Published on Web 03/24/2010
Platinum-Catalyzed Intramolecular Hydrohydrazination: Evidence for Alkene Insertion into a Pt-N Bond Jessica M. Hoover,‡ Antonio DiPasquale,† James M. Mayer,*,‡ and Forrest E. Michael*,‡ Department of Chemistry, UniVersity of Washington, Campus Box 351700, Seattle, Washington 98195-1700, and X-ray Crystallography Facility, College of Chemistry, UniVersity of California Berkeley, 32 Lewis Hall, Berkeley, California 94720 Received August 12, 2009; E-mail:
[email protected];
[email protected] Abstract: Dicationic (bpy)Pt(II) complexes were found to catalyze the intramolecular hydrohydrazination of alkenes. Reaction optimization revealed Pt(bpy)Cl2 (10 mol %) and AgOTf (20 mol %) in DMF-d7 to be an effective catalyst system for the conversion of substituted hydrazides to five- and six-membered N-amino lactams (N-amino ) N-acetamido at 120 °C, N-phthalimido at 80 °C, -OTf ) trifluoromethanesulfonate). Of the four possible regioisomeric products, only the product of 5-exo cyclization at the proximal nitrogen is formed, without reaction at the distal nitrogen or 6-endo cyclization. The resting states were found to be a 2:1 Pt-amidate complex (25, for N-acetamido) of the deprotonated hydrazide and a Pt-alkyl complex of the cyclized pyrrolidinone (20 for N-phthalimido). Both complexes are catalytically competent. Catalysis using 25 as the precatalyst shows no rate dependence on added acid (HOTf) or base (2,6-lutidine). The available mechanistic data are all consistent with a mechanism involving N-H activation of the hydrazide, followed by insertion of the alkene into the Pt-N bond, and finally protonation of the resulting cyclized alkyl complex by hydrazide to release the hydrohydrazination product and regenerate the active Pt-amidate catalyst.
Introduction
Intramolecular hydroamination reactions allow for the facile and efficient formation of nitrogen-containing heterocycles. The hydroamination of alkenes has been studied extensively and found to be effected by a variety of catalysts ranging from (d-block) transition metal and lanthanide catalysts to Brønsted acids and bases.1 The related amination reactions of alkenes with hydrazines (hydrohydrazinations) remain relatively unexplored despite the potential utility of such a reaction. The N-amino heterocycles that would result from an intramolecular hydrohydrazination reaction are motifs in a number of biologically relevant molecules2 and are used as chelating ligands for metal-mediated reactions.3 N-Aminopyrrolidines (SAMP and RAMP hydrazines) have also been used extensively as chiral controllers for a variety of transformations, either as auxiliaries (as in the SAMP and RAMP hydrazones)4 or as components of chiral ligands.5 Endocyclic dialkyl hydrazines, such as pyrazo†
University of California Berkeley. University of Washington. (1) Mu¨ller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. ReV. 2008, 108, 3795–3892. (2) Ku¨c¸u¨kgu¨zel, S. G.; Rollas, S.; Ku¨c¸u¨kgu¨zel, I.; Kiraz, M. Eur. J. Med. Chem. 1999, 34, 1093–1100, and references therein. (3) For instance: Hiroshi, Y.; Shuiji, K. Heterocycles 2007, 71, 699–709. (4) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58, 2253–2329. Dı´ez, E.; Fernandez, R.; Marque´s-Lo´pez, E.; Lassaletta, J. M. Org. Lett. 2004, 6, 2749–2752. Ferna´ndez, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.; Martı´n-Zamora, E. Angew. Chem., Int. Ed. 2002, 41, 831–833. ´ lvarez, E.; (5) Ros, A.; Alcarazo, M.; Iglesias-Sigu¨enza, J.; Dı´ez, E.; A Ferna´ndez, R.; Lassaletta, J. M. Organometallics 2008, 27, 4555– 4564. ‡
10.1021/ja906563z 2010 American Chemical Society
