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Effects of base strength on the copper-catalyzed cycloisomerization of propargylic acetates to form indolizines: A DFT study
Tetrahedron 73 (2017) 6092e6100
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Tetrahedron journal homepage: www.elsevier.com/locate/tet
Effects of base strength on the copper-catalyzed cycloisomerization of propargylic acetates to form indolizines: A DFT study Binfang Yuan, Rongxing He, Wei Shen, Ming Li* Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 June 2017 Received in revised form 18 August 2017 Accepted 8 September 2017 Available online 8 September 2017
Our calculations find that the base strength is the primary factor that controls the catalytic capability of cocatalysts CH3CN, Propargylic acetates (1a) and Et3N. In the proton-transfer process, the trend of catalytic activity increases in the order: Et3N > 1a > CH3CN, which matches well with the enhanced trend of base strength (Et3N > 1a > CH3CN). Et3N is the most appropriate for the present Cu-catalyzed cycloisomerization of propargylic acetates, which is in agreement with the experimental phenomena. Besides, our calculations give a reasonable explanation for the effects of terminal substituents (H- vs. Ph-) of alkyne on the catalytic reaction. © 2017 Elsevier Ltd. All rights reserved.
Keywords: DFT Proton-shuttle Proton-transfer Base strength Indolizines Copper-catalyzed
1. Introduction Indolizine skeletons are found in the large variety of biologically active substances,1 including synthetic pharmaceuticals2 and naturally occurring alkaloids.3 They represent a significant class of nitrogen-fused heterocycles, which have been employed as antiinflammatory agents,4 anti-HIV agents,5 H3 receptor antagonists,6 CNS depression agents7 and molecular probes8 etc. In the field of materials science, indolizines and its derivatives are also widely useful in the improvement of dyes,9 organic light emitting devices (OLEDs)10 and biological markers11 due to their unique photophysical properties. Based on the above reasons, the development of especially efficient methods for rapid construction of indolizines is still highly attractive.12 Generally, the transition metal is employed as a catalyst to synthesize indolizines owing to its relatively mild reaction conditions with the high efficiency. It is worth mentioning that the transition metal-catalyzed cycloisomerization is one of the important approaches to form indolizines and its derivatives.12d,13 For instance, the transition metal (Ag, Cu or Au)catalyzed cycloisomerization of propagyl heterocycles to the formation of 1,3-disubstituted N-fused heterocycles in good to
* Corresponding author. E-mail address: [email protected] (M. Li). http://dx.doi.org/10.1016/j.tet.2017.09.007 0040-4020/© 2017 Elsevier Ltd. All rights reserved.
excellent yields at the room temperature was reported by Gevorgyan et al. (see Eq 1 of Scheme 1).14 Subsequently, Gevorgyan's group15 presented an interesting Cu-catalyzed cyclization of propargylic mesylates to generate indolizines with low temperature (see Eq 2 of Scheme 1). Recently, an efficient Pd-catalyzed cross-coupling/cycloisomerization of 3-(2-pyridyl) propargyl carbonates with organoboronic acids has been developed by Zhang et al. (see Eq 3 of Scheme 1).12c They provided a straightforward route for the synthesis of 1,3-disubstituted indolizines with a wide variety of substituents. What's more, Liu's group16 found that the reaction strictly relied on the presence of base in the Pd/Cucatalyzed cross coupling/cycloisomerization of propargyl amines or amides with various haloheteroaromatic substrates under mild reaction conditions (see Eq 4 of Scheme 2). They believed that a suitable base could facilitate a propargyl-allenyl isomerization to an allenic intermediate or serve as a good ligand to stabilize the copper intermediates. Similarly, Liu et al.17 observed that the basic additive played an important accelerating role for the copper-catalyzed cycloisomerization of 2-pyridyl-substituted propargylic acetates and its derivatives (see Eq 5 of Scheme 2). Besides, Hu et al.18 pointed out that the use of base was advantageous for increasing reaction yield in the synthesis of indolizines by the coppercatalyzed cerobic oxidative dehydrogenative aromatization (see Eq 6 of Scheme 2). The similar fact has also been proposed by Jia's
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Table 1 The copper-catalyzed cycloisomerization of 2-pyridylsubstituted propargylic acetates to form C-1 oxygenated indolizines reported by Liu's group.
Scheme 1. Construction cycloisomerization.
of
indolizines
via
transition
metal-catalyzed
Entry
Substrate
1 2 3
1a 1a 1b
Additive
Time
Product
Yield (%)
Et3N Et3N
18 h 2h 15 min
2a 2a 2b
63 82 89
The role of substrate 1a (propargylic acetates) in the catalytic reaction. Whether the trace amounts of H2O (presented in the solvent) or the solvent CH3CN play a similar role? b) The accelerating effect of additive Et3N on the reaction. c) The difference of CH3CN, 1a, and Et3N in catalytic capacity for the proton-transfer reaction. More importantly, what causes this difference? d) The influence of terminal substituents (H- vs. Ph-) of alkyne on the reactivity.
2. Computational details
Scheme 2. The use of base in the construction of indolizines.
group12d in the Pd-catalyzed three-component cascade reaction to form densely functionalized indolizines in moderate to good yields (see Eq 7 of Scheme 2). On the basis of the above works, the base has a great influence on the synthesis of indolizines with the transition metal as a catalyst. However, the detailed mechanism of chemical reactions affected by bases (such as substrate, H2O, solvent or additive with the nature of Lewis/Bronsted base) is not illustrated clearly up to date, which is worthy of in-depth study by the experimental and theoretical methods. Herein, we choose the Cu-catalyzed cycloisomerization of 2pyridyl-substituted propargylic acetates to form C-1 oxygenated indolizines in CH3CN medium (as shown in Table 1) as a simple research system17 to better explore the following issues in detail: a)
In this work, all calculations are performed with the Gaussian 09 program suits.19 All geometric structures (including the intermediates and the transition states) are fully optimized using the Becke three-parameter hybrid functional (B3LYP)20 in the framework of density-functional theory (DFT).21 B3LYP method has been applied in the mechanistic studies of catalytic reactions successfully.22 The double-z basis set (6-31G*)23 is employed for C, N, O, and H elements except for Cu and I, which are described by the effective core potential double-z basis set (LanL2DZ).24 This combination of basis sets (6-31G* and LanL2DZ) has also been proven to be reliable in numerous theoretical simulations of mechanisms of metal-catalyzed reactions.22d,25 As a further test, several other functionals (BLYP, B3P86, BHandHLYP and M06) together with the 6-31G* basis set and several other basis sets (6-31G**, 6-31 þ G* and 6-311G*) together with the B3LYP functional are all used to compare and avoid the shortcomings of DFT functionals and basis sets, respectively (see Tables S1 and S2). Frequency calculations are carried out at the same level of theory (B3LYP/6-31G*) to identify all of the stationary points as minima (zero imaginary frequency) or transition states (one imaginary frequency). Furthermore, the intrinsic reaction coordinate (IRC) calculations26 are performed to confirm the connectivity of these transition states to the right intermediates. Solvent effect of acetonitrile (CH3CN) is simulated using a polarizable continuum model (PCM)27 through a selfconsistent reaction field (SCRF) method28 based on the gas phase optimized structures. The solution-phase single point energies are calculated with the larger functional and basis set level (PCM// M06-2X/6-311þþG**). M06-2X has been applied successfully to investigate the mechanisms of several catalytic organic reactions.29 In addition, the effect of dispersion on the energy is also considered by M06-2X-D3 calculation, but the calculation result of M06-2X-D3 is close to that of M06-2X (see Table S3). Herein, the solution-phase Gibbs free energy is determined by adding the solution-phase single point energy and gas-phase thermal correction to the Gibbs free energy obtained from the vibrational frequency calculation. Unless special emphasis, all the discussed energies are relative solution-phase Gibbs free energies (Grel, kJ/mol) in our
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Fig. 1. Energy profile of the copper-catalyzed cycloisomerization of propargyl acetates to form indolizines without the assistance of cocatalysts in CH3CN solvent.
