary to ensure that compound 4 undergoes nucleophilic addition on the alkyne moiety before it converts to compound 2 or 3. Therefore, we decided to choose ynones as hydrophosphonylation substrates. Although there is a recent report about hydrophosphonylation of the carbonyl moiety of ynones,16 chemoselective hydrophosphonylation of the alkyne moiety of ynones still remains unknown, despite that related (Z)-vinylphosphonate derivatives have shown interesting antibacterial activity.17

Phenylprop-2-yn-1-one (5a) was selected as the model substrate to evaluate the B(C6F5)3/PMP system. After stirring equimolar amounts of 5a and (EtO)2P(O)H with 10 mol% of B(C6F5)3 and PMP at room temperature for 24 hours in dichloromethane, vinylphosphonate 6a was obtained in 67% yield with a Z/E selectivity of 7[thin space (1/6-em)]:[thin space (1/6-em)]1. Increasing the loading of PMP to 30% resulted in improving the Z/E selectivity to 11[thin space (1/6-em)]:[thin space (1/6-em)]1. Further increasing the amount of base has little effect on the yield and selectivity. Replacing PMP with other organic bases, such as NEt3, 2,2,6,6-tetramethylpiperidine, 2,6-lutidine or pyridine, led to inferior results (see the ESI). A control reaction with only B(C6F5)3 or PMP as the catalyst showed no formation of 6a. After determining the optimal conditions, we investigated this FLP catalytic system with a series of different functionalized terminal ynones (Table 1). For aryl substituted ynones (entries 1–8), both electron donating and withdrawing groups are tolerated, with the latter showing better selectivity. A heteroaryl substituent, such as thiophenyl, is also compatible with the catalytic system (entry 8). Alkyl substituted ynones were also tested and the target vinylphosphonates were obtained in moderate yields with moderate to good selectivity (entries 9 and 10). However, internal ynones, such as pent-3-yn-2-one, showed no reactivity in this catalytic system.

Table 1 Hydrophosphonylation of terminal ynones

image file: c7cc05028c-u2.tif

Entry R Yielda (%) Z[thin space (1/6-em)]:[thin space (1/6-em)]Eb
a Isolated yields.b Z[thin space (1/6-em)]:[thin space (1/6-em)]E was determined via 31P NMR.c 1 equiv. of PMP was added.
1 image file: c7cc05028c-u3.tif 67 11[thin space (1/6-em)]:[thin space (1/6-em)]1
2 image file: c7cc05028c-u4.tif 82 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
3 image file: c7cc05028c-u5.tif 68 15[thin space (1/6-em)]:[thin space (1/6-em)]1
4 image file: c7cc05028c-u6.tif 63c 7[thin space (1/6-em)]:[thin space (1/6-em)]1
5 image file: c7cc05028c-u7.tif 64 13[thin space (1/6-em)]:[thin space (1/6-em)]1
6 image file: c7cc05028c-u8.tif 80 10[thin space (1/6-em)]:[thin space (1/6-em)]1
7 image file: c7cc05028c-u9.tif 72 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
8 image file: c7cc05028c-u10.tif 66 8[thin space (1/6-em)]:[thin space (1/6-em)]1
9 image file: c7cc05028c-u11.tif 55 19[thin space (1/6-em)]:[thin space (1/6-em)]1
10 image file: c7cc05028c-u12.tif 62 4[thin space (1/6-em)]:[thin space (1/6-em)]1


