Platinum-catalyzed intramolecular hydrohydrazination: Evidence for alkene insertion into a Pt-n bond

Article abstract of DOI:10.1021/ja906563z

Dicationic (bpy)Pt(II) complexes were found to catalyze the intramolecular hydrohydrazination of alkenes. Reaction optimization revealed Pt(bpy)Cl ₂ (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 A°C, N-phthalimido at 80 A°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.

Full text of DOI:10.1021/ja906563z

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: mayer@chem.washington.edu; michael@chem.washington.edu
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.
lidines, have been shown to have biological activity.6 Additionally,
Introduction
the N-N bond can be cleaved by a variety of methods to generate
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 unex-
plored despite the potential utility of such a reaction.
The N-amino heterocycles that would result from an intramo-
lecular 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-
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 knowl-
edge 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.
† University of California Berkeley.
‡ University of Washington.
(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.
(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. D´ıez, 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.; Mart´ın-Zamora, E. Angew. Chem.,
Int. Ed. 2002, 41, 831–833.
(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.
´
(5) Ros, A.; Alcarazo, M.; Iglesias-Sigu¨enza, J.; D´ıez, E.; Alvarez, E.;
Ferna´ndez, R.; Lassaletta, J. M. Organometallics 2008, 27, 4555–
4564.
(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.
9
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A R T I C L E S
Hoover et al.
Table 1. Intramolecular Hydrohydrazination of Alkenyl Hydrazides
1a,b Catalyzed by Pt Complexes
Table 2. Effect of the Protecting Group on Intramolecular
Hydrohydrazination
hydrazide
NR2
% yield of 11a
% yieldb
1a
1b
1c
1d
1e
1f
1g
1h
1i
NHAc
NPhthal
NHBz
NHTFA
NHCbz
NHBoc
NHTs
94
20 (76b)
entry
catalysta
-NHAcc (11a)
-NPhthald (11b)
77
100
22
0
7
16
16
1
Pt(bpy)Me2
66
10
76
0
2
3
[Pt(bpy)(MeCN)2](OTf)2
Pt(bpy)Cl2
95-100
0
4
5
6
7
8
9
10
11
Pt(ppy)Me(DMSO)
[Pt(ppy)Cl]2
80
64
6
67
14
4
30
15
35
65
0
NHPh
NMe2
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
Determined by H NMR. b 80 °C.
a
1
NDe
0
0
0
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.
0
a bpy ) 2,2′-bipyridine; ppy ) cyclometalated 2-phenylpyridine; bph
) 2,2′-biphenyldiyl. Determined by H NMR. c 120 °C. d 80 °C. e Not
b
1
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 hydro-
hydrazination 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)-, cyclometa-
lated 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 ) trifluo-
romethanesulfonate). Similar conversions were observed when
this catalyst was prepared in situ by addition of AgOTf to
Pt(bpy)Cl2.
Hydrazide Cyclization to N-Amino Heterocycles. The stan-
dard 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 conver-
sion 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.
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-dioxane-
d6), 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.
(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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5044 J. AM. CHEM. SOC. VOL. 132, NO. 14, 2010

Pt-Catalyzed Intramolecular Hydrohydrazination
A R T I C L E S
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 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),
1
and the ratios determined by H NMR spectroscopy and GC-
MS. 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
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 hydrohydrazi-
dation 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 cycliza-
tion; 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 N-
acetamidoallyl 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.
(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.
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A R T I C L E S
Hoover et al.
Figure 1. 1H 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).
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. Platinum Alkyl Complexes. [(bpy)Pt(CH2CH(CH2)2C(O)N-
NPhthal)(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
1H 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
1H 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 spec-
troscopy (δ ) -79.5 ppm). ESI-MS analysis (CH3CN) shows
the expected mass (m/z ) 594) and isotope pattern for 20 with
loss of solvent.
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 diaste-
reotopic 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
1
monitored by H NMR spectroscopy.
[(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
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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Pt-Catalyzed Intramolecular Hydrohydrazination
A R T I C L E S
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
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 <1 h). This appears to indicate that this process
is accelerated by the presence of hydrazide or acid. This could
be consistent with acid-promoted tautomerization to the N-bound
Pt(amidate) followed by insertion of the alkene as a possible
pathway to 21.
[(bpy)2Pt2(AcNNAc)](OTf)2 (24) and [(bpy)2Pt2(AcNNC(O)-
CH2CH2CHdCH2)](OTf)2 (25). 1,2-Diacetyl hydrazide (Ac-
NHNHAc) reacts slowly with [Pt(bpy)(MeCN)2](OTf)2 in DMF-
d7 at RT. After ∼15 h, 1H NMR spectra showed complete
conversion to a new Pt species (24, eq 5), which was precipitated
from solution with ether. The 1H NMR spectrum of 24 indicates
incorporation of 1 hydrazide per 2 (bpy)Pt fragments. No NH or
hydride resonances are observed. ESI-MS analysis (CH3CN) shows
a prominent ion with two (bpy)Pt units per hydrazide (m/z ) 965),
with an isotope pattern consistent with [Pt2bpy2(AcNNAc)(OTf)]+.
All of these data are consistent with a 2:1 complex with C2h
symmetry in which each bpy ligand is asymmetric (eq 5). This
coordination mode has been observed for monomeric phosphine-
ligated Pt complexes of hydrazides.22
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,ꢀ-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,ꢀ-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.
B. Platinum Amidate Complexes. [Pt(bpy)(K2-Me2NNdC(O)-
(CH2)2CHdCH2)](OTf) (23). To obtain insight into the reaction
mechanism prior to metallacycle formation, mixtures of
[Pt(bpy)(MeCN)2](OTf)2 and 1i in DMF-d7 were monitored by
1H NMR spectroscopy at RT (21 forms at 120 °C). Within
minutes, complete conversion to a single Pt species (23) is
observed. Complex 23 was obtained cleanly by precipitation
1
with ether. The H NMR spectrum of 23 shows eight bpy
Similarly, heating a mixture of [Pt(bpy)(MeCN)2](OTf)2 and
1a at 120 °C in DMF for 30 min results in the formation of the
analogous 2:1 complex 25 (eq 6). The 1H NMR spectrum of 25
shows 16 aryl resonances (from two asymmetric and inequiva-
lent bpy ligands), terminal alkene resonances, two methylene
resonances, and an acetyl methyl resonance; no NH signals are
observed. The alkene resonances are only slightly shifted (5.05
and 5.92 ppm in DMF-d7) from those of the free hydrazide (4.99
and 5.87 in DMF-d) and show no coupling to Pt. 19F NMR (δ
) -79.8 ppm) confirms the presence of triflate counterions.