present calculations, and the relative solution-phase Gibbs free energy of reaction substrate 1 (1a or 1b) is set as zero energy. 3. Results and discussion 3.1. Function of substrate 1a In this section, we first explore the reaction mechanism of Cucatalyzed cycloisomerizations of propargylic acetates to form indolizines in CH3CN medium,17 and then a detailed discussion is presented to understand the role of substrate 1a in the promotion of this reaction. Mechanism of synthesis of indolizines catalyzed by CuI. DFTcomputed energy profile for the Cu-catalyzed synthesis of indolizines is given in Fig. 1, and the optimized structures along the reaction path are collected in Fig. 2. The reaction starts with
coordination of CuI to the C1eC2 triple bond of 1a (other coordination modes are described in Schemes S1-3 of supporting information), forming a new coordination compound ina1. Related mechanism has been reported by Liu and Gevorgyan.14,17 Fig. 1 shows that the formation of complex ina1 is exergonic by 54.1 kJ/ mol in CH3CN medium. In ina1, the C1eC2 bond has lost a little of its triple-bond characters due to the coordination of CuI, and now its bond length is 1.225 Å (1.206 Å in 1a). It means that the C1eC2 triple bond has been activated, which is favorable for the subsequent cyclization reaction. The heterocyclic-N1 of 1a, which acts as an electron donor, attacks the activated C1eC2 triple bond to produce a cyclic intermediate ina2 via a transition state tsa1. In ina2, the C1eC2 bond is extended to 1.350 Å with the formation of N1eC1 bond (1.444 Å). It should be noted that the hydrogen-bond C3eH1/O1 (carbonyl O of 1a) exists in ina2, and the bond lengths of C3eH1 and H1/O1 are 1.099 and 2.411 Å, respectively.
Fig. 2. Optimized structures of the copper-catalyzed cycloisomerization of propargylic acetates without the assistance of cocatalysts in CH3CN solvent.
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Influenced by hydrogen-bond, the following reaction is a carbonyl O1-assisted 1,2-Hþ transfer process (see ina2 to 2a). In the Hþ-shift strategy, H1 is transferred from C3 to C2 with the regeneration of CuI (as the catalyst), passing through a transition state tsa2-1. The bond lengths of H1/O1, C3eH1 and H1eC2 are 2.063, 1.350 and 1.313 Å in tsa2-1, respectively. In principle, 2a can also be gained from ina2 through the carbonyl O1-assisted two-step Hþ-transfer reaction (see Fig. S1). In this case, the carbonyl O1 captures a proton H1 from C3, and then H1 is migrated to C2 with the leaving of CuI. However, the rate-limiting free energy barrier of the carbonyl O1assisted stepwise proton-transfer reaction is 112.1 kJ/mol, which is 10.5 kJ/mol higher than that of 1,2-Hþ shift process (112.1 vs. 101.6 kJ/mol, see Fig. S1 vs. Fig. 1). As illustrated in Fig. 1, DFT-computed energy profile of the CuIcatalyzed synthesis of indolizines includes two elementary reactions, an intramolecular cyclization and a 1,2-Hþ shift process. Their required free energy barriers are 63.5 and 101.6 kJ/mol, respectively. It is obvious that 1,2-Hþ shift process is the ratelimiting step of the whole catalytic reaction, and the rate-limiting free energy barrier is 101.6 kJ/mol. However, 101.6 kJ/mol is unfavorable for the present synthetic reaction (18 h, rt, see Entry 1 of Table 1). In our previous studies,25b,30 we have found that the reactant MeOH, which has the nature of Bronsted/Lewis base, can serve as a proton-shuttle to assist the proton migration. Inspired by these works, we turn our attention to the acceleration of substrate 1a (as a cocatalyst) on the catalytic reaction in the following sections. The acceleration of 1a on the reaction. Our calculated results indicate that the carbonyl O-assisted 1,2-Hþ shift process (tsa2-1) can be changed to the heterocyclic N-assisted two-step protontransfer reaction (another molecule 1a as the cocatalyst, heterocyclic N as the site of assistance), which is quite similar to the proton-transfer processes in proton-transport catalysis22b,31 and many enzyme-catalyzed reactions.32 What's more, the present heterocyclic N-assisted Hþ-transfer strategy can well explain the experimental phenomena17 (see Entry 1, in Table 1). The energy profile of heterocyclic N-assisted proton-transfer reaction is shown in Fig. 3, and the corresponding geometric structures are collected in Fig. 4. From Fig. 3, ina2 seizes a molecule 1a via a hydrogen-bond of C3eH1/N2 (C3eH1 ¼ 1.106 Å, H1/N2 ¼ 2.351 Å), leading to the
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generation of a new complexes ina3-2. The relative free energy of ina3-2 is only 28.3 kJ/mol higher than that of ina2, indicating that ina3-2 can be obtained smoothly at the room temperature.17 The next reaction is heterocyclic N-mediated deprotonation/protonation process. In the deprotonation of C3 (involving the C3eH1 bond cleavage), H1 is migrated from C3 to N2 through a transition state tsa2-2 to produce a new compound ina4-2. In the protonation of C2 (involving the formation of C2eH1 bond), H1 is shifted from the protonated heterocyclic N2e Hþ to C2 via a transition state tsa3-2, generating products 2a with the regeneration of catalyst CuI and cocatalyst 1a. From Figure 3, 1a acts not only as the reactant to synthesize the products 2a, but also as the proton-shuttle to assist H1 shift from C3 to C2, passing through the two-step Hþ-transfer reaction. The required free energy barrier of proton-transfer process is lowed to 88.3 kJ/mol, which is 13.3 kJ/mol lower than that of 1,2-Hþ shift ones (88.3 vs. 101.6 kJ/mol, see Fig. 3 vs. Fig. 1). The rate-limiting step is still the proton-transfer process, and the rate-limiting energy barrier is 88.3 kJ/mol. Therefore, the heterocyclic N-assisted reaction is favorable for the synthesis of 2a (see Table 1). Furthermore, the assistance of carboxyl O of 1a (as the cocatalyst) is considered, while the required free energy barrier for carboxyl Oassisted deprotonation process of C3 is as high as 120.6 kJ/mol (see Fig. S3). Besides, the propargyl-allenyl isomerization with the assistance of 1a, in which the deprotonation of H1 takes place before the ring-closure between N1 and C1 (tsa1), is taken into account. We try our best to find this reaction, but we failed (see Scheme S2). Effects of trace H2O and solvent CH3CN on the Hþ-transfer process. The previous works have reported that the trace amount of H2O30,33 and solvent33a,34 have a significant influence on the Hþtransfer reaction. Inspired by these studies, the effects of H2O and solvent CH3CN are further explored. The calculated energy profiles for H2O- and CH3CN-mediated Hþ-shift reactions are showed in Figs. 5 and 6, and the geometries of involving intermediates and transition states are given in Fig. S5. Fig. 5 shows that the H2Oassisted Hþ-transfer reaction includes a deprotonation/protonation process, which is similar to the heterocyclic N-assisted case (see Fig. 3). The corresponding reaction free energy barriers are 127.0 (tsa2-3) and 87.8 (tsa3-3) kJ/mol, respectively. However, only one
Fig. 3. Energy profile of the proton-shift reaction with the assistance of heterocyclic N of 1a (as the cocatalyst) in CH3CN solvent.
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Fig. 4. Optimized structures of the proton-shift reaction with the assistance of heterocyclic N of 1a (as the cocatalyst) in CH3CN solvent.
