Carbostannolysis mediated by bis(pentamethylcyclopentadienyl)lanthanide catalysts. Utility in accessing organotin synthons

Article abstract of DOI:10.1021/om301031e

Facile carbon-tin bond activation in the reaction of 2-(trimethylstannyl) pyridine (1) with the organolanthanide complexes Cp*₂LaCH(TMS) ₂ (2a) and [Cp*₂LaH]₂ (2b) yields Cp*₂La(2-pyridyl) (3), as well as Me₃SnCH(TMS) ₂ and Me₃SnH, respectively. At room temperature, ethylene then undergoes insertion into the resulting La-C(pyridyl) bond followed by carbostannolysis to catalytically generate 2-(2-(Me₃Sn)ethyl)pyridine (4) or, with extended reaction times, 6-ethyl-2-(2-(trimethylstannyl)ethyl) pyridine (5). In contrast to 1, 6-methyl-2-(trimethylstannyl)pyridine (6) is unreactive, likely reflecting steric constraints. With terminal alkynes, this catalytic heterocycle-SnMe₃ activation/carbostannylation process affords tin-functionalized conjugated enynes. Thus, at 60 C 2b catalyzes the conversion 1 + 1-hexyne to yield (E)-2-butyl-1-(Me₃Sn)-oct-1-en-3-yne in a 60:1 ratio E:Z isomer ratio. This reaction is available to α-monosubstituted and α-disubstituted terminal alkynes, while α-trisubstituted alkynes are too hindered for reaction. The catalytic cycle is proposed to proceed via a spectroscopically detectable Me ₃Sn-alkynyl intermediate which undergoes insertion into a Cp*₂La-alkynyl bond to produce the conjugated alkynyl product, which is subsequently protonolyzed from the Cp*₂La center by a new terminal alkyne substrate molecule. NMR spectroscopic and kinetic data support the proposed pathway and indicate turnover-limiting alkyne insertion.

Full text of DOI:10.1021/om301031e

Article
pubs.acs.org/Organometallics
Carbostannolysis Mediated by
Bis(pentamethylcyclopentadienyl)lanthanide Catalysts. Utility in
Accessing Organotin Synthons
Stephen D. Wobser, Casey J. Stephenson, Massimiliano Delferro,* and Tobin J. Marks*
Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113, United States
S
* Supporting Information
ABSTRACT: Facile carbon−tin bond activation in the reaction of
2-(trimethylstannyl)pyridine (1) with the organolanthanide com-
plexes Cp*2LaCH(TMS)2 (2a) and [Cp*2LaH]2 (2b) yields
Cp*2La(2-pyridyl) (3), as well as Me3SnCH(TMS)2 and Me3SnH,
respectively. At room temperature, ethylene then undergoes
insertion into the resulting La−C(pyridyl) bond followed by
carbostannolysis to catalytically generate 2-(2-(Me3Sn)ethyl)-
pyridine (4) or, with extended reaction times, 6-ethyl-2-(2-
(trimethylstannyl)ethyl)pyridine (5). In contrast to 1, 6-methyl-2-
(trimethylstannyl)pyridine (6) is unreactive, likely reflecting steric constraints. With terminal alkynes, this catalytic heterocycle−
SnMe3 activation/carbostannylation process affords tin-functionalized conjugated enynes. Thus, at 60 °C 2b catalyzes the
conversion 1 + 1-hexyne to yield (E)-2-butyl-1-(Me3Sn)-oct-1-en-3-yne in a 60:1 ratio E:Z isomer ratio. This reaction is available
to α-monosubstituted and α-disubstituted terminal alkynes, while α-trisubstituted alkynes are too hindered for reaction. The
catalytic cycle is proposed to proceed via a spectroscopically detectable Me3Sn−alkynyl intermediate which undergoes insertion
into a Cp*2La−alkynyl bond to produce the conjugated alkynyl product, which is subsequently protonolyzed from the Cp*2La
center by a new terminal alkyne substrate molecule. NMR spectroscopic and kinetic data support the proposed pathway and
indicate turnover-limiting alkyne insertion.
