mechanistic insights into the palladium(ii)-catalyzed intramolecular cyclization of...

Chinese Journal of Chemistry, 2009, 27, 1733—1740 Full Paper

* E-mail: [email protected]; [email protected]; Fax: 0086-021-64166128 Received January 19, 2009; revised April 15, 2009; accepted April 30, 2009. Project supported by the National Science Foundation of China (Nos. 20875097, 20572123).

© 2009 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Mechanistic Insights into the Palladium(II)-catalyzed Intramolecular Cyclization of o-Alkynylphenylphosphonamide and N-(o-Alkynylphenyl)acetamide by Electrospray Ionization

Mass Spectrometry

ZHOU, Jinga(周静) TANG, Weib(唐伟) GUO, Yinlong*,a(郭寅龙) DING, Yixiang*,b(丁贻祥)

a Shanghai Mass Spectrometry Center, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China

b CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China

The intramolecular cyclization of o-alkynylphenylphosphonamide and N-(o-alkynylphenyl)acetamide was monitored by electrospray ionization mass spectrometry (ESI-MS) and its tandem version (ESI-MS/MS). The pro-posed intermediates were successfully intercepted and characterized. In addition, the intermediates composed of the substrate coordinated to the palladium(II) center in the reaction of o-alkynylphenylphosphonamide were unexpected before, and this interesting phenomenon of the substrate coordination seems associated with the unique structure of substrates.

Keywords palladium-catalyzed cyclization, ESI-MS, intermediate

Introduction

The palladium(II)-catalyzed cyclization of alkynes bearing various oxygen- and nitrogen-containing func-tional groups is one of the most general processes in organic synthesis, which can construct various hetero-cycles in an efficient and atom economic way.1-10 The resulting heterocycles have often demonstrated impor-tant biological activities, such as cytotoxicity,11 antitu-mor,12,13 cardiotonic,14 antineoplastic,15 and many other pharmaceutically useful properties.16-20 Despite the im-portance of its synthetic utility, this kind of reaction still has a number of unaccountable features, including the mechanistic details.

Based on the information from experimental de-tails,21-26 this chemistry is considered to proceed through initial formation of a π-alkyne complex, which readily undergoes intramolecular nucleophilic attack by a neighboring nucleophile. The resulting heterocyclic or-ganopalladium intermediate can undergo a variety of very useful further transformations, including protonolysis, hydride elimination, or CO or alkene insertion, finally to give various heterocycles (Scheme 1).

From the above cycle, the π-alkyne intermediates and the organopalladium intermediates are the key for the process. Through years, the π-alkyne species and organopalladium species were identified by IR, and 1H

NMR and X-ray techniques.27-31 However, for the full process of the Pd(II)-catalyzed intramolecular cyclization, there are only a few reports. Müller and cowork-ers gave some evidence for mechanistic details and lim-iting factors for the Pd(II)-catalyzed intermocular cycli-zation by calorimetry, in situ IR and NMR spectros-copy.32 They proved that the substrate initially coordi-nated via the amine lone pair rather than the alkyne group, and the isomerization and coordination of the alkyne were necessary prior to the nucleophilic attack.

The development of electrospray ionization (ESI) techniques has provided the possibility for the detection and characterization of the organometallic intermediates in recent years.33-35 ESI-MS is a technique that allows the ions present in solution to be transferred into the gas phase, where they can be analyzed and eventually char-acterized. Thus, straightforward analytical applications of ESI-MS and its tandem version ESI-MS/MS to the char-acterization of organometallic intermediates become the technique of choice for solution mechanism studies in chemistry.36-44

Herein, we report the ESI-MS and ESI-MS/MS in-vestigation for the Pd(II)-catalyzed intramocular cycli-zation of o-alkynylphenylphosphonamide (Scheme 2) and N-(o-alkynylphenyl)acetamide (Scheme 3).45,46

1734 Chin. J. Chem., 2009, Vol. 27, No. 9 ZHOU et al.


Scheme 1 The plausible catalytic cycle for Pd(II)-catalyzed cyclization

Scheme 2 The palladium-catalyzed cyclization of o-alkynylphenylphosphonamide

Scheme 3 The palladium-catalyzed cyclization of N-(o- alkynylphenyl)acetamide

Experimental

Material and sample preparation

Solvents such as acetonitrile (CH3CN) are of HPLC-grade from Aldrich Co. (St. Louis, MO). The major substrates, o-alkynylphenylphosphonamide and N-(o-alkynylphenyl)acetamide, were prepared as de-scribed in the literature.45

Apparatus and analytical conditions

The ESI-MS control experiment and the monitoring experiment of the reacting solutions were performed on an Applied Biosystems Mariner time-of-flight mass spec-

trometer with a microspray ion source. Mass spectra were recorded in the positive ion mode. The following condi-tions were used: spray tip potential, 3800 V; nozzle po-tential, 80 V; and nozzle temperature, 140 ℃, the detec-tor voltage was 1950 V, and spectra were collected from m/z 300 to 1600 at an acquisition rate of 2 s per scan. The CSI-MS control experiment and the monitoring experi-ment of the reacting solutions were performed on the above mass spectrometer with a microspray ion source at －20 ℃. Mass spectra were recorded in the positive ion mode.