Fig. 5. Energy profile of the H2O-assisted proton-shift reaction in CH3CN solvent.
transition state tsa2-4 (see Fig. 6) is located in the CH3CN-assisted Hþ-shift, and its required free energy barrier is 124.6 kJ/mol. Obviously, both H2O- and CH3CN-assisted Hþ-transfer reactions are inherently disfavored as compared with the heterocyclic N-assisted ones (127.0 and 124.6 vs. 88.3 kJ/mol). Besides, the effects of heterocyclic N þ H2O, carboxyl O þ H2O, CH3CN þ H2O and 2H2O on the proton-transfer process are all studied, and their required free energy barriers are 102.0, 123.3, 117.3 and 112.7 kJ/mol for the deprotonation process of C3, respectively, indicating that their assistance are negative for the Hþ-shift reaction (see Figs. S6e9). 3.2. Effect of additive Et3N on the catalytic reaction In experiments, Liu and his workers17 reported that the
moderate yield (63%) was obtained in the absence of additive, while the high yield (82%) could be gained when Et3N acted as a additive (see Entries 1 and 2, in Table 1). How to understand this difference in the yields? We begin to study the effect of Et3N on the mechanism of Cu-catalyzed cycloisomerization reaction. The influence of Et3N on the intramolecular cyclization is considered firstly, as illustrated in Scheme 3. Et3N molecule coordinates with Cu(I) as a ligand. This coordination does not alter the reaction mechanism of intramolecular cyclization reaction, and the calculated free energy barrier is 70.4 kJ/mol, which is 6.9 kJ/mol higher than that of the case without Et3N as the ligand (70.4 vs. 63.5 kJ/mol). Thus, the effect of Et3N is negative on the intramolecular cyclization process. The previous reports35 have pointed out that the additive with the nature of Lewis/Bronsted base can help Hþ migration to
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Fig. 6. Energy profile of the CH3CN-assisted proton-shift reaction in CH3CN solvent.
Scheme 3. Comparison of the free energy barriers for the cyclization process without and with Et3N as the ligand in CH3CN medium.
promote the reaction yield. Encouraged by these studies, the assisting Hþ-transfer function of Et3N is discussed in this section. The calculated energy profile for Et3N-assisted two-step protontransfer reaction is described in Fig. 7, and the geometries of involving intermediates and transition states are collected in Fig. 8. Fig. 7 shows that the Et3N-assisted reaction mechanism is similar to
the heterocyclic N-assisted proton-transfer ones, including a deprotonation/protonation process. Their required free energy barriers are 46.5 and 25.6 kJ/mol, respectively. It is clear that the rate-limiting step of the whole Cu-catalyzed reaction is changed from the Hþ-shift to the intramolecular cyclization with the assistance of Et3N (46.5 vs. 63.5 kJ/mol, see Figs. 1 and 7). The ratelimiting free energy barrier is reduced to 63.5 kJ/mol, which is 24.8 kJ/mol lower than that of the case with 1a as the cocatalyst. (63.5 vs. 88.3 kJ mol). The difference value of 24.8 kJ/mol can give a reasonable explanation on the distinct yields (see Entries 1 (62%) vs. 2 (82%), in Table 1). It is worth mentioning that the propargylallenyl isomerization may take place before the ring-closure when Et3N is added to the reaction system (see Scheme S3). There are five kinds of possibilities for the propargyl-allenyl isomerization (from Path I to Path V). The activation free energy barriers of Paths IeV are 73.3, 131.9 (or 145.8), 80.7, 82.8 and 96.3 kJ/mol, respectively, which are 9.8, 68.4 (or 82.3), 17.2, 19.3 and 32.8 kJ/mol higher than the rate-limiting free energy barrier of 63.5 kJ/mol (the ring-closure process tsa1, see Figs. 1 and 7). Therefore, the base-induced propargyl-allenyl isomerization is not favored over ring-closure reaction. Besides, the effect of Et3N þ H2O on the proton-transfer process is also explored, and the reaction
Fig. 7. Energy profile of the Et3N-assisted two-step proton-shift reaction in CH3CN solvent.
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Fig. 8. Optimized structures of the Et3N-assisted two-step proton-shift reaction in CH3CN solvent.
Table 2 Comparison of the free energy barriers of CH3CN-, 1a-, and Et3N-assisted Hþ-shift in CH3CN medium. Species
tsa2-X tsa3-X
Free energy barriers (kJ/mol) CH3CN-assisted direct 1,2-Hþ shift
1a-assisted stepwise Hþ-transfer
Et3N-assisted stepwise Hþ-transfer
124.6
88.3 27.0
46.5 25.6
X ¼ 2, 4 or 5.
free energy barrier for the deprotonation of C3 is 88.2 kJ/mol (see Fig. S10). It is clear that the acceleration of Et3N þ H2O is weaker than that of Et3N (88.2 vs. 46.5 kJ/mol). 3.3. Effect of base strength on the Hþ-transfer Our calculated results indicate that all the co-catalysts (such as 1a or Et3N) can play the role of proton-transfer shuttle to help H1 migration from C3 to C2, but their catalytic abilities exhibit a significant difference. What causes this difference? Herein, CH3CN-, 1a (heterocyclic N-) and Et3N-assisted Hþ-shift reactions are chosen as a studied system to explore this interesting issue. According to Tables S4 and S5, both the dissociation energies and the Wiberg bond indices of HeN3, HeN2 and HeN4 bonds in CH3CNeHþ, 1aHþ and Et3NeHþ show that the bond energy of HeN4 (HeN3) is the maximum (minimum), and the enhanced trend of bond energy is HeN4 > HeN2 > HeN3. This means that Bronsted acid CH3CNeHþ is easy to lose a proton when compared with heterocyclic NeHþ and Et3NeHþ. On the contrary, Bronsted base Et3N is more likely to obtain a proton than CH3CN or 1a. The order of base strength is Et3N > 1a > CH3CN, which does match with the increased trend of bond energy HeN4 > HeN2 > H1eN3. From Fig. 6, only one transition state (the free energy barrier 124.6 kJ/mol) is located for the CH3CN-assisted Hþ-shift, it may be that CH3CN is too weak base to abstract H1 at C3. When 1a or Et3N acts as the proton-shuttle, the reaction mechanism of proton-transfer is changed to the deprotonation/protonation strategy (see Figs. 3 and 7). The deprotonation
of C3 is the rate-determining step of proton-transfer reaction, and the rate-determining free energy barriers are 88.3 (tsa2-2) and 46.5 (tsa3-5) kJ/mol, respectively (see Table 2). By comparing the above free energy barriers (124.6 vs. 88.3 vs. 46.5 kJ/mol), a general regularity can be obtained that the order of catalytic ability is Et3N > 1a > CH3CN in the H1-transfer process, matching well with the enhanced trend of base strength Et3N > 1a > CH3CN. Therefore, the base strength of proton-shuttles is revealed to be the primary factor that controls the catalytic activities of CH3CN, 1a and Et3N in the proton-shift reaction. Our calculated results show that Et3N is the most appropriate proton-shuttle reagent, which is in agreement with the experimental results.
3.4. Effect of terminal substituents on the catalytic reaction In experiments,17 Liu et al. observed that the reaction time was shortened to 15 min, and the reaction yield was increased to 89% with the substitution of H group by Ph group (see Entries 2 and 3, in Table 1). How terminal substituent (H- vs. Ph-) of alkyne affects the catalytic reaction. We will explain this issue in the subsequent calculations. Similar to the CuI-catalyzed reaction with H group as the substituent, the CuI-catalyzed reaction using Ph group as the substituent also includes an intramolecular cyclization and an Et3Nassisted stepwise Hþ-transfer process. Their required free energy barriers are 51.3, 46.0 and 25.7 kJ/mol, respectively (see Fig. 9), and the rate-determining step still locates in the intramolecular cyclization. However, the rate-determining free energy barrier is reduced to 51.3 kJ/mol, which is 12.2 kJ/mol lower than that the case with H group as the substituent (51.3 vs. 63.5 kJ/mol). It is obvious that Ph group is favorable for the reaction in energy with respect to H group. Our calculations give a reasonable explanation on the experimental phenomena (see Entries 2 (82%, 2 h) vs. 3 (89%, 15min), in Table 1). It is worth mentioning that the effect of substituent (H- vs. Ph-) on the Hþ-shift is quite small (46.0 vs. 46.5, 25.6 vs. 25.7 kJ/mol, see Fig. 9). How to understand the acceleration of substituent Ph-on the ring-closure reaction? The APT (Atomic Polar Tensor) charge
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Fig. 9. Energy profiles of the Cu-catalyzed cyclization of propargylic acetates to form indolizines using H- or Ph-as the terminal substituent with the assistance of Et3N.