The masses (m/z ) 1005, 428) and isotope pattern observed by
ESI-MS analysis are consistent with the formulation of 25 as a
resonances, terminal and internal alkene resonances (4.98 and
5.85 ppm in DMF-d7) that are only slightly shifted from those
of the free hydrazide (5.00 and 5.86 ppm in DMF-d7), two
methylene resonances, and a single Pt-CH3 signal (δ ) 3.32,
JPtH ) 11 Hz, Figure 1a). No NH proton is observed, and ESI-
MS analysis (m/z ) 492) indicates 23 to be isomeric with 21.
These data indicate that 23 is the Pt(amidate) monocation
with a chelating deprotonated hydrazide as shown in eq 4. X-ray
analysis performed on crystals grown from a DMF-d7/ether
solution at -37 °C confirms this assignment (Figure 2, Tables
3 and S-1). The presence of a single OTf- counterion in addition
(21) AcNHNHAc was used because it is similar to the substrates but allows
for cleaner 1H NMR differentiation from the phthalimide Pt complex
(22) Dilworth, J. R.; Kasenally, A. D. J. Organomet. Chem. 1973, 60, 203–
20.
207.
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A R T I C L E S
Hoover et al.
2:1 complex. These data together indicate 25 to be a 2:1 complex
with Cs symmetry as shown in eq 6.
cesses.24 Addition of PhSiMe3 (1 equiv) to the catalytic reaction
of 1a in DMF-d7 at 120 °C results in no change in the rate of
conversion to 11a (i.e., 100% after 15 h) and no consumption
of PhSiMe3, indicating that hydrohydrazination is not simply a
Brønsted acid-catalyzed process. To further probe the role of
acid and base in the catalytic process, a solution of isolated 25
and 1a (10 equiv) in DMF-d7 was divided into three equal
portions in three J. Young tubes. To one tube was added HOTf
(9 equiv), and to another was added 2,6-lutidine (2.5 equiv);
all three tubes were sealed, heated in a 120 °C oil bath, and
1
monitored periodically by H NMR spectroscopy. The three
Complex 25 is the predominant Pt species observed in
solution by 1H NMR spectroscopy during the catalytic conver-
sion of 1a to 11a. When isolated 25 is treated with 1a (15 equiv),
complete conversion to 11a is observed after 24 h at 120 °C.
Attempts to observe formation of a Pt-alkyl species analogous
to 20 and 21 have been unsuccessful. Heating a solution of
isolated 25 at 80 °C in DMF-d7 results in consumption of 25
and formation of 11a after 2 days. The proton required to
convert 25 to 11a could be derived from trace water in the
solvent or even the bpy ligand.23 Heating solutions of 25 in
CD3CN or CD2Cl2 similarly gives only 11a, while in THF-d8
no reaction occurs.
Treatment of isolated 24 with alkenyl hydrazide 1a also gives
complete conversion to cyclized product 11a. Heating a mixture
of the pentenoic hydrazide resting state 25 and the hexenoic
hydrazide 5a results in formation of both five- and six-membered
rings (11a and 15a, distinguishable by 1H NMR) and a mixture
of the two corresponding platinum amidate complexes even at
early reaction times (<1 h). These data suggest a rapid
equilibrium between the Pt-amidate complex 25 and the alkenyl
hydrazide.
solutions were found to undergo conversion of 1a to 11a at
similar rates (Figure S10), showing no significant acceleration
or inhibition of the formation of 11a by either acid or base. In
conjunction with the turnover experments from Section IIIA
(see above), these data suggest that the hydrazide is responsible
for the protonolysis of alkyl complex 20 rather than HOTf.
IV. The Mechanism of Hydrohydrazination. The Pt com-
plexes synthesized and characterized above, and their behavior
under catalytic conditions, provide insight into the mechanism
of catalysis. In this section, we use those results to consider the
likely mechanisms for hydrohydrazination, in particular the key
C-N bond forming step: nucleophilic attack of the hydrazide
at the alkene (mechanism A) or alkene insertion into a Pt-N
bond (mechanism B, Scheme 2).
A. Nucleophilic Attack Mechanism. In many hydroamination
and related reactions, the alkene is activated toward attack by
an external nucleophile by coordination to a metal center.1,20
For the hydrohydrazination reaction discussed here, this would
likely involve intramolecular attack of an unbound hydrazine
connected to a coordinated alkene. The predominant Pt species
in solution during catalytic hydrohydrazination of 1a is the 2:1
complex 25. In order for this nucleophilic pathway to be the
operative mechanism, 25 must access a catalytic cycle such as
mechanism A in Scheme 2. Specifically, 25 must be converted
to a platinum-alkene with a free hydrazine, which requires
protonation of the amidate complex. However, the rate of
conversion of 1a to 11a catalyzed by 25 under these conditions
shows no acid (HOTf) or base (2,6-lutidine) dependence. In
general, conversion of the amide complex to an alkene complex
that would be susceptible to nucleophilic attack would require
acid. Therefore the lack of acid catalysis and base inhibition
appears to be inconsistent with a nucleophilic attack of a
hydrazine on a bound alkene. The exchange observed between
the amidate complex 25 and the hexenamide substrate 5a likely
proceeds by proton transfer from one amide to another, without
accessing the (bpy)Pt(solv)22+ precatalyst, which would appear
to be needed for the nucleophilic attack mechanism.
The 2:1 Pt-amidate complexes, like 25, are the resting states
observed in catalytic reaction mixtures of the diacyl hydrazides
1a-6a. In the case of the disubstituted hydrazides (1b, 1i) and
those with an amine-type linker (7-8a), a Pt-alkyl complex is
the observed resting state. These resting states likely reflect the
relative stabilities of the corresponding Pt-amidate complexes.
C. Reaction Dependence on Acid and Base. Heating the
deuterated hydrazide 1a-d2 (95% ND) in DMF or DMF-d7 with
Pt(bpy)Cl2 (10 mol %) and AgOTf (20 mol %) for 2 days leads
to complete consumption of 1a-d2 (eq 7). The cyclized product
11a formed has substantial deuterium incorporation in the amide
1
group, ∼70% ND by H NMR, and some incorporation of
1
deuterium into the exocyclic methyl group (∼25% D by H
NMR). The positions of deuterium incorporation were confirmed
by 2H NMR spectroscopy. The incomplete deuterium incorpora-
tion is likely due to exchange with trace H2O present in the
solvent prior to protonation of the Pt-alkyl bond.