Scheme 2. Representative Reactions of Tin-Functionalized
Conjugated Enynes5b
INTRODUCTION
■
Reagents having C−Sn linkages find widespread application in
chemical synthesis.1 For this reason, understanding and
manipulating their reactivity with organometallic catalysts is
of fundamental importance. Organotin reagents play an
important synthetic role due to their selective reactivity,
stability, and ease of handling.2 There is also growing interest
in using organotin reagents for transmetalation reactions3 that
traditionally employ toxic organomercury reagents.4 In
particular, the carbostannylation of alkynes, a process in
which a Sn−C bond is added across a CC unsaturation
(Scheme 1), is a powerful synthetic tool which simultaneously
Scheme 1. Generic Alkyne Carbostannylation Reaction
variety of enynols, which are readily cyclized to give
functionalized furans. Furthermore, (Z)-enynols10 have dem-
onstrated pharmacological activity, including as potent
antitumor agents.11
Catalytic carbostannylation is achieved using transition-metal
agents such as palladium,5d−g,i,j,7b gold,12 nickel,5h or
ruthenium5b or by radical processes.13 Frequently these
forms new C−C and C−Sn linkages.5 The resulting Sn-
functionalized alkenes can be readily employed as synthetic
building blocks through Stille coupling reactions.2c,6 Sn-
functionalized enynes have particularly significant synthetic
utility due to the adjacent conjugation,5e,i,7 and such building
blocks have demonstrated applications in arylation,8 alkyla-
tion,5b and subsequent cyclization9 reactions (e.g., Scheme 2).
For example, facile Sn/Li transmetalation, followed by
functionalization with an alcohol can be used to prepare a
Special Issue: Recent Advances in Organo-f-Element Chemistry
Received: October 31, 2012
© XXXX American Chemical Society
A
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catalysts are limited to alkyne substrates having electron-
withdrawing substituents, and for this reason there is a need for
new approaches to the carbostannylation of unfunctionalized
alkynes.
reactivity mode is operative for the insertion of various
unsaturated groups into the pyridine α−C-H bond.14a,b,i,20
For example, the reaction of ethylene with pyridine, catalyzed
by [Cp*2MH]2 (M = La20 (2b), Y14i), produces 2-ethyl-
pyridine, as shown in Scheme 4A. The selective insertion of a
single ethylene molecule is attributed to the high stability of the
five-membered ring formed upon chelation of the 2-(2-
pyridyl)ethyl substituent (structure 7, Scheme 4A).14h,i While
similar organolanthanide activation of thiophene occurs via an
analogous pathway, the reaction with ethylene yields distinctly
different results. The chelating product formed after a single
ethylene insertion is less tightly bound by the relatively less
Lewis basic/softer thiophene substituent,16,20 and multiple
ethylene insertions are achieved using 2b at elevated pressures,
affording thiophene-capped polyethylenes (Scheme 4B).16
This reactivity of heterocyclic α-C−H positions with
organolanthanides raises the intriguing question of whether
similar processes might be employed to activate other
heterocyclic 2-position functionalities such as organometalloids.
For example, trialkyltin groups might be catalytically transferred
from the heterocyclic 2-position to generate valuable new
organotin compounds. If α-C−SnR3 activation using 2-
(trimethylstannyl)pyridine (1) as the substrate proceeded
similarly, subsequent insertive chemistry at Cp*2La(2-pyridyl)
(3) would then produce Cp*2La(2-(2-pyridyl)ethyl) com-
plexes. Subsequent α-C−SnR3/C−La σ-bond metathesis by a
new molecule of 1 would then regenerate 3 and produce 2-[2-
(trimethylstannyl)ethyl]pyridine (4). In this study we explore
the novel activation of 2-(Me3Sn)arenes as an approach to
accessing a variety of novel organotin species. It will be seen
that ethylene undergoes insertion into the La−C bond of the
Cp*2La(2-pyridyl) (3) intermediate at 25 °C, followed by
carbostannolysis, to catalytically generate 2-(2-
(trimethylstannyl)ethyl)pyridine (4). Furthermore, the organo-
lanthanide alkyl Cp*2LaCH(TMS)2 (2a) and organolanthanide
hydride (Cp*2LaH)2 (2b) both initiate the conversion of 2-
(trimethylstannyl)pyridine (1) with 1-hexyne to yield (E)-2-
butyl-1-(trimethylstannyl)-oct-1-en-3-yne ((E)-9). This trans-
formation appears to be general for α-monosubstituted and α-
disubstituted terminal alkynes.
Additionally, in these reported transformations, the product
alkene stereochemistry can be highly dependent on the nature
of the substrate. Each of these metal-catalyzed processes
involves oxidative addition/reductive elimination steps in the
catalytic cycle. Lanthanide ions, on the other hand, typically
have one readily accessible oxidation state and do not undergo
traditional oxidative addition/reductive elimination sequences.
Therefore, a lanthanide-catalyzed carbostannylation process
would be expected to proceed through a very different
mechanism. The utility of the product vinylstannanes and the
limitations of the current synthetic methods provide an impetus
to pursue alternative carbostannylation approaches, which is the
topic of the present contribution.
Several heterocycle classes, including pyridines,14 furans,15
and thiophenes,16 are known to undergo C−H activation at the
2-position by organolanthanide catalysts.17 Although activation
at the pyridine 2-position is most extensively documented,
examples of subsequent catalytic alkylation are rare.14a,i,l,18 This
regioselectivity is thought to be directed by coordination of the
strongly electrophilic lanthanide center to the heteroelement
lone pair(s),14c,d,f,i,j thereby preorganizing the α-C−H bond
proximate to the metal center and providing an intramolecular
entropic advantage for C−H activation (e.g., Scheme 3).