Fig. 10. The APT charges for ina1 and inb1.
distribution analysis is used to explore this thought-provoking issue. Both the complexes ina1 and inb1 are chosen as a studied system because the electronic nature of substituent attached to the triple bond has a crucial influence on the nucleophilic attack.36 When H group is substituted by Ph group as the substituent in inb1, the APT charge density of C1eC2 triple bond is changed from 0.136 (in ina1) to þ0.046 (see Fig. 10), which causes that the C1eC2 triple bond is more likely to be attacked by the nucleophilic site (N1). In addition, the APT charge of C1 is changed from negative (0.205, in ina1) to positive (þ0.264, in inb1) because the positive charge can be better stabilized by the aromatic ring.36 All these changes in the APT charge are advantageous to the subsequent intramolecular cyclization. Therefore, the ring-closure reaction between heterocyclic N1 and C1 of alkyne is easier to carry out in inb1 than in ina1. This fact can also be supported by comparing the bond length of C1eC2 triple bond in ina1 and inb1 (1.226 vs. 1.232 Å, see Fig. 10). 4. Conclusions In summary, the mechanisms of the CuI-catalyzed cycloisomerization of propargylic pyridines to form indolizines are computationally addressed using DFT methods. The important roles of substrate 1a and additive Et3N are revealed. In the reaction, they both act as the proton-shuttle to assist H1 transport from C3 to C2 by the deprotonation/protonation process. In addition, the solvent CH3CN and the trace H2O also play the Hþ-shuttle role in the
proton-transfer catalytic strategy, whereas the catalytic activity of them is weaker than that of 1a or Et3N. More importantly, our calculations find that the base strength is the primary factor that controls the catalytic capability of cocatalysts (CH3CN, 1a and Et3N). In the whole proton-transfer process, the trend of catalytic activity increases in the order: Et3N > 1a > CH3CN, which matches well with the enhanced trend of base strength (Et3N > 1a > CH3CN). Thus, the strong base is favorable for the H1 migration, and Et3N is the most appropriate for the present Cu-catalyzed reaction. Besides, our calculation gives a reasonable explanation on the effects of terminal substituents H- and Ph-on the reaction yields (see Entries 2 (82%, 2 h) vs. 3 (89%, 15min), in Table 1). We believe that our theoretical calculations and explorations would be valuable for understanding the effects of base strength on the transition metalcatalyzed reactions involving the proton-transfer process and provide useful guidance for the design of new catalysts or new catalytic systems. Acknowledgements We acknowledge generous financial support from "the Fundamental Research Funds for the Central Universities (grant no. XDJK2016D052) ". Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2017.09.007. References 1. (a) Balasubramanian M, Keay J. In Comprehensive Heterocyclic Chemistry II. Oxford: Pergamon Press; 1996; (b) Majumdar KC, Chattopadhyay SK. Heterocycles in Natural Product Synthesis. Wiley Online Library; 2011. 2. (a) Huang W, Zuo T, Luo X, et al. Chem Biol Drug Des. 2013;81:730e741; (b) Singh GS, Mmatli EE. Eur J Med Chem. 2011;46:5237e5257; (c) Shen Y-M, Lv P-C, Chen W, Liu P-G, Zhang M-Z, Zhu H-L. Eur J Med Chem. 2010;45:3184e3190. 3. (a) Cossy J, Willis C, Bellosta V, Saint-Jalmes L. Synthesis. 2002;2002: 0951e0957; (b) Pourashraf M, Delair P, Rasmussen MO, Greene AE. J Org Chem. 2000;65: 6966e6972. 4. (a) Huang W, Zuo T, Jin H, et al. Mol. Divers. 2013;17:221e243; (b) Oslund RC, Cermak N, Gelb MH. J Med Chem. 2008;51:4708e4714;
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(c) Molyneux RJ, James LF. Science. 1982;216:190e191. M, Tardy C, Balmahieu C, Colson P, Perez C. Cancer Res. 2003;63: 5. Facompre 7392e7399. 6. Gupta SP, Mathur AN, Nagappa AN, Kumar D, Kumaran S. Eur J Med Chem. 2003;38:867e873. 7. Harrell WB. J Pharm Sci. 1970;59, 275e275. 8. Kim E, Koh M, Ryu J, Park SB. J Am Chem Soc. 2008;130:12206e12207. 9. (a) Fletcher Jr. GL, Bender SL, Wadsworth DH. Oxoindolizine and oxoindolizinium compounds useful as dyes, Google Patents. 1986. (b) Weidner C, Wadsworth D, Bender S, Beltman D. J Org Chem. 1989;54:3660e3664. 10. Wan J, Zheng C-J, Fung M-K, Liu X-K, Lee C-S, Zhang X-H. J Mater Chem. 2012;22:4502e4510. 11. Sonnenschein H, Hennrich G, Resch-Genger U, Schulz B. Dyes Pigments. 2000;46:23e27. 12. (a) Helan V, Gulevich A, Gevorgyan V. Chem Sci. 2015;6:1928e1931; (b) Li X, Xie X, Liu Y. J Org Chem. 2016;81:3688e3699; (c) Zhang L, Li X, Liu Y, Zhang D. Chem Commun. 2015;51:6633e6636; (d) Liu RR, Lu CJ, Zhang MD, Gao JR, Jia YX. Chem Eur J. 2015;21:7057e7060; (e) Albaladejo MJ, Alonso F, Yus M. Chem Eur J. 2013;19:5242e5245. 13. (a) Hardin AR, Sarpong R. Org Lett. 2007;9:4547e4550; (b) Smith CR, Bunnelle EM, Rhodes AJ, Sarpong R. Org Lett. 2007;9:1169e1171. 14. Seregin IV, Schammel AW, Gevorgyan V. Org. Lett. 2007;9:3433e3436. 15. Chernyak D, Gadamsetty SB, Gevorgyan V. Org Lett. 2008;10:2307e2310. 16. Liu Y, Song Z, Yan B. Org Lett. 2007;9:409e412. 17. Yan B, Zhou Y, Zhang H, Chen J, Liu Y. J Org Chem. 2007;72:7783e7786. 18. Xu J, Hu H, Liu Y, Wang X, Kan Y, Wang C. Eur J Org Chem. 2017:257e261. 19. Frisch MJ, Trucks GW, Schlegel HB, et al. Gaussian 09, Revision A.02. Wallingford, CT: Gaussian, Inc.; 2009. 20. (a) Becke AD. J Chem Phys. 1993;98:5648e5652; (b) Lee C, Yang W, Parr RG. Phys Rev B. 1988;37:785. 21. Parr RG, Yang RGPW. Density-functional Theory of Atoms and Molecules. Oxford university press; 1989. 22. (a) Samec JS, B€ ackvall J-E, Andersson PG, Brandt P. Chem Soc Rev. 2006;35: 237e248; (b) Shi F-Q, Li X, Xia Y, Zhang L, Yu Z-X. J Am Chem Soc. 2007;129: 15503e15512; (c) Ruan G-Y, Zhang Y, Qi Z-H, Ai D-X, Liu W, Wang Y. Comput Theor Chem. 2015;1054:16e21; (d) Straub BF. Chem Commun. 2004:1726e1728.