An alternative nucleophilic attack mechanism could in
principle involve addition of an anionic hydrazide to a bound
alkene, which would not require acid. However, hydrazide is a
very poor leaving group, and displacement from the platinum,
either dissociatively or associatively by the alkene, is highly
unlikely. An O-bound acyl hydrazide, as in 23, could serve as
a nucleophile but not to an alkene bound to the same metal
center due to ring constraints. Attack of an O-bound acyl
hydrazide on its pendant alkene bound to a different metal center
is more difficult to exclude on steric grounds, but it would
require that the C-N bond forming step be zero-order in alkenyl
hydrazide. A brief kinetic study of the reaction of the diplatinum
Experiments were done to probe the role of acid and base in
the catalytic process. PhSiMe3 has been shown to be a valuable
probe of Brønsted acid catalysis in hydroamination by quickly
reacting with HOTf and inhibiting any acid-catalyzed pro-
(23) Minghetti, G.; Stoccoro, S.; Cinellu, M. A.; Soro, B.; Zucca, A.
(24) This takes place in 1 h at room temperature; see: McBee, J. L.; Bell,
Organometallics 2003, 22, 4770–4777.
A. T.; Tilley, T. D. J. Am. Chem. Soc. 2008, 130, 16562–16571.
9
5048 J. AM. CHEM. SOC. VOL. 132, NO. 14, 2010

Pt-Catalyzed Intramolecular Hydrohydrazination
A R T I C L E S
Scheme 2. Possible Mechanisms of Pt-Catalyzed Hydrohydrazination
complex 25 with 1a suggests a half-order dependence on the
[alkenyl hydrazide] (Figure S11). Such a half-order dependence
suggests dissociation of the dimer by reaction with 1a and a
unimolecular C-N bond forming step, and therefore argues
against a dinuclear nucleophilic attack pathway.
B. Alkene Insertion Mechanism. The available mechanistic
data suggest that Pt-amidate species directly convert to Pt-alkyl
complexes. When NR2 is N-acetamido, this conversion occurs
through reaction of the amidate resting state 25 with hydrazide
1a to give B1 as shown in Scheme 2. In the case where NR2 is
9
J. AM. CHEM. SOC. VOL. 132, NO. 14, 2010 5049

A R T I C L E S
Hoover et al.
N-dimethylamino, conversion of the Pt-amidate complex (23)
to the Pt-alkyl resting state (21) requires tautomerization from
the O-bound to an N-bound amidate and dissociation of the
chelating amine and coordination of the alkene. This would give
a species analogous to B2 that is well set up for alkene insertion
to give 21.
These conversions of Pt(amidate) to Pt(alkyl) would not need
to require acid. The half-order dependence on [alkenyl hy-
drazide] is consistent with a mechanism in which the hydrazide
1a protonates the diplatinum hydrazide(2-) catalyst resting state
25. This forms the 1:1 amidate complex in the catalytic cycle,
shown as B1 in mechanism B of Scheme 2. Complex B1 could
then rearrange to an alkene-bound isomer (B2) and undergo
alkene insertion into the Pt-N bond to give a platinum alkyl
complex similar to 20, 21, and 22.
membered N-amino lactams. A number of platinum com-
plexes have been isolated from these reaction mixtures and
shown to be relevant to the catalytic process. Addition of
acid (HOTf) or base, or an acid scavenger, has little effect
on the rate of reaction. On the basis of these data and catalytic
and stoichiometric reactions of the isolated intermediates,
we suggest a mechanism that involves N-H activation of
the hydrazide, followed by insertion of the alkene into the
Pt-N bond. Protonation of the resulting Pt-C bond in the
cyclized alkyl complex by a hydrazide releases the hydro-
hydrazination product and regenerates the catalytically active
Pt-amidate species. An alternative pathway of external attack
of the hydrazide on a bound alkene is difficult to rationalize
with the limited effect of added acid or acid scavengers.
Experimental Section
Several late metal systems have been shown to undergo
stoichiometric or catalytic insertion of alkenes into M-N
bonds. These include Ir bis(phosphine) systems that promote
the amination of norbornene25 and an amido transfer reaction
from Rh(amido) complexes that involves alkene insertion into
the Rh-N bond.26 Although the stoichiometric insertion of
activated olefins into Pt-N bonds has been reported,27 few
Pt-catalyzed amination reactions have been shown to proceed
through alkene insertion into a Pt-N bond. This mechanism,
however, has been proposed in several Pd-catalyzed amina-
tion reactions.28 Obtaining direct evidence of an alkene
insertion pathway is challenging. We have attempted to
observe both intra- and intermolecular insertions into the
isolated Pt-amidate complexes 24 and 25. Heating isolated
25 forms 11a without any observable intermediates; the
proton source is unclear. Intermolecular reactions of 24 with
both activated (acrylonitrile, methyl vinyl ketone, norbornene)
and unactivated (propene, hexene, dodecene) alkenes in
DMF-d7 do not lead to olefin incorporation products.
The cycle is completed with protonation of the Pt-alkyl
complex by an additional molecule of alkenyl hydrazide
substrate. The isolated Pt-alkyl complexes 20 and 21 are the
only resting states observed that lie in the catalytic cycle,
implying protonolysis of the Pt-alkyl complex is turnover
limiting. Protonation of a metal alkyl species is a common step
in Pd- and Pt-catalyzed hydroamination reactions.20 In our
system, the HOTf formed during the reaction is not solely
responsible for the final protonation of the Pt(alkyl) complex
since the reaction is unaffected by the addition of PhSiMe3 as
an acid trap. The N-phthalimidopyrrolidinone 11b can be
released from the Pt-alkyl complex 20 by protonation with
AcNHNHAc, confirming that the hydrazides employed in these
reactions are acidic enough to protonate a Pt-alkyl species.
General Procedures. All procedures were done air-free with
glovebox or vacuum line techniques unless otherwise noted. H,
1
13C{1H}, and 19F{1H} NMR spectra were recorded on Bruker
Avance 300 or 500 MHz spectrometers and referenced to the
residual solvent signal (1H and 13C) or an external CF3COOH
standard (19F ) -78.5);29 all coupling constants are reported in
Hz. Infrared spectra were measured on a Perkin-Elmer spectrum
RX I spectrometer. Mass spectra were collected on an a Bruker
Esquire 1100 liquid chromatograph-ion trap mass spectrometer
or an Agilent 5973 gas chromatograph-mass spectrometer. Column
chromatography was performed using silica gel (Whatman, 60 Å,
230 × 400 mesh). High-resolution mass spectra were collected on
a JEOL HX-110 mass spectrometer.
Materials. All commercial reagents were used as received unless
otherwise noted. Deuterated solvents were purchased from Cam-
bridge Isotope Laboratories, Inc. CD2Cl2 was dried over CaH2 and
distilled before use. THF-d8 was distilled from Na/benzophenone
before use. Toluene-d8 was dried over Na/K and distilled before
use. CD3CN was dried over a sequence of CaH2, P2O5, and CaH2.
DMF-d7 and dioxane-d8 were used without further purification.