Scheme 3. Activation of Pyridine at the 2-Position by an
Organolanthanide Hydride
Cationic zirconocene catalysts also display similar α-activation
selectivity with a variety of pyridine derivatives.19 Note that this
a
Scheme 4. Catalytic Cycles Proposed by Teuben et al. for the Reaction of Ethylene and (A) Pyridine or (B) Thiophene
Mediated by Lanthanocene/Pseudolanthanocene Catalysts14i,16,20
a
Note that cycle B is extremely sluggish for M = Y.
B
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1
unidentified impurities in the H NMR, which were undetectable by
GC/MS.
EXPERIMENTAL SECTION
■
Materials and Methods. All manipulations of air-sensitive
materials were carried out with rigorous exclusion of O2 and moisture
in flame- or oven-dried Schlenk-type glassware on either a dual-
manifold Schlenk line, interfaced to a high-vacuum manifold (10−6
Torr), or in a N2-filled MBraun glovebox with a high-capacity
recirculator (<1 ppm O2). Argon (Airgas) was purified by passage
through a MnO column to remove O2 and a column of Davison 4A
molecular sieves to remove water immediately before use. Solvents for
catalytic reactions were stored over Na/K alloy in resealable containers
and vacuum-transferred immediately prior to use. All liquid or volatile
solid substrates for catalytic experiments were dried over a series of
three or more beds of freshly activated Davison 4Å molecular sieves as
solutions in benzene-d6 or toluene-d8 (Cambridge Isotope Labo-
ratories, 99+ atom % D). Substrate solutions were degassed by freeze−
pump−thaw methods. Solid substrates were purified by sublimation
under high vacuum and were stored at −35 °C in a glovebox. The
NMR internal integration standard, trimethylphenylsilane, was
sublimed and exposed to high vacuum overnight before storage in
the glovebox. The precatalysts Cp*2LaCH(TMS)2 (2a) and
(Cp*2LaH)2 (2b) were prepared as reported in the literature.21
Substrates cyclohexylacetylene, 1-hexyne, and tert-butylacetylene were
purchased from Sigma-Aldrich. Substrate 1 was purchased from TCI.
The substrates 2-(trimethylstannyl)furan,22 2-(trimethylstannyl)-
thiophene,23 and 6-methyl-2-(trimethylstannyl)pyridine (6)24 were
prepared as reported in the literature, and spectra agree with literature
values.
P r e p a r a t i v e - S c a l e R e a c t i o n o f 6 - M e t h y l - 2 -
(trimethylstannyl)pyridine (6) with Ethylene. This reaction was
carried out by following the procedure for the reaction of 2-
(trimethylstannyl)pyridine with ethylene described above. Only
starting material was recovered from the reaction vessel.
Catalytic Carbostannylation of Alkynes with 2-
(Trimethylstannyl)pyridine (1). In a glovebox, a J. Young NMR
tube was charged with a weighed amount of the precatalyst 2b (ca. 4.1
mg, 0.010 mmol) and the internal standard Ph3SiMe (ca. 50 μmol,
13.5 mg). The tube was then interfaced to a high-vacuum line and
substrate solutions of the alkyne (ca. 0.20 mL of a 1.0 M solution in
C6D6, 0.20 mmol) and 2-(trimethylstannyl)pyridine (1; ca. 0.48 mL,
1.0 M solution in C7D8, 0.48 mmol) were added via syringe to a
manifold chamber directly above the NMR tube. The solutions were
mixed immediately before addition to the NMR tube at −78 °C. After
the NMR tubes were sealed, the reaction mixtures were warmed to
room temperature and shaken vigorously. Each reaction tube was then
placed in a preheated NMR spectrometer ( 0.2 °C, verified by an
ethylene glycol standard) and allowed to equilibrate for at least 6 min
before data collection began. Data were obtained with a single
transient to avoid signal saturation. Heating subsequent to the initial
12 h was carried out in temperature-controlled oil baths, from which
reaction mixtures were periodically removed for NMR analysis.
Substrate and/or product concentrations were determined relative to
the intensity of the internal standard resonance plotted versus time.
Upon completion, the reaction mixtures were filtered through a plug
of basic alumina to separate the products, and volatiles were removed
in vacuo.