Accurate mass determination and isotopic distribu-tion comparison were performed on a Bruker Daltonics APEX III ESI-FTMS instrument equipped with a 7.0 tesla shielded superconducting magnet. The vacuum was maintained by means of mechanical vacuum pumps followed by turbomolecular pumps in two different re-gions: ion source (maintained ca. 3.7×10－7 torr) and cell region (maintained ca. 6.5×10－10 torr). The ions were generated from an external electrospray ionization source. Typically, the electrospray flow rate was 10 µL/min. The spray was directed into a heated glass cap-illary drying tube with both Ni-coated ends remaining at temperature about 450 K. Typically, a high voltage of about 4500 V was applied between the endplate and the spray needle. Then the ions were accumulated in the

Palladium-catalyzed cyclization Chin. J. Chem., 2009 Vol. 27 No. 9 1735


RF-only hexapole ion storage region for 0.3 s, focused and steered through the ion transfer region. They were finally transferred into the “infinity” cell with a “side-kick” voltage perpendicular to magnetic field for trap-ping and detection. All parameters from the ion gene- ration to trapping were optimized on the tuning pars based on the maximum intensity of parent ion achieved. All experimental sequences, including scan accumula-tion and data processing, were performed with Bruker Xmass 6.1.2 software. The instrument was calibrated externally with PEG1000 methanol solutions.

Collision induced dissociation (CID, collision gas being helium) was performed in a Finnigan TSQ triple quadrupole mass spectrometer (Thermo Finnigan, Quantum Access™) equipped with a standard ESI source. The collision energy ranged from 5 to 10 eV, depending on the dissociation liability of the precursor ion. Data acquisition and analysis were done with the Xcalibur (version 2.0, Thermoquest Finnigan) software package.

Results and discussion

ESI-MS monitoring for the cyclization of o-al-kynylphenylphosphonamide

The cyclization of o-alkynylphenylphosphonamide was first studied. A solution of o-(1-alkynyl)phenyl-phosphoamide monoethyl ester 1a (0.01 mmol) and PdCl2(CH3CN)2 (0.001 mmol) in CH3CN (5 mL) was stirred at 80 ℃. Next, 2 µL of this solution was diluted with 100 µL of CH3CN and transferred into the ESI source to monitor the cationic species formed.

After ten minutes of the reaction with

o-alkynylphenylphosphonamide monoethyl ester 1a, two clusters at m/z 885 and 1274 were seen clearly, which could be assigned to the cationic species 4a and 4a' (Figure 1). These palladium species involved in the catalytic cycle were also detected and characterized by high resolution accurate mass measurements of their corresponding ions with the ESI-FTMS instrument (principal ion of m/z 885.1577 in Figure S2: calculated for C42H49Cl2N2O4P2

106Pd＋ of m/z 885.1573; principal ion of m/z 1274.2889 in Figure S3: calculated for C63H74Cl3N3O6P3

106Pd＋ of m/z 1274.2888). The reac-tion was continuously monitored for 4 h, and no other cationic species was detected while the signal intensity for 4a and 4a' decreased as time went on.

For further structural characterization, the 106Pd iso-topologue ions of m/z 885 and 1274 were selected for ESI-(＋)-MS/MS experiments via collision dissociation (CID), respectively. The precursor ion at m/z 1274 yielded m/z 885 by the loss of 389 Da, and the precursor ion at m/z 885 displayed the similar dissociation pattern of the precursor ion at m/z 1274 by the loss of 389 Da to yield m/z 496 (Figure 2). Because the molecular weights of the substrate 1a and product 2a are the same (389 Da), it is difficult to decide which one is coordinating to pal-ladium from the MS experiment. However, considering the fact that the coordinating potential of 1a is recog-nized to be stronger than 2a, it was thought that 4a and 4a' were substrate-coordinating intermediates. Besides, the experimental isotopic distributions of the palladium- containing species matched the theoretical ones, as simu-lated by the Bruker Xmass 6.1.2 program. So, the palla-dium species could be further confirmed as [(1a)Pd- C21H24ClNO2P]＋ 4a and [(1a)2Pd-C21H24ClNO2P]＋ 4a', respectively.

Figure 1 ESI-(＋)-MS of the sample taken at 10 min after mixing o-alkynylphenylphosphonamide monoethyl ester 1a and PdCl2(CH3CN)2.



Figure 2 MS/MS for ions at: (a) m/z 885, (b) m/z 1274.

