Mechanistic Studies on a Cooperative NHC Organocatalysis

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Mechanistic studies on a cooperative NHC organocatalysis/ palladium catalysis system: uncovering significant lessons for mixed chiral Pd(NHC)(PR3) catalyst design Chang Guo, Daniel Janssen-Müller, Mirco Fleige, Andreas Lerchen, Constantin Gabriel Daniliuc, and Frank Glorius J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b00462 • Publication Date (Web): 06 Mar 2017 Downloaded from http://pubs.acs.org on March 6, 2017

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Journal of the American Chemical Society

Mechanistic studies on a cooperative NHC organocatalysis/palladium catalysis system: uncovering significant lessons for mixed chiral Pd(NHC)(PR3) catalyst design Chang Guo*, Daniel Janssen-Müller, Mirco Fleige, Andreas Lerchen, Constantin G. Daniliuc and Frank Glorius* Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany ABSTRACT: A comprehensive investigation of the mechanism of the highly enantioselective Pd(PPh3)4/NHC-

catalyzed annulation of vinyl benzoxazinanones and enals has been conducted. A study of reaction orders supports the postulated cooperative catalysis. Interestingly, a detailed investigation of the catalytically active palladium species pointed towards a dual-role of the NHC acting as an organocatalyst and forming a novel mixed ligand Pd/NHC/phosphine complex. The catalytically active Pd/NHC/phosphine complex represents a new class of chiral palladium catalyst. Remarkably, phosphine plays a crucial role in this transformation. These complexes could be characterized by X-ray crystallographic analysis and employed as catalysts for the enantioselective [4+1] annulation reaction of vinyl benzoxazinones and sulphur ylides in good yields and good enantioselectivities.

I. INTRODUCTION The advances made by employing chiral catalysts to create new carbon−carbon bonds with high levels of stereoselectivity have become a widely used synthetic methodology.1 The use of N-heterocylic carbenes (NHCs)2 has witnessed a rapid development in the last decade acting both as ligands3 and organocatalysts.4 The development of dual catalytic systems5 would dramatically expand the scope of NHC organocatalysis by opening up new metalcatalyzed reaction pathways for acyl anion equivalent or homoenolate intermediates,4 while simultaneously expanding the scope of metal catalysis to include umpolung processes. Methods for the combination of NHCs and a second mode of activation have been reported,6 but most reactions that have been studied before focused on Lewis acid7 or Brønsted acid catalysis.8 It is still a great challenge in terms of efficiency and selectivity of cooperative systems that combine late transition metal and NHC catalysis.9 Scheme 1. Pd(PPh3)4/NHC catalyzed enantioselective umpolung annulation of enals

catalyzed annulation, employing vinyl benzoxazinanones and enals to afford the benzazepines with excellent enantio- and regioselectivities (Scheme 1).10 However, there are several challenges associated with the development of this reaction, such as (1) the structure of the catalytically active palladium complex; (2) the identity of the catalytic modes of NHC and palladium in the enantio-determining step. Detailed understanding of this Pd/NHC cooperatively catalyzed reaction could be of enormous importance in this field. We thus conducted a detailed mechanistic investigation of our cooperative asymmetric Palladium/NHCcatalyzed transformation. Our results clearly provide hints on the individual steps of the catalytic cycle and support the hypothesis that a cooperative mechanism is responsible for the high catalytic activity of this system. Surprisingly, we found that the NHC catalyst plays a dual role in this transformation, in which NHC is responsible for the organocatalytic formation of the homoenolate intermediate, while it also serves as a co-ligand for palladium catalysis. We found a clear clue that a novel mixed NHC/phosphine catalyst [Pd(NHC)(PR3)] is the active transition metal catalyst in this type of reaction.11 More importantly, this novel chiral palladium-NHC-phosphine complex could be used as a highly enantioselective catalyst for asymmetric allylic alkylation reactions. These experimental findings and the implication of the results for rational catalyst design are described herein.

We recently reported the first example of an enantioselective and intermolecular cooperative palladium/NHC-

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Figure 1. Plot of initial rates vs. catalyst concentrations reveal nearly first-order kinetics for both catalysts.