K2PtCl4 was purchased from Pressure Chemical.
General Procedure for the Catalytic Hydrohydrazination
Reaction. Reactions were prepared in an N2 glovebox. Acros
low water (<50 ppm) DMF was used; other drying and
purification methods yielded irreproducible yields. A sealed tube
was charged with hydrazide (1 equiv), Pt(bpy)Cl2 (0.1 equiv),
AgOTf (0.2 equiv), and DMF (0.16 M). The reaction mixture
was submerged in an oil bath (120 °C for substrates a and c, 80
°C for substrates b) for 1 day (unless otherwise indicated). After
removal of the solvent in Vacuo, the product was purified by
silica column chromatography using the solvent system listed
with each compound.
N-Acetamido-2-methylpyrrolidin-5-one (11a). Reaction of 1a
(36 mg, 230 µmol) with Pt(bpy)Cl2 (10 mg, 24 µmol) and AgOTf
(12 mg, 47 µmol) in DMF (1.4 mL) followed by silica column
chromatography with 10% MeOH in CH2Cl2 provided 11a as a
1
Conclusions
colorless oil (31 mg, 86%). H NMR (CDCl3, 500 MHz): δ 8.45
(s, 1H, NH), 4.03 (m, 1H, CH), 2.45 (m, 2H, CH2), 2.32 (m, 1H,
CH2), 2.06 (s, 3H, AcCH3), 1.68 (m, 1H, CH2) 1.21 (d, J ) 6.5
Hz, 3H, CH3). 13C{1H} NMR (CDCl3, 75 MHz): δ 174.5 (CO),
169.6 (CO), 54.8, 28.5, 25.6, 20.9, 19.2. FTIR (thin film, cm-1):
3423, 3232, 1702, 1655, 1537, 1419, 1378, 1270. ESI-MS
(MeOH, m/z): 179 [M + Na]+ (8), 195 [M + K]+ (1). HRMS
(FAB): calcd for C7H13N2O2 [M + H]+ m/z 157.09770, found
m/z 157.09783.
Dicationic (bpy)Pt(II) complexes catalyze the intramolecular
hydrohydrazination of hydrazides to form five- and six-
(25) (a) Casalnuovo, A. L.; Calabrese, J. C.; Milstein, D. J. Am. Chem.
Soc. 1988, 110, 6738–6744. (b) Zhou, J.; Hartwig, J. F. J. Am. Chem.
Soc. 2008, 130, 12220–12221.
(26) Zhao, P. J.; Krug, C.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127,
12066–12073.
N-Aminophthalimido-2-methylpyrrolidin-5-one (11b). Reac-
tion of 1b (46 mg, 188 µmol) with Pt(bpy)Cl2 (8 mg, 19 µmol)
and AgOTf (10 mg, 39 µmol) in DMF (1.2 mL) followed by silica
(27) (a) Cowan, R. L.; Trogler, W. C. J. Am. Chem. Soc. 1989, 111, 4750–
4761. (b) Villanueva, L. A.; Abboud, K. A.; Boncella, J. M. J. Am.
Chem. Soc. 1992, 11, 2963–2965.
(28) (a) Mun˜iz, K.; Ho¨velmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008,
130, 763–773. (b) Ney, J. E.; Wolfe, J. P. Angew. Chem. 2004, 116,
3689–3692. (c) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129,
6328–6335.
(29) Walstrom, A.; Pink, M.; Tsvetkov, N. P.; Fn, H.; Ingleson, M.; Caulton,
K. G. J. Am. Chem. Soc. 2005, 127, 16780–16781.
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5050 J. AM. CHEM. SOC. VOL. 132, NO. 14, 2010

Pt-Catalyzed Intramolecular Hydrohydrazination
A R T I C L E S
column chromatography with 3:2 hexanes/EtOAc provided 11b as
a white solid (37 mg, 80%), mp 164 °C. H NMR (CD2Cl2, 500
N-Aminophthalimido-4,5-dimethylpyrrolidin-2-one (13b). Re-
action of 3b (48 mg, 186 µmol) with Pt(bpy)Cl2 (8 mg, 19 µmol)
and AgOTf (10 mg, 39 µmol) in DMF (1.2 mL) followed by silica
column chromatography with 3:2 hexanes/EtOAc provided 13b as
a mixture of diastereomers (1:6 cis:trans), white solid (30.6 mg,
1
MHz): δ 7.90 (m, 2H, Ar), 7.82 (m, 2H, Ar), 4.05 (m, 1H, CH),
2.52 (m, 2H, CH2), 2.41 (m, 1H, CH2), 1.85 (m, 1H, CH2), 1.25
(d, J ) 4 Hz, 3H, CH3). 13C{1H} NMR (CD2Cl2, 125 MHz): δ
173.1 (CO Ac), 165.2 (CO phthal), 165.0 (CO phthal), 134.9 (Ar),
134.8 (Ar), 130.3 (Ar), 130.00(Ar), 124.2 (Ar), 124.0 (Ar), 55.3,
28.3, 26.1, 19.5. FTIR (thin film, cm-1): 1736 (s), 1720 (s), 1353,
1249, 1113, 1085, 881, 712. ESI-MS (MeOH, m/z): 163 (8), 245
[M + H]+ (1), 277 (3), 299 (10), 315 (8). HRMS (FAB): calcd for
C13H13N2O3 [M + H]+ m/z 245.09262, found m/z 245.09272.
N-Acetamido-3,5-dimethylpyrrolidin-2-one (12a). Reaction of
2a (20 mg, 118 µmol) with Pt(bpy)Cl2 (6 mg, 14 µmol) and AgOTf
(6 mg, 23 µmol) in DMF (0.75 mL) followed by silica column
chromatography with 10% MeOH in CH2Cl2 provided 12a as a
mixture of diastereomers (1:3 cis:trans), colorless oil (16 mg, 78%).