Physical and Analytical Measurements. NMR spectra were
recorded on a Mercury 400 (400 MHz, H; 100 MHz, 13C; 149.1
1
MHz, 119Sn), Inova 500 (500 MHz, H; 125 MHz, 13C), or Bruker
1
Kinetic Analysis. Kinetic analysis of the NMR-scale reactions
described above was carried out by collecting numerous (>15) data
points early in the reaction before substrate concentrations were
appreciably depleted.25 Under these conditions, the reaction can be
approximated as pseudo zero order with respect to the substrate
concentrations. Data were fit by least-squares analysis (R2 > 0.995)
according to eq 1, where t is time and [product] is the concentration
of product at time t. The turnover frequency (Nt) was then calculated
according to eq 2, where [catalyst]0 is the initial catalyst concentration.
Avance III 500 instrument (500 MHz, H; 125, 13C). Chemical shifts
1
(δ) for H and 13C are referenced to internal solvent resonances and
1
reported relative to SiMe4. 119Sn NMR chemical shifts are reported
relative to SnMe4. Quoted values of J(Sn−C) refer to J(119Sn−C)
when the 119Sn and 117Sn satellites are resolvable. NMR experiments
on air-sensitive samples were conducted in Teflon-valve-sealed J.
Young NMR tubes. High-resolution mass spectra were acquired on a
Waters GC-TOF GCT Premier Micromass MS.
n
n
NMR-Scale Reaction of 2-(Trimethylstannyl)pyridine (1) with
Ethylene. In the glovebox, 8.4 mg (0.015 mmol) of 2a was weighed
into a vial, dissolved in 0.5 mL of toluene-d8, and transferred by pipet
to a J. Young NMR tube. The sealed tube was removed from the
glovebox and then interfaced to a high-vacuum manifold, and 0.2 mL
of a 1.0 M solution of 1 (0.2 mmol) was added. The tube was degassed
by manual agitation and brief exposure to vacuum and then cooled to
−78 °C and exposed to 1.0 atm of ethylene. The tube was then
warmed to room temperature and shaken, and the ensuing reaction
was monitored by NMR. Since most ethylene was consumed within 90
min at room temperature, this procedure for adding ethylene was
repeated. After 16 h at room temperature, reaction progress had
plateaued, and no further consumption of ethylene was observable
over an additional 2 days at room temperature. The product, 6-ethyl-2-
(2-trimethyltin)ethylpyridine (5), was characterized by 1H, 13C,
COSY, and HSQC NMR (see the Supporting Information). HMBC
NMR confirms that both ethyl groups are bound to the 2- and 6-
positions of a single pyridine core.
[product] = mt
(1)
m
N (h−1) =
t
[catalyst]0
(2)
(Z)-2,4-Dicyclohexyl-1-(trimethylstannyl)-but-1-en-3-yne
((Z)-8). 1H NMR (500 MHz, C6D6): δ 6.11 (s, 1H; 80.8 Hz, 2J
(
119Sn−1H), 2.40 (t, 1H), 2.13 (t, 1H), 1.11−1.94 (m, 20H), 0.29 (s,
2
9H; 54.4, J (119Sn−1H)). 13C NMR (125 MHz, C6D6): δ 148.52,
133.44, 95.45, 83.09, 49.90, 33.73, 33.62, 33.19, 33.15, 33.08, 26.88,
25.85, −8.44 (354.4 Hz, J (119Sn−1H)). 119Sn NMR (149.1 MHz,
2
C6D6): δ −52.49. MS (m/z): [(M − Me)+] calcd for C18H29Sn,
365.129; found, 365.127.
(Z)-2-Butyl-1-(trimethylstannyl)-oct-1-en-3-yne ((Z)-9). 1H
NMR (500 MHz, C6D6): δ 6.12 (s, 1H; 82.2 Hz, 2J (119Sn−1H),
2.31 (t, 2H), 2.16 (t, 2H), 1.61 (m, 2H), 1.40 (m, 2H), 1.34 (m, 2H),
1.31 (m, 2H), 0.88 (t, 3H), 0.80 (t, 3H), 0.31 (s, 9H). 13C NMR (125
MHz, C6D6): δ 142.96, 136.26, 90.82, 83.87, 42.07, 31.54, 31.47,
Preparative-Scale Reaction of 2-(Trimethylstannyl)pyridine
(1) with Ethylene. In the glovebox, a three-neck Morton flask was
charged with 25 mL of dry toluene and 12.0 mg (0.020 mmol) of 2b.
The apparatus was removed from the glovebox and interfaced to a
high-vacuum manifold. To this solution was added 1.0 mL of a 1.0 M
solution of 1 in toluene (1.0 mmol) by syringe under argon flush. The
solution was stirred and degassed by brief exposure to high vacuum.
After 15 min, the degassed solution was exposed to a feed of 1.0 atm of
ethylene for 2.0 h with vigorous stirring. The reaction was quenched
with 10 mL of methanol, and the volatiles were removed under
22.87, 22.70, 19.69, 14.57, 14.08, −8.68 (354.9 Hz, J (119Sn−1H)).