lidines, have been shown to have biological activity.6 Additionally, the N-N bond can be cleaved by a variety of methods to generate the corresponding amines, providing an alternate route to the corresponding hydroamination products.7 Odom and co-workers have developed a titanium-catalyzed addition of 1,1-disubstituted hydrazines to alkynes to yield the corresponding hydrazones and indoles.8 Carreira and co-workers have developed a versatile route to alkyl hydrazines from the reductive addition of azodicarboxylates to alkenes.9 The Rh(I) and Ir(I) hydroamination catalysts developed by Messerle, Field, and co-workers10 have recently been applied to catalyze the addition of mono- and 1,2-disubstituted hydrazines to alkynes.11 Additions of hydrazines to dienes have been achieved with a [Pd(allyl)Cl]2 catalyst,12 and a thermal hydrohydrazination reaction has recently been reported.13 There are to our knowledge no previous reports of a metal-catalyzed addition of a hydrazine N-H bond to an alkene. We describe here a platinum(6) Lebold, T. P.; Kerr, M. A. Org. Lett. 2009, 11, 4354–4357, and references therein. (7) Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637–640. (8) (a) Cao, C.; Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853–2856. (b) Li, Y.; Shi, Y.; Odom, A. J. Am. Chem. Soc. 2004, 126, 1796–1803. (c) Banerjee, S.; Barnea, E.; Odom, A. L. Organometallics 2008, 27, 1005–1014. (9) Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2006, 128, 11693–11712. (10) Burling, S.; Field, L. D.; Messerle, B. A.; Turner, P. Organometallics 2004, 23, 1714–1721. (11) Dabb, S. L.; Messerle, B. A. Dalton Trans. 2008, 6368–6371. (12) Johns, A. M.; Liu, Z.; Hartwig, J. F. Angew. Chem., Int. Ed. 2007, 46, 7259–7261. (13) Roveda, J.-G.; Clavette, C.; Hunt, A. D.; Gorelsky, S. I.; Whipp, C. J.; Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 8740–8741. J. AM. CHEM. SOC. 2010, 132, 5043–5053
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Table 1. Intramolecular Hydrohydrazination of Alkenyl Hydrazides 1a,b Catalyzed by Pt Complexes
Table 2. Effect of the Protecting Group on Intramolecular
Hydrohydrazination
% yieldb entry
catalysta
-NHAcc (11a)
-NPhthald (11b)
1 2 3 4 5 6 7 8 9 10 11
Pt(bpy)Me2 [Pt(bpy)(MeCN)2](OTf)2 Pt(bpy)Cl2 Pt(ppy)Me(DMSO) [Pt(ppy)Cl]2 Pt(ppy)Cl(DMSO) [Pt(ppy)(MeCN)2](OTf) [Pt(bph)(SEt2)]2 Pt(bph)(MeCN)2 [Pt(MeCN)4](OTf)2 Pt(PPh3)2Cl2
66 95-100 0 80 64 6 67 14 4 0 0
10 76 0 30 15 35 65 0 NDe 0 0
a bpy ) 2,2′-bipyridine; ppy ) cyclometalated 2-phenylpyridine; bph ) 2,2′-biphenyldiyl. b Determined by 1H NMR. c 120 °C. d 80 °C. e Not determined.
catalyzed intramolecular hydrohydrazination of olefins that likely proceeds through N-H activation of an alkenyl hydrazide followed by olefin insertion into a Pt-N bond. Results and Discussion I. Development of Catalytic Hydrohydrazination Reaction. Catalytic Conditions. Our studies began with Pt(bpy)Me2
because it is known to undergo oxidative addition to several heteroatom-heteroatom bonds14 and because of our interest in the oxidative addition of N-N bonds.15 Instead of N-N bond cleavage, treatment of alkenyl hydrazide 1a with 10 mol % Pt(bpy)Me2 results in catalytic cyclization of the hydrazide to the N-aminopyrrolidinone 11a, a net addition of the hydrazide N-H to the alkene. [In this report, compounds 1-7 are substrates, 11-17 are their respective cyclized products, and 20-25 are platinum complexes.] Of the four possible hydrohydrazination products, only a single regioisomer of 11a is formed. No cyclization of the distal nitrogen was observed, and the proximal nitrogen undergoes 5-exo cyclization exclusively. After investigation of a series of bipyridine (bpy)-, cyclometalated 2-phenylpyridine (ppy)-, and 2,2′-biphenyldiyl (bph)ligated Pt complexes, we found several other bpy and ppy complexes to be competent catalysts for this hydrohydrazination reaction (Table 1). The highest conversion was observed using [Pt(bpy)(MeCN)2](OTf)2 as the catalyst (-OTf ) trifluoromethanesulfonate). Similar conversions were observed when this catalyst was prepared in situ by addition of AgOTf to Pt(bpy)Cl2. Dimethylformamide (DMF) proved necessary as a solvent. When other polar or high-boiling solvents were employed (DMSO-d6, CD3CN, CD2Cl2, THF-d8, toluene-d8, p-dioxaned6), low conversion of 1a to 11a was observed (0-15% after 10 h at 120 °C), while reactions in DMF-d7 under the same conditions reached 48% completion. The quality of the DMF (14) Rendina, L. M.; Puddephatt, R. J. Chem. ReV. 1997, 97, 1735–1754. (15) Hoover, J. M.; Freudenthal, J.; Michael, F. E.; Mayer, J. M. Organometallics 2008, 27, 2238–2245. 5044
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a
hydrazide
NR2
% yield of 11a
1a 1b 1c 1d 1e 1f 1g 1h 1i
NHAc NPhthal NHBz NHTFA NHCbz NHBoc NHTs NHPh NMe2
94 20 (76b) 77 100 22 0 7 16 16
Determined by 1H NMR. b 80 °C.