23. (a) Rassolov VA, Ratner MA, Pople JA, Redfern PC, Curtiss LA. J Comput Chem. 2001;22:976e984; (b) Rassolov VA, Pople JA, Ratner MA, Windus TL. J Chem Phys. 1998;109: 1223e1229; (c) Hehre WJ, Ditchfield R, Pople JA. J Chem Phys. 1972;56:2257e2261. 24. Hay PJ, Wadt WR. J Chem Phys. 1985;82:299e310. 25. (a) Xia Y, Dudnik AS, Gevorgyan V, Li Y. J Am Chem Soc. 2008;130:6940e6941; (b) Yuan B, He R, Shen W, Huang C, Li M. J Org Chem. 2015;80:6553e6563. 26. (a) Gonzalez C, Schlegel HB. J Chem Phys. 1989;90:2154e2161; (b) Gonzalez C, Schlegel HB. J Phys Chem. 1990;94:5523e5527. 27. (a) Miertus S, Tomasi J. Chem Phys. 1982;65:239e245; (b) Cossi M, Scalmani G, Rega N, Barone V. J Chem Phys. 2002;117:43e54; (c) Mineva T, Russo N, Sicilia E. J Comput Chem. 1998;19:290e299. 28. Wong MW, Wiberg KB, Frisch MJ. J Am Chem Soc. 1992;114:1645e1652. 29. (a) Yang H, Wong MW. J Am Chem Soc. 2013;135:5808e5818; (b) Yuan H, Zheng Y, Zhang J. J Org Chem. 2016;81:1989e1997. 30. Yuan B, He R, Shen W, Hu W, Li M. RSC Adv. 2016;6:20294e20305. 31. (a) Zhang X, Houk K. J Org Chem. 2005;70:9712e9716; (b) Roy D, Patel C, Sunoj RB. J Org Chem. 2009;74:6936e6943; (c) Verma P, Patni PA, Sunoj RB. J Org Chem. 2011;76:5606e5613; (d) Nakamura I, Shiraiwa N, Kanazawa R, Terada M. Org Lett. 2010;12: 4198e4200. 32. (a) Bruice TC, Bruice PY. J Am Chem Soc. 2005;127:12478e12479; (b) Schramm VL. Chem Rev. 2006;106:3029e3030; (c) Gao J, Ma S, Major DT, Nam K, Pu J, Truhlar DG. Chem Rev. 2006;106: 3188e3209; (d) Ragsdale SW. Chem Rev. 2006;106:3317e3337; (e) Zhang X, Houk K. Acc Chem Res. 2005;38:379e385. 33. (a) Yuan H, Zhang J. J Comput Chem. 2015;36:1295e1303; (b) Hossein Bagi A, Khaledi Y, Ghari H, et al. J Am Chem Soc. 2016;138: 14599e14608; (c) Xia Y, Liang Y, Chen Y, et al. J Am Chem Soc. 2007;129:3470e3471. 34. (a) Sarrafi Y, Hamzehloueian M, Alimohammadi K, Yeganegi S. J Mol Struct. 2012;1030:168e176; (b) Xiao P, Yuan H, Liu J, Zheng Y, Bi X, Zhang J. ACS Catal. 2015;5:6177e6184. € rster C, Heinze K. Beilstein J Org Chem. 2016;12:1322e1333; 35. (a) Veit P, Fo (b) Chen D, Xing G, Zhou H. Org Chem Front. 2015;2:947e950; (c) Yuan H, Zheng Y, Li B, Li W, Zhang J. J Comput Chem. 2015;36:731e738. 36. Guven S, Ozer MS, Kaya S, Menges N, Balci M. Org Lett. 2015;17:2660e2663.
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Tetrahedron journal homepage: www.elsevier.com/locate/tet
Effects of base strength on the copper-catalyzed cycloisomerization of propargylic acetates to form indolizines: A DFT study Binfang Yuan, Rongxing He, Wei Shen, Ming Li* Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 June 2017 Received in revised form 18 August 2017 Accepted 8 September 2017 Available online 8 September 2017
Our calculations find that the base strength is the primary factor that controls the catalytic capability of cocatalysts CH3CN, Propargylic acetates (1a) and Et3N. In the proton-transfer process, the trend of catalytic activity increases in the order: Et3N > 1a > CH3CN, which matches well with the enhanced trend of base strength (Et3N > 1a > CH3CN). Et3N is the most appropriate for the present Cu-catalyzed cycloisomerization of propargylic acetates, which is in agreement with the experimental phenomena. Besides, our calculations give a reasonable explanation for the effects of terminal substituents (H- vs. Ph-) of alkyne on the catalytic reaction. © 2017 Elsevier Ltd. All rights reserved.
Keywords: DFT Proton-shuttle Proton-transfer Base strength Indolizines Copper-catalyzed
1. Introduction Indolizine skeletons are found in the large variety of biologically active substances,1 including synthetic pharmaceuticals2 and naturally occurring alkaloids.3 They represent a significant class of nitrogen-fused heterocycles, which have been employed as antiinflammatory agents,4 anti-HIV agents,5 H3 receptor antagonists,6 CNS depression agents7 and molecular probes8 etc. In the field of materials science, indolizines and its derivatives are also widely useful in the improvement of dyes,9 organic light emitting devices (OLEDs)10 and biological markers11 due to their unique photophysical properties. Based on the above reasons, the development of especially efficient methods for rapid construction of indolizines is still highly attractive.12 Generally, the transition metal is employed as a catalyst to synthesize indolizines owing to its relatively mild reaction conditions with the high efficiency. It is worth mentioning that the transition metal-catalyzed cycloisomerization is one of the important approaches to form indolizines and its derivatives.12d,13 For instance, the transition metal (Ag, Cu or Au)catalyzed cycloisomerization of propagyl heterocycles to the formation of 1,3-disubstituted N-fused heterocycles in good to
* Corresponding author. E-mail address: [email protected] (M. Li). http://dx.doi.org/10.1016/j.tet.2017.09.007 0040-4020/© 2017 Elsevier Ltd. All rights reserved.
excellent yields at the room temperature was reported by Gevorgyan et al. (see Eq 1 of Scheme 1).14 Subsequently, Gevorgyan's group15 presented an interesting Cu-catalyzed cyclization of propargylic mesylates to generate indolizines with low temperature (see Eq 2 of Scheme 1). Recently, an efficient Pd-catalyzed cross-coupling/cycloisomerization of 3-(2-pyridyl) propargyl carbonates with organoboronic acids has been developed by Zhang et al. (see Eq 3 of Scheme 1).12c They provided a straightforward route for the synthesis of 1,3-disubstituted indolizines with a wide variety of substituents. What's more, Liu's group16 found that the reaction strictly relied on the presence of base in the Pd/Cucatalyzed cross coupling/cycloisomerization of propargyl amines or amides with various haloheteroaromatic substrates under mild reaction conditions (see Eq 4 of Scheme 2). They believed that a suitable base could facilitate a propargyl-allenyl isomerization to an allenic intermediate or serve as a good ligand to stabilize the copper intermediates. Similarly, Liu et al.17 observed that the basic additive played an important accelerating role for the copper-catalyzed cycloisomerization of 2-pyridyl-substituted propargylic acetates and its derivatives (see Eq 5 of Scheme 2). Besides, Hu et al.18 pointed out that the use of base was advantageous for increasing reaction yield in the synthesis of indolizines by the coppercatalyzed cerobic oxidative dehydrogenative aromatization (see Eq 6 of Scheme 2). The similar fact has also been proposed by Jia's
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Table 1 The copper-catalyzed cycloisomerization of 2-pyridylsubstituted propargylic acetates to form C-1 oxygenated indolizines reported by Liu's group.