2
119Sn NMR (149.1 MHz, C6D6): δ −53.66. MS (m/z): [(M −- Me)+]
calcd for C14H25Sn, 313.098; found, 313.315.
(E)-2-Butyl-1-(trimethylstannyl)-oct-1-en-3-yne ((E)-9). 1H
NMR (500 MHz, C6D6): δ 6.44 (s, 1H; 70.4 Hz, 2J (119Sn−1H),
2.26 (t, 2H), 2.21 (t, 2H), 1.72 (m, 2H), 1.40 (m, 2H), 1.37 (m, 2H),
1.35 (m, 2H), 0.91 (t, 3H), 0.81 (t, 3H), 0.14 (s, 9H). 13C NMR (125
MHz, C6D6): δ 141.95, 137.10, 89.12, 83.65, 40.50, 32.34, 31.76,
1
vacuum, leaving a colorless oil. The oil was determined by H NMR
23.18, 22.63, 19.71, 14.71, 14.11, −8.31 (352.6 Hz, J (119Sn−1H)).
2
and GC/MS to be an ∼83:2:15 ratio mixture of 2-[2-
(trimethylstannyl)ethyl]pyridine (4) to 6-ethyl-2-[2-
(trimethylstannyl)ethyl]pyridine (5) to starting material 1 with ∼5%
119Sn NMR (149.1 MHz, C6D6): δ −55.45. MS (m/z): [(M − Me)+]
calcd for C14H25Sn, 313.098; found, 312.850.
C
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In situ 1H NMR monitoring indicates that 4 is the
predominant intermediate in the 1 → 5 conversion (Scheme
5). On the basis of these results, the reaction was next
performed on a larger scale with excess ethylene in a stirred
reactor. Note that these conditions do not effect the insertion
of multiple ethylene units at either carbon position. However,
insertion of a single ethylene into the C−Sn bond versus the α-
C−H bond is observed with a selectivity of >100×, producing
compound 4. Halting the reaction with ∼85% of 1 consumed
reveals minimal involvement of the α-C−H bond at this stage.
The reaction can be quenched at this point or allowed to
proceed through cycle B, where subsequent C−H activation/
ethylene insertion yields 7. Scheme 6 details a possible catalytic
cycle for these transformations.
RESULTS
■
The goal of this research was to investigate the activation of the
Sn−C(aryl) bond in 2-(trimethylstannyl)pyridine (1) by the
organolanthanide complexes/precatalysts Cp*2LaCH(TMS)2
(2a) and [Cp*2LaH]2 (2b) in the presence of C−C
unsaturation. The reaction of 2a with 1 is found to be
significantly slower than that of complex 2b, likely due to the
steric congestion around the metal center. For ethylene, the
reaction proceeds through a Cp*2La(2-pyridyl) (3) intermedi-
ate identified by NMR spectroscopy, followed by CC
insertion into the resulting La−C bond and subsequent
carbostannolysis to generate 2-[2-(trimethylstannyl)ethyl]-
pyridine (4) catalytically. With terminal alkynes such as 1-
hexyne, this (heterocycle)C−SnMe3 activation/carbostannyla-
tion process yields Me3Sn-functionalized conjugated enynes
(E)-2-butyl-1-(trimethylstannyl)-oct-1-en-3-yne ((E)-9) in a
60:1 E:Z isomer ratio. This reaction is available to α-
monosubstituted and α-disubstituted terminal alkynes, while
α-trisubstitued alkynes are unreactive.
To investigate substrate steric effects, a preparative-scale
reaction was carried out using 6-methyl-2-(trimethylstannyl)-
pyridine (6) as the substrate. Here, ethylene insertion is not
observed at either the 2- or the 6-position, and only starting
material is recovered (eq 3).
Ethylene Insertion Reactivity. Initial NMR-scale studies
of the reaction of 1 with ethylene, catalyzed by 2a, indicate that
both the pyridine 2- and 6-positions can be activated by the
metal center (Scheme 5). While organolanthanide-mediated
Reactivity of Terminal Alkynes. When hydride 2b is
treated with 20 equiv of substrate 1 and 48 equiv of
cyclohexylacetylene at 60 °C for 12 h, followed by 120 °C
overnight, both starting materials are completely consumed.
Initial in situ 1H NMR monitoring indicates essentially
Scheme 5. Reaction of Pyridine Derivative 1 with Ethylene,
Catalyzed by Cp*2LaCH(TMS)2
1
instantaneous H2 formation (δ 4.48). After heating, H, 13C,
HSQC, and HMBC NMR spectra of the reaction mixture
(Supporting Information) indicate that the major products are
(Z)-2,4-dicyclohexyl-1-(Me3Sn)-but-1-en-3-yne, (Z)-8, and 1.0
equiv of pyridine (eq 4) with the double-bond Z orientation
C−H bond activation at this position is established,14a−k C−Sn
bond activation in this manner by d0 or f0 centers was
previously unknown. In situ monitoring of the NMR-scale
reaction indicates that the (pyridine)C−Sn bond is indeed
activated and subsequent ethylene insertion occurs at this
position (Scheme 5). Within 16 h at room temperature, the
reaction is complete by NMR. The absence of characteristic 1H
NMR downfield pyridine signals at δ ∼8.5 indicates that the
C−H α to the N atom has been selectively functionalized, and
disappearance of the 117,119Sn-coupled methyl signal at δ 0.32
indicates that the Me3Sn group has been displaced.