was found to be crucial; low water content DMF purchased from ACROS was necessary for reproducibly high conversion.16 Protecting Groups. Alkenyl hydrazides bearing various protecting groups (1a-i) were submitted to the optimized catalytic conditions of 24 h at 120 °C in DMF-d7 with 10 mol % [Pt(bpy)(MeCN)2](OTf)2 (Table 2). It was found that substrates with an amide protecting group on the distal nitrogen (1a-d) resulted in the highest yields. The N-aminophthalimide substrate (1b) decomposes at 120 °C to give predominantly isomerization to internal alkenes, but at 80 °C this isomerization is reduced and much higher conversion to 11b is obtained within 24 h. Carbamates (1e,f) and sulfonamides (1g) gave much poorer conversion; in the case of the Boc-protected substrate, thermal deprotection was observed. More basic hydrazines, such as alkyl- and aryl-substituted compounds 1h and 1i, also gave low conversion (16%). The trifluoroacetamide-protected substrate gave the highest yield but was not chosen for further study due to the instability of H2NNHTFA.17 Instead we have focused on the acetyl protecting group (a) or in some cases phthalimide (b) due to its milder reaction and deprotection conditions. II. Scope of Catalytic Hydrohydrazination Reaction. Synthesis of Hydrazide Substrates. A variety of alkenyl hy-
drazide substrates were chosen for further study. Hydrazides connected to the alkenyl substituent via an amide linkage (1-6) were prepared by reaction of the terminal hydrazide (AcNHNH2 (a) or PhthalNNH2 (b)) with the corresponding acid chloride. The acetyl-protected alkyl hydrazide (7a) was generated by nucleophilic addition of AcNHNH2 to the corresponding alkyl bromide. The phthalimide-protected alkyl hydrazide (7b) was instead prepared from the condensation of N-aminophthalimide with the appropriate aldehyde followed by reduction of the hydrazone to the hydrazine. Hydrazide Cyclization to N-Amino Heterocycles. The standard hydrohydrazination conditions are effective at forming both five- and six-membered ring cyclization products of hydrazides (Scheme 1). The cyclizations to form N-aminolactams 11-16 proceed without the formation of byproducts, and in most cases complete conversion is achieved within 24 h. Selective conversion to a single regioisomer is observed; no reaction occurs at the distal nitrogen, and no 6-endo cyclization product forms. The more basic hydrazides 7a,c are more challenging substrates. (16) Benchtop solvent, even freshly distilled, resulted in inconsistent yields. (17) Bredikhin, A.; Tu´brik, O.; Sillard, R.; Ma¨eorg, U. Synlett 2005, 1939– 1941.
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Scheme 1. Intramolecular Hydrohydrazination To Form N-Amino Heterocycles
a Yields given are isolated yields after 1 day unless otherwise noted. Pt(bpy)Cl2 (10 mol %); AgOTf (20 mol %); DMF; T ) 80 °C when NR2 ) NPhthal, 120 °C when NR2 ) NHAc. b 2 days. c Reaction mixture was resubmitted to reaction conditions to obtain complete conversion. d Percent conversion by 1H NMR.