Scheme 1. Construction cycloisomerization.
of
indolizines
via
transition
metal-catalyzed
Entry
Substrate
1 2 3
1a 1a 1b
Additive
Time
Product
Yield (%)
Et3N Et3N
18 h 2h 15 min
2a 2a 2b
63 82 89
The role of substrate 1a (propargylic acetates) in the catalytic reaction. Whether the trace amounts of H2O (presented in the solvent) or the solvent CH3CN play a similar role? b) The accelerating effect of additive Et3N on the reaction. c) The difference of CH3CN, 1a, and Et3N in catalytic capacity for the proton-transfer reaction. More importantly, what causes this difference? d) The influence of terminal substituents (H- vs. Ph-) of alkyne on the reactivity.
2. Computational details
Scheme 2. The use of base in the construction of indolizines.
group12d in the Pd-catalyzed three-component cascade reaction to form densely functionalized indolizines in moderate to good yields (see Eq 7 of Scheme 2). On the basis of the above works, the base has a great influence on the synthesis of indolizines with the transition metal as a catalyst. However, the detailed mechanism of chemical reactions affected by bases (such as substrate, H2O, solvent or additive with the nature of Lewis/Bronsted base) is not illustrated clearly up to date, which is worthy of in-depth study by the experimental and theoretical methods. Herein, we choose the Cu-catalyzed cycloisomerization of 2pyridyl-substituted propargylic acetates to form C-1 oxygenated indolizines in CH3CN medium (as shown in Table 1) as a simple research system17 to better explore the following issues in detail: a)
In this work, all calculations are performed with the Gaussian 09 program suits.19 All geometric structures (including the intermediates and the transition states) are fully optimized using the Becke three-parameter hybrid functional (B3LYP)20 in the framework of density-functional theory (DFT).21 B3LYP method has been applied in the mechanistic studies of catalytic reactions successfully.22 The double-z basis set (6-31G*)23 is employed for C, N, O, and H elements except for Cu and I, which are described by the effective core potential double-z basis set (LanL2DZ).24 This combination of basis sets (6-31G* and LanL2DZ) has also been proven to be reliable in numerous theoretical simulations of mechanisms of metal-catalyzed reactions.22d,25 As a further test, several other functionals (BLYP, B3P86, BHandHLYP and M06) together with the 6-31G* basis set and several other basis sets (6-31G**, 6-31 þ G* and 6-311G*) together with the B3LYP functional are all used to compare and avoid the shortcomings of DFT functionals and basis sets, respectively (see Tables S1 and S2). Frequency calculations are carried out at the same level of theory (B3LYP/6-31G*) to identify all of the stationary points as minima (zero imaginary frequency) or transition states (one imaginary frequency). Furthermore, the intrinsic reaction coordinate (IRC) calculations26 are performed to confirm the connectivity of these transition states to the right intermediates. Solvent effect of acetonitrile (CH3CN) is simulated using a polarizable continuum model (PCM)27 through a selfconsistent reaction field (SCRF) method28 based on the gas phase optimized structures. The solution-phase single point energies are calculated with the larger functional and basis set level (PCM// M06-2X/6-311þþG**). M06-2X has been applied successfully to investigate the mechanisms of several catalytic organic reactions.29 In addition, the effect of dispersion on the energy is also considered by M06-2X-D3 calculation, but the calculation result of M06-2X-D3 is close to that of M06-2X (see Table S3). Herein, the solution-phase Gibbs free energy is determined by adding the solution-phase single point energy and gas-phase thermal correction to the Gibbs free energy obtained from the vibrational frequency calculation. Unless special emphasis, all the discussed energies are relative solution-phase Gibbs free energies (Grel, kJ/mol) in our
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Fig. 1. Energy profile of the copper-catalyzed cycloisomerization of propargyl acetates to form indolizines without the assistance of cocatalysts in CH3CN solvent.
present calculations, and the relative solution-phase Gibbs free energy of reaction substrate 1 (1a or 1b) is set as zero energy. 3. Results and discussion 3.1. Function of substrate 1a In this section, we first explore the reaction mechanism of Cucatalyzed cycloisomerizations of propargylic acetates to form indolizines in CH3CN medium,17 and then a detailed discussion is presented to understand the role of substrate 1a in the promotion of this reaction. Mechanism of synthesis of indolizines catalyzed by CuI. DFTcomputed energy profile for the Cu-catalyzed synthesis of indolizines is given in Fig. 1, and the optimized structures along the reaction path are collected in Fig. 2. The reaction starts with
coordination of CuI to the C1eC2 triple bond of 1a (other coordination modes are described in Schemes S1-3 of supporting information), forming a new coordination compound ina1. Related mechanism has been reported by Liu and Gevorgyan.14,17 Fig. 1 shows that the formation of complex ina1 is exergonic by 54.1 kJ/ mol in CH3CN medium. In ina1, the C1eC2 bond has lost a little of its triple-bond characters due to the coordination of CuI, and now its bond length is 1.225 Å (1.206 Å in 1a). It means that the C1eC2 triple bond has been activated, which is favorable for the subsequent cyclization reaction. The heterocyclic-N1 of 1a, which acts as an electron donor, attacks the activated C1eC2 triple bond to produce a cyclic intermediate ina2 via a transition state tsa1. In ina2, the C1eC2 bond is extended to 1.350 Å with the formation of N1eC1 bond (1.444 Å). It should be noted that the hydrogen-bond C3eH1/O1 (carbonyl O of 1a) exists in ina2, and the bond lengths of C3eH1 and H1/O1 are 1.099 and 2.411 Å, respectively.
Fig. 2. Optimized structures of the copper-catalyzed cycloisomerization of propargylic acetates without the assistance of cocatalysts in CH3CN solvent.
B. Yuan et al. / Tetrahedron 73 (2017) 6092e6100
Influenced by hydrogen-bond, the following reaction is a carbonyl O1-assisted 1,2-Hþ transfer process (see ina2 to 2a). In the Hþ-shift strategy, H1 is transferred from C3 to C2 with the regeneration of CuI (as the catalyst), passing through a transition state tsa2-1. The bond lengths of H1/O1, C3eH1 and H1eC2 are 2.063, 1.350 and 1.313 Å in tsa2-1, respectively. In principle, 2a can also be gained from ina2 through the carbonyl O1-assisted two-step Hþ-transfer reaction (see Fig. S1). In this case, the carbonyl O1 captures a proton H1 from C3, and then H1 is migrated to C2 with the leaving of CuI. However, the rate-limiting free energy barrier of the carbonyl O1assisted stepwise proton-transfer reaction is 112.1 kJ/mol, which is 10.5 kJ/mol higher than that of 1,2-Hþ shift process (112.1 vs. 101.6 kJ/mol, see Fig. S1 vs. Fig. 1). As illustrated in Fig. 1, DFT-computed energy profile of the CuIcatalyzed synthesis of indolizines includes two elementary reactions, an intramolecular cyclization and a 1,2-Hþ shift process. Their required free energy barriers are 63.5 and 101.6 kJ/mol, respectively. It is obvious that 1,2-Hþ shift process is the ratelimiting step of the whole catalytic reaction, and the rate-limiting free energy barrier is 101.6 kJ/mol. However, 101.6 kJ/mol is unfavorable for the present synthetic reaction (18 h, rt, see Entry 1 of Table 1). In our previous studies,25b,30 we have found that the reactant MeOH, which has the nature of Bronsted/Lewis base, can serve as a proton-shuttle to assist the proton migration. Inspired by these works, we turn our attention to the acceleration of substrate 1a (as a cocatalyst) on the catalytic reaction in the following sections. The acceleration of 1a on the reaction. Our calculated results indicate that the carbonyl O-assisted 1,2-Hþ shift process (tsa2-1) can be changed to the heterocyclic N-assisted two-step protontransfer reaction (another molecule 1a as the cocatalyst, heterocyclic N as the site of assistance), which is quite similar to the proton-transfer processes in proton-transport catalysis22b,31 and many enzyme-catalyzed reactions.32 What's more, the present heterocyclic N-assisted Hþ-transfer strategy can well explain the experimental phenomena17 (see Entry 1, in Table 1). The energy profile of heterocyclic N-assisted proton-transfer reaction is shown in Fig. 3, and the corresponding geometric structures are collected in Fig. 4. From Fig. 3, ina2 seizes a molecule 1a via a hydrogen-bond of C3eH1/N2 (C3eH1 ¼ 1.106 Å, H1/N2 ¼ 2.351 Å), leading to the