Furthermore, HSQC, COSY, and HMBC NMR spectra (see
the Supporting Information) indicate there is a single pyridine
skeleton in the product, substituted at both the 2- and 6-
positions.
Scheme 6. Proposed Pathway for Conversion of Pyridine Derivative 1 to 4 and Then to 5
D
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confirmed by NOESY NMR. Note that this stereochemistry
determination was made after heating at 120 °C overnight.
Furthermore, the excess cyclohexylacetylene is converted to an
unfunctionalized dimer (eq 4) via a known organolanthanide-
catalyzed process.14h,26 When the above terminal alkyne + 1
reaction is repeated with 1-hexyne, the reaction is >90%
complete within 1 day at only 60 °C by 1H NMR (see Table 1).
(i.e., vinyl, SnMe3) are evident as well-separated signal pairs.
Selective 1-D NOESY NMR irradiation of the (Z)-9 SnMe3
signal in the mixture confirms the stereochemistry (Figure 1).
1
The H NMR alkyl region shows a complex pattern from the
four n-butyl groups in the isomeric mixture. However, HMBC
and HSQC NMR spectroscopy allow unambiguous assignment
of the 1H and 13C signals (Supporting Information). Elucidating
the CC orientation and subsequent isomerization process for
product 9 prompted closer examination of the process forming
(Z)-8. When the cyclohexylacetylene + 1 reaction is examined
Table 1. Alkyne Effects in Reactions with 2-
(Trimethylstannyl)pyridine (1) Catalyzed by 5 mol %
[Cp*2LaH]2
1
in situ by H NMR, the E:Z isomer ratio is 95:5 after heating
for 12 h at 60 °C. However, after heating overnight at 120 °C,
the E:Z ratio falls to 11:89, arguing that the catalytic cycle first
produces E CC stereochemistry, which then undergoes
isomerization by a known thermal/radical process (vide
infra).13,27 The reaction of 1 + cyclohexylacetylene without
an organolanthanide catalyst was also investigated under
identical conditions. After heating at 60 °C for 30 h, negligible
reaction is observed by 1H NMR, confirming that these
processes are mediated by the organolanthanide catalyst.
Reaction Kinetics. The reaction of 1 with 1-hexyne
catalyzed by 2b was monitored in situ by NMR at 60 °C.
The tin-coupled vinyl signal characteristic of product (E)-9 was
monitored, and conversion is plotted versus time in Figure 2.
Note that the rate of product formation falls as the reaction
proceeds. Note also that a number of new signals are observed
a
b
At t = 12 h, by in situ 1H NMR. Initial rate derived from a linear fit
(R2 > 0.995) of product formation vs time for the first 5−15%
conversion (see the Experimental Section for details).
1
in H and 13C NMR spectra of the 25 °C reaction mixture,
corresponding to pyridine and the known compound Me3Sn(1-
Furthermore, NOESY NMR indicates that the product, (E)-9,
has a double-bond orientation opposite to that of the
cyclohexylacetylene product (Z)-8. Subsequent heating of
(E)-9 at 120 °C affords a mixture of (E)-9 and (Z)-9. Clearly,
the E isomer is the kinetic product and subsequently isomerizes
to the Z product by known processes (vide infra). After 2.5 h of
heating at 120 °C, nearly equivalent amounts of (E)-9 and (Z)-
9 are present in the reaction mixture. Although the four n-butyl
hexynyl)28 before any (E)-9 is observed (Figure 3).
The proposed catalytic cycle in Scheme 7 accounts for the
formation of the initially formed products (E)-8 and (E)-9.
Here, lanthanide hydride precatalyst 2b is activated by the
terminal alkyne substrate, generating Cp*2La−alkynyl species A
1
and H2, the latter of which is observed by H NMR (δ 4.48).
Cycle A in Scheme 7 may operate independently of cycle B and
proceeds by a σ-bond metathesis with 1, eliminating
intermediate Me3Sn(alkynyl) species B and generating
1
groups in the mixture overlap significantly in the H NMR
spectrum, several nonoverlapping, highly characteristic signals
Figure 1. (middle) 1H NMR of (E)-9 and (Z)-9 mixture from the 1 + 1-hexyne reaction (Scheme 8). (top) Selective irradiation of the SnMe3 signal
of (Z)-9 using 1D NOESY NMR. (bottom) Selective irradiation of SnMe3 of (E)-9 using 1D NOESY NMR.