Figure 2. Plot of initial rates vs. substrate concentrations reveal zero-order kinetics for both starting-materials. II. RESULTS AND DISCUSSION 1. Kinetic experiments To gain a better understanding of the mechanistic details of this process, we did some kinetic experiments under catalytic conditions and measured initial rates of the reaction by in situ 1H NMR spectroscopy. The reaction appeared to have a nearly first-order dependence on the Pd-catalyst and NHC 4a (Figure 1), and a zero-order dependence on substrates 1a and 2a (see Figure 2 and Supporting Information for details). The zero-order dependence of the substrates 1a and 2a shows that substrate incorporations into the catalytic cycles (addition of the NHC to 2a and olefin coordination of 1a to palladium) are not rate-limiting. The first-order dependence on the catalysts indicates that both catalysts are involved in ratelimiting steps. To investigate if the addition of the nucleophilic NHC-homoenolate to the π-allyl-palladium species, the stereodetermining key step in this cooperative mechanism, is rate-limiting, we performed a Hammett-

plot study of para-substituted cinnamaldehydes (ρ = +0.34, R² = 0.94, see Figure 3), in which electrondeficient aldehydes led to a higher initial rate. The Hammett-plot experiments strongly indicate that homoenolate addition to the π-allyl-palladium species is not the rate-limiting step under these catalytic conditions.

0.3 NO2 0.2

log (kX/kH)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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0.1 Cl H 0.0

-0.1

y = 0.3383x - 0.0448 R² = 0.9368

F OMe Me

-0.2 -0.4

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

σpara

Figure 3. Hammett-plot of para-substituted cinnamaldehyde derivatives.


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The combination of kinetic results and Hammett-plot experiments suggests that formation of the Breslowintermediate is rate-limiting in the organocatalysis cycle. Since the palladium catalyst also show a first-order relation, it is likely that the palladium catalyst-cycle contains an additional rate-limiting step. The concentrations of the two catalytic intermediates (NHC-homoenolate and allylpalladium) would therefore both influence the rate of product formation, which is consistent with the reaction of two transient species. 2. The effect of the phosphine ligand Then we studied the structure of the catalytically active palladium complex. First, we investigated the effect of the phosphine employed for the cooperative Pd/NHCcatalyzed umpolung annulation of 1a and 2. Interestingly, no product 3a was formed in the absence of phosphine ligand by using 5 mol% Pd(dba)2 and 15 mol% NHC 4a as catalysts (Table 1, entry 1). This unusual result encouraged us to test a series of phosphine ligands in order to determine their influence on the reactivity and enantioselectivity of the transformation. As shown in Table 1, large variations in the ee’s were observed (entries 2 to 5), and no desired annulation product 3a was observed using the sterically bulky tri(o-tolyl)phosphine 5c, which probably prevents the formation of the catalytically active palladium complex (entry 4). Furthermore, the use of DavePhos 5d as the phosphine ligand led to the cycloadduct 3a in only 12% yield with 12% ee (entry 5). Table 1. The influence of phosphine ligand on the NHC/palladium catalyzed asymmetric umpolung annulation of vinyl benzoxazinanone 1a with enal 2aa

This result clearly shows that the phosphine directly influences the enantio-determining step. Although the yield of the cycloadduct 3a was found to be dependent on the concentration of the phosphine ligand PPh3, there is no noticeable impact on the ee of the product observed (entries 6 to 10). 3. Dual role of the NHC catalyst To gain more information about the possible intermediates, we turned our attention to study the loading of NHC. We found that the desired product 3a could be obtained in 86% yield and 99% ee at room temperature using 15 mol% of NHC 4a along with 5 mol% of Pd(PPh3)4 as catalysts. The fact that only a trace amount of product was detected when 5 mol% of NHC 4a : Pd(PPh3)4 (1 : 1 ratio) were employed, indicates that the NHC, which was initially designed to only work as an organocatalyst for conjugated umpolung reactivity, might also coordinate to the palladium species (eq 1), resulting in partial deactivation for the organocatalytic pathway.