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generation of a new complexes ina3-2. The relative free energy of ina3-2 is only 28.3 kJ/mol higher than that of ina2, indicating that ina3-2 can be obtained smoothly at the room temperature.17 The next reaction is heterocyclic N-mediated deprotonation/protonation process. In the deprotonation of C3 (involving the C3eH1 bond cleavage), H1 is migrated from C3 to N2 through a transition state tsa2-2 to produce a new compound ina4-2. In the protonation of C2 (involving the formation of C2eH1 bond), H1 is shifted from the protonated heterocyclic N2e Hþ to C2 via a transition state tsa3-2, generating products 2a with the regeneration of catalyst CuI and cocatalyst 1a. From Figure 3, 1a acts not only as the reactant to synthesize the products 2a, but also as the proton-shuttle to assist H1 shift from C3 to C2, passing through the two-step Hþ-transfer reaction. The required free energy barrier of proton-transfer process is lowed to 88.3 kJ/mol, which is 13.3 kJ/mol lower than that of 1,2-Hþ shift ones (88.3 vs. 101.6 kJ/mol, see Fig. 3 vs. Fig. 1). The rate-limiting step is still the proton-transfer process, and the rate-limiting energy barrier is 88.3 kJ/mol. Therefore, the heterocyclic N-assisted reaction is favorable for the synthesis of 2a (see Table 1). Furthermore, the assistance of carboxyl O of 1a (as the cocatalyst) is considered, while the required free energy barrier for carboxyl Oassisted deprotonation process of C3 is as high as 120.6 kJ/mol (see Fig. S3). Besides, the propargyl-allenyl isomerization with the assistance of 1a, in which the deprotonation of H1 takes place before the ring-closure between N1 and C1 (tsa1), is taken into account. We try our best to find this reaction, but we failed (see Scheme S2). Effects of trace H2O and solvent CH3CN on the Hþ-transfer process. The previous works have reported that the trace amount of H2O30,33 and solvent33a,34 have a significant influence on the Hþtransfer reaction. Inspired by these studies, the effects of H2O and solvent CH3CN are further explored. The calculated energy profiles for H2O- and CH3CN-mediated Hþ-shift reactions are showed in Figs. 5 and 6, and the geometries of involving intermediates and transition states are given in Fig. S5. Fig. 5 shows that the H2Oassisted Hþ-transfer reaction includes a deprotonation/protonation process, which is similar to the heterocyclic N-assisted case (see Fig. 3). The corresponding reaction free energy barriers are 127.0 (tsa2-3) and 87.8 (tsa3-3) kJ/mol, respectively. However, only one
Fig. 3. Energy profile of the proton-shift reaction with the assistance of heterocyclic N of 1a (as the cocatalyst) in CH3CN solvent.
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Fig. 4. Optimized structures of the proton-shift reaction with the assistance of heterocyclic N of 1a (as the cocatalyst) in CH3CN solvent.
Fig. 5. Energy profile of the H2O-assisted proton-shift reaction in CH3CN solvent.
transition state tsa2-4 (see Fig. 6) is located in the CH3CN-assisted Hþ-shift, and its required free energy barrier is 124.6 kJ/mol. Obviously, both H2O- and CH3CN-assisted Hþ-transfer reactions are inherently disfavored as compared with the heterocyclic N-assisted ones (127.0 and 124.6 vs. 88.3 kJ/mol). Besides, the effects of heterocyclic N þ H2O, carboxyl O þ H2O, CH3CN þ H2O and 2H2O on the proton-transfer process are all studied, and their required free energy barriers are 102.0, 123.3, 117.3 and 112.7 kJ/mol for the deprotonation process of C3, respectively, indicating that their assistance are negative for the Hþ-shift reaction (see Figs. S6e9). 3.2. Effect of additive Et3N on the catalytic reaction In experiments, Liu and his workers17 reported that the
moderate yield (63%) was obtained in the absence of additive, while the high yield (82%) could be gained when Et3N acted as a additive (see Entries 1 and 2, in Table 1). How to understand this difference in the yields? We begin to study the effect of Et3N on the mechanism of Cu-catalyzed cycloisomerization reaction. The influence of Et3N on the intramolecular cyclization is considered firstly, as illustrated in Scheme 3. Et3N molecule coordinates with Cu(I) as a ligand. This coordination does not alter the reaction mechanism of intramolecular cyclization reaction, and the calculated free energy barrier is 70.4 kJ/mol, which is 6.9 kJ/mol higher than that of the case without Et3N as the ligand (70.4 vs. 63.5 kJ/mol). Thus, the effect of Et3N is negative on the intramolecular cyclization process. The previous reports35 have pointed out that the additive with the nature of Lewis/Bronsted base can help Hþ migration to
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Fig. 6. Energy profile of the CH3CN-assisted proton-shift reaction in CH3CN solvent.
Scheme 3. Comparison of the free energy barriers for the cyclization process without and with Et3N as the ligand in CH3CN medium.
promote the reaction yield. Encouraged by these studies, the assisting Hþ-transfer function of Et3N is discussed in this section. The calculated energy profile for Et3N-assisted two-step protontransfer reaction is described in Fig. 7, and the geometries of involving intermediates and transition states are collected in Fig. 8. Fig. 7 shows that the Et3N-assisted reaction mechanism is similar to
the heterocyclic N-assisted proton-transfer ones, including a deprotonation/protonation process. Their required free energy barriers are 46.5 and 25.6 kJ/mol, respectively. It is clear that the rate-limiting step of the whole Cu-catalyzed reaction is changed from the Hþ-shift to the intramolecular cyclization with the assistance of Et3N (46.5 vs. 63.5 kJ/mol, see Figs. 1 and 7). The ratelimiting free energy barrier is reduced to 63.5 kJ/mol, which is 24.8 kJ/mol lower than that of the case with 1a as the cocatalyst. (63.5 vs. 88.3 kJ mol). The difference value of 24.8 kJ/mol can give a reasonable explanation on the distinct yields (see Entries 1 (62%) vs. 2 (82%), in Table 1). It is worth mentioning that the propargylallenyl isomerization may take place before the ring-closure when Et3N is added to the reaction system (see Scheme S3). There are five kinds of possibilities for the propargyl-allenyl isomerization (from Path I to Path V). The activation free energy barriers of Paths IeV are 73.3, 131.9 (or 145.8), 80.7, 82.8 and 96.3 kJ/mol, respectively, which are 9.8, 68.4 (or 82.3), 17.2, 19.3 and 32.8 kJ/mol higher than the rate-limiting free energy barrier of 63.5 kJ/mol (the ring-closure process tsa1, see Figs. 1 and 7). Therefore, the base-induced propargyl-allenyl isomerization is not favored over ring-closure reaction. Besides, the effect of Et3N þ H2O on the proton-transfer process is also explored, and the reaction
Fig. 7. Energy profile of the Et3N-assisted two-step proton-shift reaction in CH3CN solvent.
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Fig. 8. Optimized structures of the Et3N-assisted two-step proton-shift reaction in CH3CN solvent.