E
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regenerating Cp*2La−alkynyl species A. Cycle B then proceeds
via insertion of intermediate B (generated from cycle A) into
the La−alkynyl bond of A (cycle B, step ii). The resulting
Cp*2La−vinyl complex C produced in this reaction then
undergoes protonolysis by a new terminal alkyne molecule,
eliminating the (E)-8 or (E)-9 product (cycle B, step iii).
Under identical conditions, using tert-butylacetylene as the
substrate, no Me3Sn-functionalized enyne is observed, even
after 12 h at 80 °C. However, after 3 days at 120 °C, the tert-
1
butylacetylene is completely consumed, and H, 13C, and 119Sn
NMR spectroscopic analysis identifies the known Me3SnC
CtBu29 as the only Sn-containing species. The remainder of the
tert-butylacetylene is converted to the known nonfunctionalized
alkyne dimer via an established process.14h,26
Figure 2. Plot of (E)-9 formation versus time in the reaction of 1 + 1-
hexyne catalyzed by organolanthanide complex 2b (5 mol %) at 60 °C:
[1]0 = 294 mM; [1-hexyne]0 = 706 mM; [2b]0 = 14.7 mM.
Non-Pyridine Arenes as Substrates. To explore whether
the aforementioned reactivity is unique to pyridine, a series of
experiments was performed with a variety of heterocycle−
SnMe3 reagents. To facilitate observation of the various
structures by NMR, cyclohexane-d12 was used as the solvent.
A reaction under identical conditions using 1 and cyclo-
hexylacetylene demonstrated that the choice of aromatic
hydrocarbons or cyclohexane as solvent does not affect the
reaction rate or products. When 1 and cyclohexylacetylene were
added to catalyst 2b, free pyridine was detected, indicating
−SnMe3 transfer. To evaluate whether a heterocycle is required
in the Ar−SnMe3 activation step, PhSnMe3 was investigated as
the substrate with cyclohexylacetylene. Additionally, both 2-
(trimethylstannyl)thiophene and 2-(trimethylstannyl)furan
were examined as −SnMe3 sources. Importantly, negligible
reaction of these Ar−SnMe3 reagents is observed. However,
within minutes at 25 °C, each of these mixtures results in
complete alkyne conversion to the nonfunctionalized alkyne
Figure 3. Stack plot showing the Me3Sn region of the 1H NMR
spectra of the reaction of 1 with 1-hexyne catalyzed by 2b (5 mol %):
[1]0 = 294 mM; [1-hexyne]0 = 706 mM; [2b]0 = 14.7 mM; t = 8 min,
25 °C; t = 14 min, 60 °C; t = 720 min, 60 °C.
1
dimer,14i as determined by H and 13C NMR.
Disubstituted Alkynes and Alkenes as Substrates.
Successful −SnMe3 functionalization using terminal alkynes
prompted exploration of other unsaturated substrates. To
investigate the possibility of functionalizing internal alkynes, the
reaction of 1 + 2-pentyne, catalyzed by 2b, was investigated.
However, under the reaction conditions used for terminal
alkynes (60 °C, 12 h), there is no obvious catalytic turnover by
Cp*2La-pyridyl complex 3 (cycle A, step ii). Species 3 then
undergoes protonolysis by a new terminal alkyne substrate
molecule (cycle A, step iii), eliminating pyridine and
Scheme 7. Proposed Pathway for the Organolanthanide-Mediated Formation of Products (E)-8 and (E)-9 from Terminal
Alkynes and 1
F
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1H NMR. The reaction temperature was then gradually
increased, and after 2 days at 120 °C, there was still no
obvious reaction. Additionally, a similar reaction was
investigated using methylenecyclopentane as the substrate.
Again, even after 2 days at 120 °C, no reaction was observable
Scheme 9. α-Methyl Group Deactivation of Pyridine
Metalation in 6-Methyl-2-(trimethylstannyl)pyridine and α-
Picoline with Organolanthanide and Organoyttrium
Complexes17c
1
by H NMR. These results indicate the chemistry described in
Scheme 9 is only available to terminal alkynes.