1H NMR (C6D6, 500 MHz): δ 9.77 (s, 1H, NH, trans), 9.64 (s, 1H,
NH, cis), 3.93 (m, 1H, CH, trans), 3.88 (m, 1H, CH, trans), 2.34
(m, 1H, cis), 2.26 (m, 1H, CH, trans), 2.05 (s, 3H, Ac CH3, trans
and cis), 1.86 (m, 1H, cis), 1.49 (m, 1H, CH2, trans), 1.31 (m, 1H,
CH2, trans), 1.18 (d, J ) 7.5 Hz, 3H, CH3, trans), 1.09 (d, J ) 7
Hz, 3H, CH3, cis), 1.04 (d, J ) 6 Hz, 3H, CH3, cis), 1.00 (d, J )
6 Hz, 3H, CH3, trans), 0.8 (m, 1H, cis). 13C{1H} NMR (C6D6, 75
MHz): δ 177.8 (CO, cis), 177.1 (CO, trans), 169.5 (CO, cis), 169.3
(CO, cis), 53.5 (cis), 53.4 (trans), 35.9 (cis), 35.4 (cis), 34.2 (trans),
34.0 (trans), 21.1 (trans), 21.1 (cis), 19.5 (cis), 18.9 (trans), 16.7
(trans), 16.3 (cis). FTIR (thin film, cm-1): 3449 (br), 3230 (br),
2974, 1707(s), 1669(s), 1531, 1453, 1417, 1374, 1262. GC-MS (EI,
m/z (relative intensity)): 170(1) [M], 155(2), 128 (20), 113 (40),
99(3), 85(5), 69(8), 59(10), 43(12). ESI-MS (MeOH, m/z): 193 [M
+ Na]+ (5), 209 [M + K]+. HRMS (FAB): calcd for C18H15N2O2
[M + H]+ m/z 171.11335, found m/z 171.11344.
1
64%). H NMR (CDCl3, 300 MHz): δ 7.90 (m, 2H, Ar, cis and
trans), 7.80 (m, 2H, Ar, cis and trans), 4.12 (m, 1H, CH, cis) 3.65
(m, 1H, CH, trans), 2.71 (m, 1H, CH, cis and trans), 2.24 (m, 2H,
CH2, cis and trans), 1.26 (d, J ) 6 Hz, 3H, CH3, trans), 1.24 (d,
J ) 6 Hz, 3H, CH3, trans), 1.18 (d, J ) 3.5 Hz, 3H, CH3, cis),
1.17 (d, J ) 3.5 Hz, 3H, CH3). 13C{1H} NMR (CDCl3, 125 MHz):
δ 172.8, 165.4, 165.1, 135.0, 134.9, 130.4, 130.4, 124.3, 124.1,
62.3 (trans), 58.6 (cis), 36.8 (trans), 36.4 (cis), 35.0 (trans), 30.1
(cis), 17.8 (trans), 17.7 (trans), 15.2 (cis), 13.8 (cis). ESI-MS
(MeOH, m/z): 163(10), 259 (1) [M + H]+, 291 (5), 313 (7). HRMS
(FAB): calcd for C14H15N2O3 [M + H]+ m/z 259.10827, found m/z
259.10721.
N-Acetamido-3,3,5-trimethylpyrrolidin-2-one (14a). Reaction
of 4a (35 mg, 190 µmol) with Pt(bpy)Cl2 (8 mg, 19 µmol) and
AgOTf (10 mg, 39 µmol) in DMF (1.2 mL) for 2 days followed
by silica column chromatography with 1% to 3% MeOH in CH2Cl2
gradient elution provided 14a as a colorless oil (24.6 mg, 70%).
1H NMR (CDCl3, 300 MHz): δ 8.53 (s, 1H, NH), 3.70 (m, 1H,
CH), 1.84 (dd, J ) 12.5, 6.5 Hz, 1H, CH2), 1.78 (s, 3H, AcCH3),
1.19 (dd, J ) 12.5, 9 Hz, 1H, CH2), 0.96 (s, 3H, CH3), 0.92 (s, 3H,
CH3), 0.91 (d buried, 3H, CH3). 13C{1H} NMR (CDCl3, 125 MHz):
δ 180.1 (CO), 169.5 (CO), 51.9, 42.2, 39.2, 25.6, 25.0 21.0, 19.4.
FTIR (thin film, cm-1): 3234 (br), 2964, 1720 (s), 1676, 1460, 1365,
1264. ESI-MS (MeOH, m/z): 143 [M + H - C2O]+ (4), 185 [M +
H]+ (5), 207 [M + Na]+ (10), 223 [M + K]+ (2). HRMS (FAB):
calcd for C9H17N2O2 [M + H]+ m/z 185.12900, found m/z
185.12877.
N-Aminophthalimido-3,5-dimethylpyrrolidin-2-one (12b). Re-
action of 2b (52 mg, 201 µmol) with Pt(bpy)Cl2 (9 mg, 21 µmol)
and AgOTf (11 mg, 43 µmol) in DMF (1.2 mL) followed by silica
column chromatography with 3:2 Hex/EtOAc provided 12b as a
mixture of diastereomers (1:1 cis:trans), white solid (44.5 mg, 85%),
N-Aminophthalimido-3,3,5-trimethylpyrrolidin-2-one (14b). Re-
action of 4b (137 mg, 503 µmol) with Pt(bpy)Cl2 (21 mg, 50 µmol)
and AgOTf (26 mg, 101 µmol) in DMF (3.2 mL) followed by silica
column chromatography with 1:1 hexanes/EtOAc provided 14b as
1
a white solid (118 mg, 86%), mp 81 °C. H NMR (CDCl3, 300
1
mp 116 °C. H NMR (C6D6, 500 MHz): δ 7.33 (m, 4H, Ar), 6.77
MHz): δ 7.92 (m, 2H, Ar), 7.81 (m, 2H, Ar), 4.06 (m, 1H, CH),
2.23 (t, J ) 6 Hz, 1H, CH2), 1.76 (m, 1H, CH2), 1.35 (s, 3H, CH3),
1.32 (s, 3H, CH3), 1.27 (d, J ) 6 Hz, 3H, CH3). 13C{1H} NMR
(CDCl3, 125 MHz): δ 178.6 (CO), 165.5 (CO), 165.2 (CO), 134.9
(Ar), 134.8 (Ar), 130.5 (Ar), 130.1 (Ar), 124.2 (Ar), 124.0 (Ar),
52.6, 42.4, 39.3, 25.3, 25.1, 19.4. FTIR (thin film, cm-1): 1795,
1742 (s), 1467, 1384, 1354, 1256, 1214, 1116, 881, 710. GC-MS
(EI, m/z (relative intensity)): 272(1) [M], 257 (10), 229(1), 202(1),
189(1), 162(12), 148(1), 132(2), 104(4), 83(25), 67(4), 55(8), 41(5).
HRMS (FAB): calcd for C15H17N2O3 [M + H]+ m/z 273.12388,
found m/z 273.12274.