Table 2 Comparison of the free energy barriers of CH3CN-, 1a-, and Et3N-assisted Hþ-shift in CH3CN medium. Species
tsa2-X tsa3-X
Free energy barriers (kJ/mol) CH3CN-assisted direct 1,2-Hþ shift
1a-assisted stepwise Hþ-transfer
Et3N-assisted stepwise Hþ-transfer
124.6
88.3 27.0
46.5 25.6
X ¼ 2, 4 or 5.
free energy barrier for the deprotonation of C3 is 88.2 kJ/mol (see Fig. S10). It is clear that the acceleration of Et3N þ H2O is weaker than that of Et3N (88.2 vs. 46.5 kJ/mol). 3.3. Effect of base strength on the Hþ-transfer Our calculated results indicate that all the co-catalysts (such as 1a or Et3N) can play the role of proton-transfer shuttle to help H1 migration from C3 to C2, but their catalytic abilities exhibit a significant difference. What causes this difference? Herein, CH3CN-, 1a (heterocyclic N-) and Et3N-assisted Hþ-shift reactions are chosen as a studied system to explore this interesting issue. According to Tables S4 and S5, both the dissociation energies and the Wiberg bond indices of HeN3, HeN2 and HeN4 bonds in CH3CNeHþ, 1aHþ and Et3NeHþ show that the bond energy of HeN4 (HeN3) is the maximum (minimum), and the enhanced trend of bond energy is HeN4 > HeN2 > HeN3. This means that Bronsted acid CH3CNeHþ is easy to lose a proton when compared with heterocyclic NeHþ and Et3NeHþ. On the contrary, Bronsted base Et3N is more likely to obtain a proton than CH3CN or 1a. The order of base strength is Et3N > 1a > CH3CN, which does match with the increased trend of bond energy HeN4 > HeN2 > H1eN3. From Fig. 6, only one transition state (the free energy barrier 124.6 kJ/mol) is located for the CH3CN-assisted Hþ-shift, it may be that CH3CN is too weak base to abstract H1 at C3. When 1a or Et3N acts as the proton-shuttle, the reaction mechanism of proton-transfer is changed to the deprotonation/protonation strategy (see Figs. 3 and 7). The deprotonation
of C3 is the rate-determining step of proton-transfer reaction, and the rate-determining free energy barriers are 88.3 (tsa2-2) and 46.5 (tsa3-5) kJ/mol, respectively (see Table 2). By comparing the above free energy barriers (124.6 vs. 88.3 vs. 46.5 kJ/mol), a general regularity can be obtained that the order of catalytic ability is Et3N > 1a > CH3CN in the H1-transfer process, matching well with the enhanced trend of base strength Et3N > 1a > CH3CN. Therefore, the base strength of proton-shuttles is revealed to be the primary factor that controls the catalytic activities of CH3CN, 1a and Et3N in the proton-shift reaction. Our calculated results show that Et3N is the most appropriate proton-shuttle reagent, which is in agreement with the experimental results.
3.4. Effect of terminal substituents on the catalytic reaction In experiments,17 Liu et al. observed that the reaction time was shortened to 15 min, and the reaction yield was increased to 89% with the substitution of H group by Ph group (see Entries 2 and 3, in Table 1). How terminal substituent (H- vs. Ph-) of alkyne affects the catalytic reaction. We will explain this issue in the subsequent calculations. Similar to the CuI-catalyzed reaction with H group as the substituent, the CuI-catalyzed reaction using Ph group as the substituent also includes an intramolecular cyclization and an Et3Nassisted stepwise Hþ-transfer process. Their required free energy barriers are 51.3, 46.0 and 25.7 kJ/mol, respectively (see Fig. 9), and the rate-determining step still locates in the intramolecular cyclization. However, the rate-determining free energy barrier is reduced to 51.3 kJ/mol, which is 12.2 kJ/mol lower than that the case with H group as the substituent (51.3 vs. 63.5 kJ/mol). It is obvious that Ph group is favorable for the reaction in energy with respect to H group. Our calculations give a reasonable explanation on the experimental phenomena (see Entries 2 (82%, 2 h) vs. 3 (89%, 15min), in Table 1). It is worth mentioning that the effect of substituent (H- vs. Ph-) on the Hþ-shift is quite small (46.0 vs. 46.5, 25.6 vs. 25.7 kJ/mol, see Fig. 9). How to understand the acceleration of substituent Ph-on the ring-closure reaction? The APT (Atomic Polar Tensor) charge
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Fig. 9. Energy profiles of the Cu-catalyzed cyclization of propargylic acetates to form indolizines using H- or Ph-as the terminal substituent with the assistance of Et3N.
Fig. 10. The APT charges for ina1 and inb1.
distribution analysis is used to explore this thought-provoking issue. Both the complexes ina1 and inb1 are chosen as a studied system because the electronic nature of substituent attached to the triple bond has a crucial influence on the nucleophilic attack.36 When H group is substituted by Ph group as the substituent in inb1, the APT charge density of C1eC2 triple bond is changed from 0.136 (in ina1) to þ0.046 (see Fig. 10), which causes that the C1eC2 triple bond is more likely to be attacked by the nucleophilic site (N1). In addition, the APT charge of C1 is changed from negative (0.205, in ina1) to positive (þ0.264, in inb1) because the positive charge can be better stabilized by the aromatic ring.36 All these changes in the APT charge are advantageous to the subsequent intramolecular cyclization. Therefore, the ring-closure reaction between heterocyclic N1 and C1 of alkyne is easier to carry out in inb1 than in ina1. This fact can also be supported by comparing the bond length of C1eC2 triple bond in ina1 and inb1 (1.226 vs. 1.232 Å, see Fig. 10). 4. Conclusions In summary, the mechanisms of the CuI-catalyzed cycloisomerization of propargylic pyridines to form indolizines are computationally addressed using DFT methods. The important roles of substrate 1a and additive Et3N are revealed. In the reaction, they both act as the proton-shuttle to assist H1 transport from C3 to C2 by the deprotonation/protonation process. In addition, the solvent CH3CN and the trace H2O also play the Hþ-shuttle role in the
proton-transfer catalytic strategy, whereas the catalytic activity of them is weaker than that of 1a or Et3N. More importantly, our calculations find that the base strength is the primary factor that controls the catalytic capability of cocatalysts (CH3CN, 1a and Et3N). In the whole proton-transfer process, the trend of catalytic activity increases in the order: Et3N > 1a > CH3CN, which matches well with the enhanced trend of base strength (Et3N > 1a > CH3CN). Thus, the strong base is favorable for the H1 migration, and Et3N is the most appropriate for the present Cu-catalyzed reaction. Besides, our calculation gives a reasonable explanation on the effects of terminal substituents H- and Ph-on the reaction yields (see Entries 2 (82%, 2 h) vs. 3 (89%, 15min), in Table 1). We believe that our theoretical calculations and explorations would be valuable for understanding the effects of base strength on the transition metalcatalyzed reactions involving the proton-transfer process and provide useful guidance for the design of new catalysts or new catalytic systems. Acknowledgements We acknowledge generous financial support from "the Fundamental Research Funds for the Central Universities (grant no. XDJK2016D052) ". Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2017.09.007. References 1. (a) Balasubramanian M, Keay J. In Comprehensive Heterocyclic Chemistry II. Oxford: Pergamon Press; 1996; (b) Majumdar KC, Chattopadhyay SK. Heterocycles in Natural Product Synthesis. Wiley Online Library; 2011. 2. (a) Huang W, Zuo T, Luo X, et al. Chem Biol Drug Des. 2013;81:730e741; (b) Singh GS, Mmatli EE. Eur J Med Chem. 2011;46:5237e5257; (c) Shen Y-M, Lv P-C, Chen W, Liu P-G, Zhang M-Z, Zhu H-L. Eur J Med Chem. 2010;45:3184e3190. 3. (a) Cossy J, Willis C, Bellosta V, Saint-Jalmes L. Synthesis. 2002;2002: 0951e0957; (b) Pourashraf M, Delair P, Rasmussen MO, Greene AE. J Org Chem. 2000;65: 6966e6972. 4. (a) Huang W, Zuo T, Jin H, et al. Mol. Divers. 2013;17:221e243; (b) Oslund RC, Cermak N, Gelb MH. J Med Chem. 2008;51:4708e4714;
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