Motivated by this finding, we wanted to investigate whether the NHC was also enhancing catalytic activity of the palladium species by serving as an activating ligand, explaining the high catalytic activity of this cooperative Pd/NHC catalytic system in contrast to previously thought mutual catalyst deactivation. Therefore, we performed a nonlinear effect study to determine the relationship between the ee of the NHC and that of the generated product. The interaction of a chiral NHC-bound palladium with the chiral NHC catalyst could result in a nonlinear relationship between the enantiopurity of the catalyst and the product 3a. Seven reactions were performed using a catalyst with different levels of enantiopurity (racemic, 20%, 40%, 50%, 60%, 80% and >99% ee), and the obtained product enantioselectivies were plotted against ee of the initial catalyst mixture (Figure 4). 100 90

Entry 1 2 3 4 5 6 7 8 9 10

5 5a 5b 5c 5d PPh3 PPh3 PPh3 PPh3 PPh3

x (mol%) 20 20 20 5 10 15 20 30

Yield (%)b nr 56 85 trace 12 49 62 72 85 74

drc 10:1 9:1 3:1 12:1 12:1 12:1 12:1 12:1

ee (%)d 96 97 12 97 98 98 98 98

Enantiopurity of product 3a [% ee]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


80 70 60 50 40 30 20 10 0 0

20

40 60 Enantiopurity of NHC-4a [% ee]

80

100

a

The reactions were performed using 1.0 equiv of 1a (0.1 mmol) and 2.0 equiv of 2a in 1.5 mL THF, 24 h. bYields determined by 1H NMR spectroscopy analysis using dibromomethane as internal standard. cDetermined by 1H NMR spectroscopy. dThe ee value of 3a was determined by HPLC analysis using a chiral column.

Figure 4. Nonlinear relationship between the optical activity of NHC 4a and cycloadduct 3a in the annulation reaction.


Journal of the American Chemical Society Indeed, a pronounced positive nonlinear effect observed is an interaction of a matched-case of chiral organocatalyst and chiral Pd complex, which implies that the NHC 4a might be a good ligand of palladium for the enantioselective allylic alkylation. This observation strongly indicated NHC 4a is involved in the enantio-determining step, unraveling a dual role of the NHC catalyst: one as an organocatalyst and the second 12 as a chiral ligand to palladium. 4. Identification of the active palladium catalyst Considering the hints above, including the necessity and influence of the phosphine ligands and nonlinear effect of the chiral NHC, it seems that the phosphine ligand and the chiral NHC are both ligated to palladium during the enantio-determining step simultaneously.

725.16258 z=1

100

749.31618 z=1

5a). To our delight, this proposed structural assignment in the crude reaction solution was supported by ESI-MS analysis for our standard reaction (Figure 5b).13 The signals at m/z = 985.2526 and 723.1619 with their characteristic isotope distribution by mass spectrometry matched with the calculated patterns for the 6 [Pd(π-allyl)(NHC 4a)(PPh3)] (Figure 5c) and 7 [Pd(π-allyl)(NHC 4a)] (Figure 5d). We suggest that cycloadduct 3a could be afforded via the complex 6. Recently, the You group reported the first example of using a chiral triazolium NHC-iridium(I) complex as catalyst in the highly enantioselective intramolecular allylic amination reaction.14 However, no cycloadduct 3a was formed with [Pd(π-allyl)(NHC)] species 7 in the absence of phosphine ligand in our annulation reaction, which supports that complex 7 is not the active palladium complex.

T: FTMS + p NSI Full ms [200.00-1500.00]

90 722.16382 z=1

80

Relative Abundance

70 60

750.31959 z=1

50 721.16268 z=1

40

879.35833 z=1

617.25837 z=1

30 20

618.26172 z=1

10

859.30380 z=1

751.32292 z=1

681.13417 z=1

857.06058 z=1

880.36183 z=1 987.25389 z=1

902.34117 z=1

1014.28381 z=1

0

100

722.16382 z=1

700

725.16258 z=1

723.16196 z=1

721.16268 z=1

40 20

800

Experimental data NL: 9.70E5

726.16606 z=1

80 60

750

0.22-0.80 AV: 21 T: FTMS + p NSI Full ms [200.00-1500.00]

727.16379 z=1

724.16533 z=1

728.16716 z=1 729.17067 z=1

719.16422 z=1

0 723.16288

100

Calculated data. 725.16239

80

722.16354

60 727.16364

724.16495

40

721.16218 719.16370

60 40 20

724

726

728

981.23553 z=1

985.25261 z=1

60

NL: 5.00E4 0.22-0.80 AV: 21 T: FTMS + p NSI Full ms [200.00-1500.00]