To shed light on the reaction mechanism, we tested the activity of compounds 2 and 3 for the hydrophosphonylation reaction and discovered that neither of them proved catalytically competent, thus ruling them out as catalytically relevant intermediates. To further investigate the reaction mechanism, DFT (M06-2X) calculations were performed with ynone 5i chosen as the substrate (Fig. 2). Our study suggested that upon mixing B(C6F5)3, PMP, (EtO)2P(O)H and 5i, adduct 1 is formed, which is −19.2 kcal mol−1 more stable than the free B(C6F5)3 and (EtO)2P(O)H in free energy. Subsequently, the P–H bond is deprotonated by PMP to afford compound 4, which needs to overcome a free-energy barrier of 10.8 kcal mol−1. The next step is the nucleophilic attack of the phosphite anion of 4 on the terminal carbon of the alkyne moiety of 5i with the concomitant formation of a hydrogen bond between the internal carbon atom of the alkyne moiety and the nitrogen atom of PMP to produce intermediate IM1. This step proceeds through the transition state TS2 with a free-energy barrier of 17.7 kcal mol−1. The hydrogen bond was found trans to the newly formed C–P bond and this orientation is crucial for the Z/E selectivity: transformation from IM1 to B(C6F5)3 coordinated phosphate (Z)-7 and PMP is essentially barrierless,18 whereas the conversion of IM1 to (E)-7 and PMP needs to go through TS3 with a free-energy barrier of 6.1 kcal mol−1. The release of final product (Z)-6i and (E)-6i needs to overcome a binding energy of 25.0 and 21.5 kcal mol−1, respectively, and this step appears as the rate-limiting step. Although the overall free-energy barrier for the formation of (Z)-6i is 3.5 kcal mol−1 higher than (E)-6i, the ratio of (Z)-7 to (E)-7 in the reaction mixture also affects the selectivity of the final products. As the conversion of (Z)-7 to (E)-7 requires to surpass a relatively high free-energy barrier (29.6 kcal mol−1) through IM1, the ratio of (Z)-7 to (E)-7 is largely defined by the energy difference between TS3 and TS3′, which is about 6.1 kcal mol−1.18 Therefore, the formation of (Z)-6i is still favored over (E)-6i by a ratio of 80[thin space (1/6-em)]:[thin space (1/6-em)]1 (for calculation details see the ESI), in relatively good agreement with the experimental Z/E ratio of 19[thin space (1/6-em)]:[thin space (1/6-em)]1.


image file: c7cc05028c-f2.tif
Fig. 2 The Gibbs free energy profile at 298 K for the reaction between 5i, (EtO)2P(O)H, PMP and B(C6F5)3.

In summary, we have found that the frustrated Lewis pair comprised of B(C6F5)3 and PMP can activate the P–H bond of a dialkyl phosphonate and shift the equilibrium between phosphonate and phosphite by the formation of a borane/amine stabilized phosphite. This frustrated Lewis pair can be applied as a catalyst to realize unprecedented Z-selective hydrophosphonylation of terminal ynones. This reaction is metal-free and shows good chemo-, regio- and Z/E selectivities under ambient conditions. Our mechanistic studies revealed that the trans arrangement of the phosphite nucleophilic attack and hydrogen bond formation on the alkyne moiety is responsible for the observed Z-selectivity of this hydrophosphonylation reaction.

Financial support from the National Natural Science Foundation of China (21372048, 21573044, 21672039) and the Shanghai Science and Technology Committee (16DZ2270100) is gratefully acknowledged. We also thank the High Performance Computer Center of Fudan University for the allocation of computing time. We thank Dr Yue-Jian Lin for help with crystallographic studies.

There are no conflicts to declare.