(m, 4H, Ar), 3.67 (m, 2H, NCH, cis and trans), 2.23 (m, 2H, CH,
cis and trans), 1.73 (m, 1H, CH2, trans), 1.40 (m, 2H, CH2, cis
and trans), 1.33 (m, 1H, CH2, cis), 1.09 (d, J ) 7.5 Hz, 3H, CH3,
cis), 1.02 (d, J ) 7 Hz, 3H, CH3, trans), 0.96 (d, J ) 6.5 Hz, 6H,
cis and trans). 13C{1H} NMR (C6D6, 75 MHz): δ 175.58 (CO),
165.66 (CO), Ar buried under solvent, 53.99, 53.69, 36.01, 35.29,
34.42, 33.62, 19.57, 16.66, 16.05. 13C{1H} NMR (CDCl3, 75 MHz):
δ 176.0, 165.4, 135.0, 134.9, 130.4, 130.3, 130.1, 130.0, 124.3,
124.1, 53.9, 53.7, 35.8, 35.1, 34.4, 33.7, 19.4, 16.0. FTIR (thin
film, cm-1): 1795, 1741 (s), 1720 (s), 1356, 1249, 1224, 1113, 1085,
882, 711. ESI-MS (MeOH, m/z): 163(10), 259 [M + H]+ (1), 291
(3), 313 (10). HRMS (FAB): calcd for C14H15N2O3 [M + H]+ m/z
259.10827, found m/z 259.10713.
N-Acetamido-2-methylpiperidinone (15a). Reaction of 5a (31
mg, 182 µmol) with Pt(bpy)Cl2 (8 mg, 19 µmol) and AgOTf (10
mg, 39 µmol) in DMF (1.1 mL) followed by silica column
chromatography with 10% MeOH in CH2Cl2 afforded 15a as a
N-Acetamido-4,5-dimethylpyrrolidinon-2-one (13a). Reaction
of 3a (29 mg, 170 µmol) with Pt(bpy)Cl2 (7 mg, 17 µmol) and
AgOTf (10 mg, 39 µmol) in DMF (1.0 mL) followed by silica
column chromatography with 10% MeOH in CH2Cl2 provided 13a
as a mixture of diastereomers (1:2.6 cis:trans), colorless oil (22
1
colorless oil (28 mg, 90%). H NMR (CDCl3, 300 MHz): δ 8.86
(s, 1H, NH), 3.86 (sext, J ) 4 Hz, 1H, CH), 2.49 (m, 1H, CH2),
2.41 (m, 1H, CH2), 2.07 (m, 1H, CH2), 2.03 (s, 3H, AcCH3), 1.82
(m, 1H, CH2), 1.61 (m, 1H, CH2), 1.21 (d, J ) 4 Hz, 3H, CH3).
13C{1H} NMR (CD2Cl2, 125 MHz) δ 170.5, 169.7, 56.2, 32.7, 30.8,
21.1, 19.8, 18.2. GC-MS (EI, m/z (relative intensity)): 170 (1) [M],
155(2), 128(50), 113(90), 99(20), 84(40), 55(25), 43(30). HRMS
(FAB): calcd for C8H15N2O2 [M + H]+ m/z 171.11335, found m/z
171.11336.
1
mg, 75%). H NMR (CDCl3, 300 MHz): δ 8.52 (s, 1H, NH, cis),
8.40 (s, 1H, NH, trans), 4.05 (m, 1H, NCH, cis), 3.58 (m, 1H,
NCH, trans), 2.62 (m, 1H, CH, cis), 2.55 (m, J ) 5 Hz, CH2, 1H
trans, 1H cis), 2.14 (m, 1H, CH2, trans), 2.08 (m overlapping, 2H,
CH2, cis), 2.05 (s, 3H, AcCH3, cis and trans), 1.98 (m, 1H, CH,
trans), 1.20 (d, J ) 3.6 Hz, 3H, CH3, trans), 1.17 (d, J ) 4.2 Hz,
3H, CH3, trans), 1.08 (d, J ) 4.2 Hz, 3H, CH3, cis), 1.04 (d, J )
3.9 Hz, 3H, CH3, cis). 13C{1H} NMR (CDCl3, 75 MHz): δ 174.2
(trans), 173.7 (minor), 169.5 (trans), 169.4 (minor), 61.9 (trans),
58.2 (minor), 37.1(trans), 36.4 (cis), 34.7 (trans), 29.1 (cis), 21.1
(trans), 18.0 (trans), 17.6 (trans), 15.1 (cis), 13.1 (cis). GC-MS
(EI, m/z (relative intensity)): 170(1) [M], 155(2), 128(50), 113(75),
112(45), 96(8), 85(5), 69(15), 59(30), 43(15).
N-Acetamido-3,3,6-trimethylpiperidinone (16a). Initial reaction
of 6a (29 mg, 146 µmol) with Pt(bpy)Cl2 (7 mg, 16 µmol) and
AgOTf (8 mg, 31 µmol) in DMF (1 mL) followed by silica column
chromatography with 2% MeOH in CH2Cl2 yielded a mixture of
16a and 6a (20.6 mg, 70% yield with 8% 6a), which was
resubmitted to the reaction conditions to yield pure 16a as a
colorless oil after silica column chromatography with 5% MeOH
1
in CH2Cl2 (20.1 mg, 69%). H NMR (CDCl3, 300 MHz): δ 8.54
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A R T I C L E S
Hoover et al.
(s, 1H, NH), 3.83 (m, 1H, CH), 2.09 (m, 1H, CH2), 2.03 (s, 3H,
AcCH3), 1.69-1.57 (m, 3H, CH2), 1.23-1.19 (m, 9H, 3CH3).
13C{1H} NMR (CD2Cl2, 125 MHz): δ 176.7 (CO), 169.8 (CO),
56.6 (CH), 39.0, 32.9, 27.5, 29.0, 21.2, 20.0. FTIR (thin film, cm-1):
3264, 2973, 2967, 1682 (s), 1638 (s), 1460, 1420, 1376, 1305, 1202,
1051. ESI-MS (MeOH, m/z): 157(2) [M + H - C2O]+ (2), 199
[M + H]+ (4), 221 [M + Na]+ (2), 237 [M + K]+ (1). HRMS
(FAB): calcd for C10H19N2O2 [M + H]+ m/z 199.14465, found m/z
199.14465.
13.5, 19 Hz, JPtH ) 69 Hz Hz, 1H, Pt-CH2). 19F NMR (DMF-d7,
282 MHz): δ -79.5. ESI-MS (CH3CN, m/z): 594 [(bpy)Pt(CH2CH-
(CH2)2C(O)N-Nphthal]+ (positive mode); 148 [OTf]- (negative
mode).
[(bpy)Pt(CH2CH(CH2)2C(O)N-N(CH3)2)](OTf) (21). [Pt(bpy)-
(MeCN)2](OTf)2 (24.0 mg, 32.8 µmol) and 1i (24.0 mg, 169 µmol)
were combined in DMF-d7 (500 µL). After heating at 120 °C for
1
21 h ∼86% conversion to 21 was observed by H NMR analysis.
Complex 21 was then purified according to the general procedure.