988.25780 z=1 989.25485 z=1

990.25901 z=1

985.25453

Calculated data. 987.25419

NL: 2.25E5

984.25483 986.25663 988.25657 989.25559

40

983.25339

990.25776 991.25886

20

m/z

m/z

Experimental data

0

C 37 H 37 N 4 O 3 Pd 1 S 1 c (gss, s /p:40)(Val) Chrg 1 R: 30000 Res .Pwr . @FWHM

730

1000

987.25389 z=1

986.25689 z=1

983.25472 z=1

100

0 722

984.25525 z=1

950

80

80

0 720

900

100

NL: 2.39E5

728.16619 729.16606

20

850

Relative Abundance

650

Relative Abundance

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981.25483 982

984

986

988

990

992

C 55 H 52 N 4 O 3 P 1 Pd 1 S 1 c (gss, s /p:40)(Val) Chrg 1 R: 30000 Res .Pwr . @FWHM

m/z

Figure 5. ESI-MS analysis of the crude reaction solution for detection of palladium complexes. a) A proposed step for the palladium/NHC catalyzed annulation reaction. b) Monitoring of the standard reaction by ESI-MS spectroscopy: palladium complex 6, calcd. for C55H52N4O3PPdS+: 985.2527, found: 985.2526; palladium complex 7, calcd. for C37H37N4O3PdS+: 723.1616, found: 723.1619. c) Isotope distribution of palladium complex 6. d) Isotope distribution of palladium complex 7. We were interested, if one could detect such mixed ligand palladium complexes in our cooperative catalysis reaction. A proposed mechanism for the palladium/NHC catalyzed annulation of enals with vinyl benzoxazinanone 1a begins with the decarboxylation of the vinyl benzoxazinanone to generate palladium complex 6 or 7 (Figure

Figure 6. Synthesis of palladium complex 9. a) Synthesis of [Pd(π-allyl)(NHC 4b)Cl] complex 8. b) Synthesis of mixed [Pd(π-allyl)(NHC 4b)(PPh3)BF4] complex 9. c) Xray structure of palladium complex 9: ORTEP diagram, Selected bond lengths and bond angles: C1-Pd1, 2.074(6) Å; P1-Pd1, 2.3167(17) Å; Pd1-C33, 2.220(12) Å; Pd1-C32, 2.187(10) Å; Pd1-C31, 2.194(14) Å; C31-C32-C33, 116.8(16)°; C41-P1-Pd1, 115.6(2) °; C1-Pd1-P1, 101.4(2) °. Ellipsoids are shown at 50% probability and hydrogen atoms are omitted for clarity. d) ESI-MS results of species 6-9 (See Supporting Information for details). The palladium intermediate 6, which is in agreement with our postulated mechanism, may be the catalytically active palladium species for the cooperative umpolung annulation. Although we were not able to isolate complex 6 for full characterization and X-ray diffraction analysis, we isolated its analogue 9, containing simple π-allyl as the ligand. Indeed, the [Pd(π-allyl)(NHC 4b)] chloride 8 can


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be conveniently synthesized in 70% yield by treating {[Pd(π-allyl)Cl]2} and NHC 4b with Et3N at room temperature (Figure 6a). Treatment of 8 with PPh3 in the presence of NaBF4 led to the 9 [(π-allyl)Pd(NHC 4b)(PPh3)(BF4)] in 75% yield (Figure 6b). 11c The structure of this mixed complex 9 was confirmed by ESI-MS spectroscopy and X-ray crystallography (Figure 6c).15 The solid-state structure contains a π-allyl ligand and an NHC 4b ligand in addition to the phosphine (Figure 6d). Furthermore, no interaction of the palladium center with the ortho-methyl group on the NHC ligand was observed. The features of this palladium complex, including accessibility and good air and moisture stability, promoted us to explore the catalytic potential of Pd/NHC/PR3 systems in another asymmetric reaction (vide infra, Table 3). Table 2. Combination of palladium complex and a NHC

Entry 1 2 3

[Pd] Complex 8 Complex 9 Complex 9

NHC 4b 4b 4a

3 3a’ 3a

Yield (%)b 45 50

drc 13:1 11:1

ee (%)d 96 36

a

The reactions were performed using 1.0 equiv of 1a (0.1 mmol) and 2.0 equiv of 2a in 1.5 mL THF, 12 h. b Isolated yield. cDetermined by 1H NMR spectroscopy. dThe ee value of 3 was determined by HPLC using a chiral column.