Notes and references

  1. (a) L. Coudray and J.-L. Montchamp, Eur. J. Org. Chem., 2008, 3601 CrossRef CAS PubMed; (b) D. Zhao and R. Wang, Chem. Soc. Rev., 2012, 41, 2095 RSC; (c) Q. Xu and L.-B. Han, J. Organomet. Chem., 2008, 696, 130 CrossRef; (d) M. Tanaka, Top. Organomet. Chem., 2013, 43, 167 CrossRef CAS.
  2. C. S. Demmer, N. Krogsgaard-Larsen and L. Bunch, Chem. Rev., 2011, 111, 7981 CrossRef CAS PubMed.
  3. A. Mucha, P. Kafarski and L. Berlicki, J. Med. Chem., 2011, 54, 5955 CrossRef CAS PubMed.
  4. G. J. Schlichting, J. L. Horan, J. D. Jessop, S. E. Nelson, S. Seifert, Y. Yang and A. M. Herring, Macromolecules, 2012, 45, 3874 CrossRef CAS.
  5. B. Janesko, H. C. Fisher, M. J. Bridle and J.-L. Montchamp, J. Org. Chem., 2015, 80, 10025 CrossRef CAS PubMed.
  6. A. Dondoni and A. Marra, Org. Biomol. Chem., 2015, 13, 2212 CAS.
  7. Kuramshin et al. reported Z-selective hydrophosphonylation of phenylacetylene catalyzed by Mo(CO)6 under harsh reaction conditions (>140 °C). See: A. I. Kuramshin, A. A. Nikolaev and R. A. Cherkasov, Mendeleev Commun., 2005, 155 CrossRef CAS . So far we have not been able to reproduce this result in our laboratory (see the ESI).
  8. (a) G. C. Welch, R. R. S. Juan, J. D. Masuda and D. W. Stephan, Science, 2006, 314, 1124 CrossRef CAS PubMed; (b) D. W. Stephan and G. Erker, Angew. Chem., Int. Ed., 2010, 49, 46 CrossRef CAS PubMed; (c) D. W. Stephan and G. Erker, Angew. Chem., Int. Ed., 2015, 54, 6400 CrossRef CAS PubMed.
  9. (a) J. Z. Chan, W. Yao, B. T. Hastings, C. K. Lok and M. Wasa, Angew. Chem., Int. Ed., 2016, 55, 13877 CrossRef CAS PubMed; (b) M. Shang, X. Wang, S. M. Koo, J. Youn, J. Z. Chan, W. Yao, B. T. Hastings and M. Wasa, J. Am. Chem. Soc., 2017, 139, 95 CrossRef CAS PubMed.
  10. M. A. Beckett, D. S. Brassington, M. E. Light and M. B. Hursthouse, Dalton Trans., 2001, 1768 RSC.
  11. G. C. Welch, R. Prieto, M. A. Dureen, A. J. Lough, O. A. Labeodan, T. Höltrichter-Rössmann and D. W. Stephan, Dalton Trans., 2009, 1559 RSC.
  12. T. Wada, M. Shimizu, N. Oka and K. Saigo, Tetrahedron Lett., 2002, 43, 4137 CrossRef CAS.
  13. (a) Y. Zhao and D. G. Truhlar, J. Chem. Phys., 2006, 125, 194101 CrossRef PubMed; (b) Y. Zhao and D. G. Truhlar, J. Phys. Chem. A, 2006, 110, 5121 CrossRef CAS PubMed.
  14. (a) Y. Zhao and D. G. Truhlar, J. Chem. Phys., 2006, 125, 194101 CrossRef PubMed; (b) Y. Zhao and D. G. Truhlar, J. Phys. Chem. A, 2006, 110, 5121 CrossRef CAS PubMed.
  15. K. Wolinski, J. F. Hilton and P. Pulay, J. Am. Chem. Soc., 1990, 112, 8251 CrossRef CAS.
  16. D. Uraguchi, T. Ito, S. Nakamura and T. Ooi, Chem. Sci., 2010, 1, 488 RSC.
  17. P. W. Smith, A. J. Chamiec, G. Chung, K. N. Cobley, K. Duncan, P. D. Howes, A. R. Whittington and M. R. Wood, J. Antibiot., 1995, 48, 73 CrossRef CAS PubMed.
  18. The lower of the free energy of the transition state than the intermediate is caused by the rigid-rotor and harmonic-oscillator approximation since the potential energy of the transition state is just 0.8 kcal mol−1 higher than that of the intermediate.

Footnote

Electronic supplementary information (ESI) available. CCDC 1543215. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7cc05028c

This journal is © The Royal Society of Chemistry 2017