The conversions of 7a,c to 17a,c reach only ∼70% with 10 mol % catalyst. Surprisingly, longer reaction times (2 days) and higher catalyst loadings (20 mol %) do not improve conversion. In addition, the phthalimide-protected analogue, 7b, shows no reaction under the hydrohydrazination conditions. The poor yield of N-acetamidopiperidine product 17a is due to difficulty in separating it from starting hydrazide by silica column chromatography. The benzoyl protected analogue (17c) did not suffer from this problem. The thermal hydrohydrazidation of 7c has recently been reported,13 and the Pt-catalyzed conditions reported here appear to provide no significant improvement over the thermal conversion of hydrazides with an amine-type linker (Scheme 1, entry 7). The hydrazides with an amide-type linker, however, do not undergo thermal cyclization; no conversion of 1a is achieved in the absence of a Pt catalyst after 1 day at 120 °C in DMF-d7. Both longer chains (N-acetamidoheptenamide) and internal alkenes (N-acetamido- and N-phthalimido-4-hexenamide) are unreactive under these conditions, in addition to the Nacetamidoallyl carboxamide. The related amines (such as N-benzyl-4-pentenamide) do not cyclize to the pyrrolidine under these conditions, suggesting that this reaction may be unique to hydrazides.
The protecting group on the distal nitrogen appears to have some influence on the diastereoselectivity of the cyclization, as indicated by products 12 and 13. The diastereomers were assigned by 2D COSY and NOESY analyses (Figures S1-S9), and the ratios determined by 1H NMR spectroscopy and GCMS. In almost all cases, we found the trans isomer to be favored, with ratios varying from 1:1 to 3:1 for 12 and from 2.5:1 to 6:1 for 13 depending upon the choice of -NR2. The influence of protecting groups on diastereoselectivity has been observed in the formation of pyrazoles where cyclization occurs at the protected distal nitrogen.18 The related effect observed in the formation of these N-amino lactams in which the relevant protecting group is on an exocyclic nitrogen is less pronounced. The N-amidopyrrolidinones and N-phthalimidopyrrolidinones can be deprotected to give the free N-aminopyrrolidinones (see Supporting Information).19 III. Isolation and Characterization of Platinum Complexes. A number of platinum complexes have been isolated as part of efforts to understand the mechanism of hydrohydrazination. The synthesis and characterization of platinum-alkyl complexes and (18) de los Santos, J. M.; Lo´pez, Y.; Aparicio, D.; Palacios, F. J. Org. Chem. 2008, 73, 550–557. (19) Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637–640. J. AM. CHEM. SOC.
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Figure 1.
Hoover et al.
1
H NMR spectra of (a) Pt-amidate complex 23 and (b) Pt-alkyl complex 21 in DMF-d7 at 300 MHz.
then -amidate complexes are described, as well as the potential involvement of these species in the catalytic cycle(s). A. Platinum Alkyl Complexes. [(bpy)Pt(CH2CH(CH2)2C(O)NNPhthal)(CD3CN)](OTf) (20). The reaction of [Pt(bpy)(MeCN)2]-
(OTf)2 and 1b in DMF-d7 at 80 °C forms a new Pt-alkyl complex (20) as the sole platinum species observed in solution under both catalytic and stoichiometric conditions (eq 1). Complex 20 is also formed on treatment of [Pt(bpy)(MeCN)2](OTf)2 with 1b in DMF-d7 at room temperature, and no intermediates are observed. Complex 20 has the expected 1 H NMR spectrum for a complex with an unsymmetrical Pt center with key resonances including a characteristic methine multiplet at 4.1 ppm in addition to an upfield methylene signal (δ ) 1.47) that displays coupling to Pt (JPtH ) 69 Hz). The couplings and connectivity of these signals, as indicated by 1D 1 H NMR and 2D COSY experiments, are consistent with the assignment of 20 as the Pt-alkyl complex shown in eq 1. The presence of a -OTf anion was confirmed by 19F NMR spectroscopy (δ ) -79.5 ppm). ESI-MS analysis (CH3CN) shows the expected mass (m/z ) 594) and isotope pattern for 20 with loss of solvent.