1H NMR (DMF-d7, 300 MHz): δ 9.19 (d, J ) 4.8 Hz, 1H, Ar),
8.98 (d, J ) 5.7 Hz, 1H, Ar), 8.86 (d, J ) 7.6 Hz, 1H, Ar), 8.78
(d, J ) 8.1 Hz, 1H, Ar), 8.56 (t, J ) 7.8 Hz, 1H, Ar), 8.53 (t, J )
7.5 Hz, 1H, Ar), 8.06 (t (overlapping with solvent), J ) 6 Hz, 1H,
Ar), 7.84 (t, J ) 6 Hz, 1H, Ar), 4.34 (m, 1H, CH), 4.14 (s, JPt-H
) 14.7 Hz, 3H, CH3), 3.77 (s, JPt-H ) 14.1 Hz, 3H, CH3), 2.77
(m, 2H, CH2), 2.47 (m, 1H, CH2), 2.21 (m, 2H, Pt-CH2), 1.69 (m,
1H, CH2). 19F NMR (DMF-d7, 282 MHz): δ -79.6. ESI-MS
(CH3CN, m/z): 492 [M - OTf]+ (positive mode); 148 [OTf]-
(negative mode).
N-Phthalimido-3,3,6-trimethylpiperidinone (16b). Reaction of
6b (52 mg, 182 µmol) with Pt(bpy)Cl2 (8 mg, 19 µmol) and AgOTf
(10 mg, 39 µmol) in DMF (1.2 mL) followed by silica column
chromatography with 2:1 Hex/EtOAc provided 16b as a white solid
1
(43 mg, 82%). H NMR (CDCl3, 300 MHz): δ 7.86 (m, 2H, Ar),
7.75 (m, 2H, Ar), 3.99 (m, 1H, CH), 2.10 (m, 1H, CH2), 1.83 (m,
3H, CH2), 1.32 (s, 3H, CH3), 1.26 (s, 3H, CH3), 1.25 (d, J ) 6.6
Hz, 3H, CH3). 13C{1H} NMR (CDCl3, 75 MHz): δ 175.2 (CO),
166.2 (CO phthal), 165.9 (CO phthal), 134.8 (Ar), 134.7 (Ar), 130.3
(Ar), 130.1 (Ar), 124.1 (Ar), 123.9 (Ar), 57.7, 39.2, 33.5, 27.6,
27.5, 27.3, 20.4. FTIR (thin film, cm-1): 2974, 2936, 1975, 1737
(s), 1676, 1469, 1381, 1302, 1219, 1121, 1082, 883, 714. HRMS
(FAB): calcd for C16H19N2O3 [M + H]+ m/z 287.12957, found m/z
287.13936.
[(bpy)Pt(CH2CH(CH2)4N-NHAc](OTf) (22). A mixture of hex-
5-enyl-N′-acetyl hydrazide (32.0 mg, 205 µmol), Pt(bpy)Cl2 (9.0
mg, 21 µmol), and AgOTf (11.0 mg, 21.4 µmol) was combined in
DMF (1.2 mL). After heating at 120 °C for 24 h, the solvent was
removed under vacuum, and the residue extracted into CDCl3.
N-Acetamido-2-methylpyrrolidine (17a). Reaction of 7a (31
mg, 218 µmol) with Pt(bpy)Cl2 (10 mg, 24 µmol) and AgOTf (12
mg, 47 µmol) in DMF (1.4 mL) followed by silica column
chromatography with 2% MeOH in CH2Cl2 provided 17a as a
colorless oil (8 mg, 26%). 1H NMR (CDCl3, 300 MHz): δ 8.34 (s,
1H, NH), 4.02 (m, 1H, CH), 2.48-2.43 (m, 2H, CH2), 2.31 (m,
2H, CH2), 2.06 (s, 1H, AcCH3), 1.74 (br m, 1H, CH2), 1.66 (m,
1H, CH2), 1.29 (d, J ) 6.5 Hz, 3H, CH3). 13C{1H} NMR (CD2Cl2,
125 MHz): δ 174.4 (CO), 169.4 (CO), 54.9, 28.5, 25.6, 21.1, 19.3.
HRMS (FAB): calcd for C7H15N2O [M + H]+ m/z 143.11844, found
m/z 143.11842.
N-Benzamido-2-methylpyrrolidine (17c). Reaction of 7c (35
mg, 171 µmol) with Pt(bpy)Cl2 (8 mg, 19 µmol) and AgOTf (10
mg, 39 µmol) in DMF (1.1 mL) followed by silica column
chromatography with 1% MeOH in CH2Cl2 provided 17c as a white
solid (23.0 mg, 66%). The spectral data in DMSO-d6 are consistent
with published parameters.13 1H NMR (CDCl3, 300 MHz): δ 7.75
(d, J ) 6.9 Hz, 2H, o), 7.43 (m, 3H, m and p), 6.69 (s br, 1H, NH),
3.44 (dt, J ) 8.4, 2.7 Hz, 1H CH), 2.87(m, 1H, CH2), 2.72 (q, J )
8.7 Hz, 1H, CH2), 2.06-1.75 (m, 3H, CH2), 1.60 (m, 1H, CH2),
1.20 (d, J ) 6.3 Hz, 3H, CH3). 13C{1H} NMR (CD2Cl2, 125 MHz):
δ 166.9 (CO), 134.2 (Ar), 131.7 (Ar), 128.8 (Ar), 127.2 (Ar), 62.4,
55.9, 30.4, 20.5, 18.4. ESI-MS (MeOH, m/z): 205 [M + H]+ (20),
227 [M + Na]+ (1). HRMS (FAB): calcd for C12H17N2O [M +
H]+ m/z 205.13409, found m/z 205.13375.
General Procedure for Synthesis of Pt Complexes. [Pt(bpy)-
(MeCN)2](OTf)2 was treated with the appropriate hydrazide in
DMF and heated as described below. The Pt species was then
precipitated with the addition of ether and filtered through glass
wool, and the residue was extracted into DMF-d7. Due to the
noncrystalline nature of the complexes, elemental analyses are
not available. 1H NMR spectra for complexes 20-25 are included
in the Supporting Information as an indication of purity. In all
cases either the solution was decanted following precipitation
or the mixture was filtered through glass wool and the solids
were extracted into DMF-d7, and in some cases CD3CN, for
spectroscopic analysis.