The existence of the palladium species 4a and 4a'

could indicate that the heterocyclic organopalladium intermediates indeed existed. However, the π-alkyne spe-cies were not intercepted. This kind of species may be too unstable to be detected under the ESI experimental conditions. Because cold-spray ionization (CSI) tech-nique was thought to be an efficient method to detect unstable species,47-49 subsequently a CSI-MS experi-ment was performed. With the operations addressed above, extra two palladium ion signals at m/z 573 and 921 were found as show in Figure 3, and they were as-signed to the phosphonamide coordinated cationic spe-cies [(1a)PdCl(CH3CN)]＋ 3a and [(1a)2PdCl]＋ 3a'. Because the equilibria of coordination via alkyne and coordination via amide were reported by Müller and coworkers (see the equation between 3A and 3B in Scheme 1), the existence of phosphonamide coordinated cationic species 3a and 3a' could support the existence of the π-alkyne intermediates in certain degree.

Compared with the intermediates shown in Scheme 1, the palladium species 3a, 3a', 4a and 4a' are composed of one or two molecules of the substrate, which is an interesting phenomenon. We searched carefully for the substrate-free coordinated species, but drew a blank. This interesting phenomenon of multi-substrate coordi-nation may be due to unique structure of the substrate. To see if this kind of phenomenon exists in other cycli-zation, the reaction of N-(o-alkynylphenyl)acetamide was then investigated.

ESI-MS observation for the cyclization of N-(o-alkynylphenyl)acetamide

With the operations addressed above, the acetonitrile solution of N-[o-(1-alkynyl)phenyl]acetamide 1b and PdCl2(CH3CN)2 was infused into the ESI source to monitor the cationic species formed. Figure 4 showed a typical ESI-(＋)-MS of the reaction mixture. As shown, there are four clusters at m/z 225, 381, 419 and 444 at-tributable to the cationic species [PdCl(CH3CN)2]

＋ , [C16H12NO-Pd(CH3CN)]＋ (4b), [(1b)PdCl(CH3CN)]＋ (3b) and [Pd2Cl3(CH3CN)3]

＋ , respectively. Clearly, there was no multi-substrate coordinated species ob-served.

The 106Pd isotopologue ions of m/z 381 and 419 were also selected for ESI-(＋ )-MS/MS characterization. They mainly fragment via a structurally diagnostic pathway that proceeds by the loss of CH3CN to give [C16H12NO-Pd]＋ of m/z 340 and [1bPdCl]＋ of m/z 378 (Figure 5). The existence of the palladium species 3b and 4b could indicate the proposed intermediates 3 and 4 in Scheme 1.

Through the full monitoring process, no multi- substrate coordinated palladium species like 3a and 4a was detected. Although more experiments of substrates with different structures should be carried out, now it is still reasonable to say that the phenomenon of multi- substrate coordination is associated with the structure of substrate.



Figure 3 CSI-(＋ )-MS of the sample taken from the solution of o-alkynylphenylphosphonamide monoethyl ester 1a and PdCl2(CH3CN)2.

Figure 4 ESI-(＋)-MS of the sample taken at 10 min after mixing N-[o-(1-alkynyl)phenyl]acetamide 1b and PdCl2(CH3CN)2.



Figure 5 MS/MS for ions at: (a) m/z 381, (b) m/z 419.

Scheme 4 Proposed catalytic cycle for the Pd(II)-catalyzed cyclization based on the MS study



Proposed catalytic cycle for the Pd(II)-catalyzed cy-clization

In this study, the intermediates 3b (m/z 419) and 4b (m/z 381) were observed for the cyclization of N-(o-alkynylphenyl)acetamide, and the multi-substrate coordinated intermediates 3a (m/z 573), 3a' (m/z 921), 4a (m/z 885) and 4a' (m/z 1274) were seen for the cy-clization of o-alkynylphenylphosphonamide. Based on the above information, it was possible to interpret the mechanism of the intramolecular cyclization, and the catalytic cycle was shown as Scheme 4. When the reac-tion was initiated, substrate 1 coordinated to palladium and intermediates 3A and 3B were formed. Following a nucleophilic attack by nitrogen on the complex took place to afford intermediate 4, which is a substrate- coordinated vinyl-palladium complex. Then, the palla-dium-carbon single bond is protonated irreversibly with final product 2 formed.

Conclusion

In conclusion, the intermediates in the intramolecular cyclization of o-alkynylphenylphosphonamide and N-(o- alkynylphenyl)acetamide were successfully intercepted and characterized by ESI-MS and ESI-MS/MS. Based on these, the proposed catalytic cycle could be con-firmed. The intermediates composed of the substrate coordinated to the palladium center in the reaction of o-alkynylphenylphosphonamide were unexpected before, and this interesting phenomenon of multi-substrate co-ordination seems associated with the unique structure of substrates.

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(E0901191 Cheng, F.; Zheng, G.)

mechanistic insights into the palladium(ii)-catalyzed intramolecular cyclization of...

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