[(bpy)Pt(CH2CH(CH2)2C(O)N-N(CH3)2)](OTf) (21). Heating [Pt(bpy)(MeCN)2](OTf)2 with N,N-dimethylaminohydrazide 1i at 120 °C in DMF-d7 also results in formation of a Pt-alkyl complex (21), similar to 20 but with the chelating dimethylamino group taking the place of solvent (eq 2). Like 20, the 1H NMR spectrum of 21 shows the expected bpy and methylene resonances, and the characteristic methine multiplet at 4.34 ppm. In addition, there are two diastereotopic methyl groups each with distinct Pt-satellites (4.14 and 3.77 ppm, 3JPtH ) 14.7 and 14.1 Hz, Figure 1b), indicating that the dimethylamino group is coordinated to Pt. The 19F NMR spectrum (δ ) -79.6 ppm) and ESI-MS (m/z ) 492) analysis are consistent with this 5046
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assignment of 21. These resting states 20 and 21 are analogous to those observed in Pt- and Pd-catalyzed hydroamination systems, which involve protonation of a metal-alkyl species to release the cyclized hydroamination product.20
A related Pt-alkyl metallacycle (22) has been isolated from the catalytic reaction mixtures of hydrazide 8a. The cyclized hydrohydrazination product appears to be formed in good yield (60-70% yield) by 1H NMR spectroscopy but, like 17a, could not be purified by silica column chromatography. Complex 22 has been characterized by 1H, 19F, and 2D COSY NMR spectroscopies. The 1H NMR spectrum of 22 shows the characteristic methine resonance (δ ) 4.2 ppm), eight diastereotopic methylene proton resonances, and a broad singlet at 11.2 ppm suggestive of an NH. The ESI-MS analysis (m/z ) 506) is consistent with a monocation of this type. All of the data indicate a Pt-alkyl complex as shown in eq 3. Unlike 20 and 21, which are formed from alkenyl hydrazide 1 with the amide linker, 22 is the Pt-alkyl complex formed from an alkenyl hydrazide with an amine linker. Complex 22 is the predominant Pt species in solution during the catalytic reaction of 8a when monitored by 1H NMR spectroscopy.
Catalytic Activity of [(bpy)Pt(CH2CH(CH2)2C(O)N-N(CH3)2)](OTf) (20). Complex 20 is a competent catalyst for the hydro-
hydrazination reaction. Heating a solution of isolated 20 with (20) (a) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127, 1070–1071. (b) Cochran, B. M.; Michael, F. E. J. Am. Chem. Soc. 2008, 130, 2786–2792.
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to the double-bond character of C13-N4 (1.295 (7) Å) confirm the deprotonation of N4.
Figure 2. ORTEP of [Pt(bpy)(κ2-Me2NNdC(O)(CH2)2CHdCH2)]+, the cation of 23, with 50% probability ellipsoids. The triflate counterion was omitted for clarity. Table 3. Selected Bond Distances (Å) and Angles (deg) in 23
Pt1-O1 Pt1-N3 N3-N4 O1-C13 N4-C13 C16-C17
1.980(3) 2.034(4) 1.497(6) 1.312(6) 1.295(7) 1.304(8)
O1-Pt1-N3 O1-C13-N4
173.87(16) 125.3(5)
10 equiv of 1b under the typical reaction conditions (DMF-d7, 80 °C) results in 70% conversion of 1b to 11b after 24 h. Treatment of 20 with HOTf (2 µL, 3 equiv) results in formation of 10b in ∼25% yield after 3 days at 80 °C, with isomerization of 1b to the R,β-unsaturated hydrazide accounting for the remaining organic material. Although significant isomerization is not observed under the chosen catalytic conditions (80 °C), it has been observed under more forcing conditions (120 °C, see Section I). Additionally, treatment of 20 with the hydrazide AcNHNHAc21 (40 equiv) results in formation of 11b and isomerization of 1b to the R,β-unsaturated hydrazide (1:1 ratio) and complete conversion of 20 to the amidate complex 24 (see below) after 24 h heating at 80 °C in DMF-d7. These data suggest that turnover from 20 is capable of proceeding through protonation by the hydrazide 1b.
Heating isolated 23 in DMF-d7 results in slow conversion to 21 over the course of 2 weeks at 120 °C (eq 4). When 23 is added to a catalytic hydrohydrazination reaction of 1i in progress, the conversion of 23 to 21 is much faster (complete conversion in