1
Complete conversion to complex 22 was observed by H NMR
analysis. The solvent was removed under vacuum, the residue was
extracted into DMF, and complex 22 was isolated as described in
the general procedure. 1H NMR (DMF-d7, 300 MHz): δ 11.2 (s br,
1H, NH), 9.14 (d, J ) 5.7 Hz, 1H, bpy), 9.00 (d, J ) 5.7 Hz, 1H,
bpy), 8.79 (t, J ) 7.5 Hz, 2H, bpy), 8.53 (t, J ) 7.5 Hz, 2H, bpy),
7.97 (obscured by solvent, 1H, bpy), 7.84 (t, J ) 7.5 Hz, 1H, bpy),
4.12 (m, 1H, CH), 3.58 (m, 1H, CH2), 3.28 (d, J ) 11 Hz, 1H,
CH2), 2.81 (m obscured by solvent, 1H, CH2), 2.45 (m, 1H, CH2),
2.22 (s, 3H, CH3), 2.18 (m, 2H, CH2), 1.94 (m, 1H, CH2), 1.79 (m,
1H, CH2), 1.53 (m, 1H, CH2). ESI-MS (CH3CN, m/z): 506
[(bpy)Pt(CH2CH(CH2)4N-NHAc]+ (positive mode); 148 [OTf]-
(negative mode).
[Pt(bpy)(K2-Me2NNdC(O)(CH2)2CHdCH2)](OTf) (23). [Pt(bpy)-
(MeCN)2](OTf)2 (20.0 mg, 27.3 µmol) and 1i (15.0 mg, 105 µmol)
were combined in DMF-d7 (0.5 mL), and the mixture was allowed
to react at RT. After 1.5 h, complete conversion to 23 was observed
1
by H NMR analysis, and complex 23 was then precipitated with
1
ether and isolated as described in the general procedure. H NMR
(DMF-d7, 300 MHz): δ 9.15 (t, J ) 5.7 Hz, 2H, bpy), 8.84 (dd, J
) 3, 7.5 Hz, 2H, bpy), 8.62 (t, J ) 6 Hz, 2H, bpy), 8.02 (quin, J
) 7 Hz, 2H, bpy), 5.92 (m, 1H, dCH), 5.05 (dd, J ) 17.5, 10.2
Hz, 2H, dCH2), 3.32 (s, JPtH ) 11 Hz, 6H, CH3), 2.48 (m, 4H,
CH2). ESI-MS (CH3CN, m/z): 492 [Pt(bpy)(η2-Me2NNdC(O)-
(CH2)2CHdCH2)]+ (positive mode); 148 [OTf]- (negative mode).
[Pt2bpy2(AcNNAc)](OTf)2 (24). [Pt(bpy)(MeCN)2](OTf)2 (10 mg,
14 µmol) and AcNHNHAc (5 mg, 43 µmol) were combined in
DMF-d7. After heating at 120 °C for 18 h ∼90% conversion to 24
was observed by 1H NMR analysis. Complex 24 was then isolated
1
as described in the general procedure. H NMR (DMF-d7, 500
MHz): δ 9.36 (d, J ) 5.5 Hz, 1H, bpy NdCH), 9.00 (d, J ) 5.5
Hz, 1H, bpy NdCH), 8.86 (d, J ) 8.5 Hz, 1H, bpy), 8.82 (d, J )
8 Hz, 1H, bpy), 8.68 (t, J ) 7 Hz, 1H, bpy), 8.62 (t, J ) 8 Hz, 1H,
bpy), 8.09 (t, J ) 6.5 Hz, 1H, bpy), 7.96 (t, J ) 6 Hz, 1H, bpy),
2.76 (s, 3H, CH3). ESI-MS (CH3CN, m/z): 965 [Pt2bpy2(AcNNAc)-
(OTf)]+, 408 [Pt2bpy2(AcNNAc)]2+ (positive mode); 148 [OTf]-
(negative mode).
[(bpy)2Pt2(AcNNC(O)(CH2)2CHdCH2)](OTf)2 (25). Pt(bpy)Cl2
(14.6 mg, 34.6 µmol), AgOTf (20 mg, 78 µmol), and 1a (11.5 mg,
73.7 µmol) were combined in DMF-d7 (0.5 mL), and the mixture
was allowed to react at RT. After 22 h, >95% conversion to 25
was observed by 1H NMR analysis. Complex 25 was then isolated
as described in the general procedure. Attempts to isolate Pt
complex 25 on larger scales (50-100 mg Pt(bpy)Cl2) by filtration
[(bpy)Pt(CH2CH(CH2)2C(O)N-Nphthal)(CD3CN)](OTf)(20). [Pt-
(bpy)(MeCN)2](OTf)2 (9.7 mg, 13 µmol) and 1b (7.4 mg, 30 µmol)
were combined in DMF-d7 (400 µL). After heating at 80 °C for
1
5 h ∼88% conversion to 20 was observed by H NMR analysis.
Complex 20 was then purified according to the general procedure.
1H NMR (CD3CN, 500 MHz): δ 8.64 (d, JHH ) 10 Hz, JPtH ) 46.5
Hz, 1H, bpy), 8.31 to 8.01 (m, 6H, bpy), 7.65 (m, 1H, bpy), 7.53
to 7.42 (m, 4H, phthal Ar), 4.15 (m, 1H, CH), 2.54 to 2.41 (m, 2H,
CH2), 2.23 (m, 1H, Pt-CH2), 1.88 (m, 2H, CH2), 1.47 (dd, JHH
)
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Pt-Catalyzed Intramolecular Hydrohydrazination
A R T I C L E S
through an air-free frit were unsuccessful due to formation of gooey
material, which clogged the frit. 1H NMR (DMF-d7, 300 MHz): δ
9.39 (d, J ) 5.7 Hz, 1H, bpy NdCH), 9.30 (d, J ) 5.7 Hz, 1H,
bpy), 9.16 (d, J ) 5.7 Hz, 1H, bpy), 9.04 (d, J ) 5.7 Hz, 1H, bpy),
8.88 (m, 4H, bpy), 8.67 (m, 4H, bpy), 8.11 (t, J ) 6 Hz, 2H, bpy),
7.94 (m, 2H, bpy), 5.92 (m, 1H, dCH), 5.04 (dd, J ) 16.2, 10.2
Hz, 2H, dCH2), 3.15 (t, J ) 7.2 Hz, 2H, CH2), 2.74 (m beneath
solv, 5H, 2CH2 and 3CH3). 19F NMR (DMF-d7, 282 MHz): δ -79.1.
ESI-MS (CH3CN, m/z): 1007 [(bpy)2Pt2(AcNNC(O)(CH2)2CHd
CH2)(OTf)]+, 428 [(bpy)2Pt2(AcNNC(O)(CH2)2CHdCH2)]2+ (posi-
tive mode); 148 [OTf]- (negative mode).
Acknowledgment. We are grateful to the University of Wash-
ington and the National Science Foundation (Grant No. CHE-
0513023 to J.M.M.) for support of this work.
Supporting Information Available: The CIF for compound
23, full experimental details, characterization data for all new
compounds, descriptions of stereochemical assignments, and
kinetic data. This information is available free of charge via
the Internet at http://pubs.acs.org.
JA906563Z
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J. AM. CHEM. SOC. VOL. 132, NO. 14, 2010 5053