To distinguish between the potential role of π-allylpalladium 8 and 9 as an active catalyst or precursor, we distinguished the competency of palladium complex 8 and 9 in the catalytic process. No cycloadduct was formed when phosphine was omitted from the catalytic reaction of complex 8 (Table 2, entry 1). This lack of formation of cycloadduct is consistent with the lack of product formed in the catalytic reaction without phosphine additive (Table 1, entry 1). To our delight, the catalytic reaction of

complex 9 with precatalyst 4b in the presence of 1a and 2a at room temperature formed (4R,5S)-enantiomer of 3a’ in 45% yield and 96% ee after 12 h (Table 2, entry 2). The yield and enantiomeric excess is comparable to the results obtained with the in situ formed catalyst in the presence of 5 mol% of PPh3 (Table 1, entry 6, 49% yield and 97% ee). These results imply that a [Pd(π-allyl)(NHC)(PPh3)] species exists in the reaction pathway. By in situ mixing 9/NHC 4a in a ratio of 1:2 (entry 3), 36% ee of product 3a fits to the result obtained in the nonlinear relationship (Figure 4), indicating that the NHC coordinating to the palladium and NHC ligand exchange are fast. 5. The proposed mechanism Taking into account the combined results of this mechanistic study, a plausible mechanistic cycle, in which palladium catalysis is combined with asymmetric NHC organocatalysis, is outlined in Figure 7. Herein, the catalysis is initiated by the coordination of vinyl benzoxazinanone 1a to the mixed [Pd(NHC 4)(phosphine)] complex A, followed by the formation of an electrophilic palladium complex (B) upon decarboxylation.16 In the organocatalytic cycle, the addition of NHC organocatalyst 4 to the enal 2a forms the NHC-homoenolate C17 which undergoes conjugate addition to the in situ formed palladium complex B. The nucleophilic NHC-homoenolate C and the electrophilic palladium complex B operate in a cooperative fashion during this transformation (left cycle). Following the carbon–carbon bond formation, the release of the palladium complex A and tautomerization give rise to acyl azolium E, which then undergoes N-acylation cyclization to furnish the final product 3a and regenerates the NHC organocatalyst 4. 6. Extension of the palladium/NHC/PR3 complex Considering the detailed mechanism of the in situ reaction, a chiral nucleophilic NHC-homoenolate and a chiral electrophilic palladium complex are responsible for the observed enantioinduction in our cooperative annulation

Figure 7. Proposed catalytic cycles.



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reaction. These factors do not distinguish the excellent enantioselectivity for attack on [Pd(π-allyl)(NHC)(PPh3)] species from that for attack on [Pd(π-allyl)(PPh3)2] species. Further mechanistic studies were required to determine the active palladium catalytic species. This promoted us to explore the catalytic potential of Pd/NHC/PPh3 systems in other asymmetric reactions. Recently, the Xiao group reported an asymmetric palladium catalyzed protocol of a Pd(0) and chiral phosphoramidite for the annulation of sulphur ylides and vinyl benzoxazinanones in excellent stereoselectivities.18 To further study the interaction between the NHC, phosphine and palladium, we evaluated the palladium-catalyzed cycloaddition of the benzoxazinanone 1a with sulphur ylide 10a (Table 3). Table 3. Pd/NHC/PPh3-catalyzed asymmetric [4+1] a annulation reaction

Entry 1 2 3 4d 5 6 7 8 9 10e 11

[Pd] Pd(PPh3)4 Pd(PPh3)4 Complex 9 Complex 9 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(dba)2 Pd(dba)2 Pd(PPh3)4 Pd(dba)2

Phosphine none none none none none none none 5a 5b none none

NHC 4b none 4b 4c 4d 4e 4c 4c 4c 4c

Conv.(%)b 82 89 82 90 92 48 39 82 86 90

Mechanistic Studies on a Cooperative NHC Organocatalysis

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