DISCUSSION
■
Ethylene Insertion Reactivity. The reaction of 1 and
ethylene, catalyzed by 2a, is found to first yield compound 4
(Scheme 6). While activation of pyridine 2-C−SnR3 groups by
organolanthanide catalysts was previously unknown, it bears
some similarity to the known activation of the pyridine 2-C−H
position by organolanthanides, and it is plausible that the
catalytic cycles follow similar pathways involving four-center
transition states (Scheme 3).14b,i Importantly, the 2-C−SnMe3
group reactivity is found to be significantly greater than that of
the corresponding 2-C−H functionality. Reported mechanisms
for lanthanide-mediated 2-C−H activation invoke pyridine
precomplexation, followed by Ln−H/(pyridine)C−H σ-bond
metathesis (Scheme 3),14c,d,f,i,j and such a pathway is plausible
for C−Sn activation as well (Scheme 8). Indeed, the greater C−
Scheme 10. Preferential Protonolysis by Alkyne versus
Insertion into La−Pyridyl Species
reasonable, given that alkynyl protons are ∼15 pKa units
more acidic than vinyl protons,32 and the formation of the
strong Cp*2La−alkynyl bond (eq 5), ∼93 kcal/mol33 versus
Scheme 8. Preferential C−Sn over C−H Bond Activation in
a
1, in the Context of the Reaction in Schemes 5 and 6
Table 2. Calculated Reaction Enthalpies for Cp*2La−
Alkynyl and Cp*2La(η2-pyridyl) Formation
a
For clarity, dative py→La interactions are not shown in the transition
state.
Sn bond length/steric accessibility relative to C−H (ca. 2.203
and 0.948 Å, respectively)30 and weaker metalloid−C bond
enthalpy31 would appear to favor enhanced C−Sn reactivity.
Furthermore, the greater C−SnMe3 electron richness and
length of the C−Sn bonds should promote agostic interactions
with the electrophilic lanthanide metal ion, a likely prerequisite
for C−Sn activation.14c,d,f,i,j While 2-(trimethylstannyl)pyridine
(1) reacts readily with ethylene at 25 °C, 6-methyl-2-
(trimethylstannyl)pyridine (6) fails to undergo detectable
ethylene insertion. A plausible explanation is that the 6-methyl
group of 6 significantly congests/destabilizes the four-center
transition state (Scheme 8). The σ-bond metathesis step is
likely severely hindered. This observation is in accord with
related work on organoyttrium complexes, which readily
metalate at the 2-hydrogen of pyridine but fail to metalate
the corresponding 6-hydrogen of 2-picoline (Scheme 9).17c
similar explanation was invokedthe bulky substituent
destabilizes the four-center transition state at the crowded Y
center.
Terminal Alkyne Reactivity. On the basis of the ethylene
insertion chemistry described in Scheme 4, the initial
expectation for terminal alkynyl substrates was a similar
insertive process. However, terminal alkynes display reactivity
distinctly different from that of ethylene in the reaction of 1
catalyzed by 2b. For terminal alkynes, protonolytic reactivity
greatly exceeds insertive reactivity (Scheme 10). This is
A
a
With Ln/An adjustments.
∼65 kcal/mol estimated for Cp*2La(η2-pyridyl) bonding,34
represents a significant thermodynamic driving force. This
reaction selectivity leads to the unexpected Sn-functionalized
enyne products. The estimated reaction enthalpies (ΔH =
∑ΔHbonds broken − ∑ΔHbonds formed) for Cp*2La−alkynyl and
Cp*2La(η2-pyridyl) were estimated as shown in Table 2.
These thermodynamic estimates agree with the experimental
observations; specifically, the exothermic Ln−H + alkyne
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reaction gives rise to La−alkynyl species and H2, both detected
by NMR spectroscopy. In contrast, the products of the
essentially thermoneutral Ln−H + Sn−Ar reaction, in presence
of alkynes, are not observed in the activation process by NMR
spectroscopy. In previous organolanthanide-mediated alkyne
dimerization studies, the Lewis base free reaction proceeds via
Cp*2Ln(μ-CCR)2LnCp*2 dimers (eq 7).38 In contrast,
(step ii, cycle A, Scheme 7), yielding intermediate B and
complex 2b. In the next step (step iii, cycle A), 2b undergoes
protonolysis by terminal alkyne, regenerating A and releasing
pyridine. The process in cycle A must transfer the Me3Sn group
of 1 to form complex B before cycle B is activated.
In cycle B (Scheme 7), complex B undergoes insertion into
Cp*2La−alkynyl species A, generating an intermediate
Cp*2La−vinyl complex C, which readily undergoes proto-
nolysis by terminal alkyne, releasing the desired Me3Sn-
functionalized enyne, (E)-8 or (E)-9 (step iii, cycle B, Scheme
7). Complex A could potentially undergo terminal alkyne
insertion rather than that of the Sn-substituted alkyne required
in step ii, cycle B, Scheme 7. Indeed, in the absence of a Lewis
base, f-element and group 3 metallocenes are reported to
catalyze rapid (Nt > 5000 h−1 at 20 °C)17c protonolysis/
insertion cycles, affording terminal alkyne dimers or oligomer-
s.17a,38b,39 However, the presence of a strong Lewis base such as
pyridine significantly inhibits alkyne insertion.14i,17c,40 In the
present work, despite significant inhibition by Lewis basic
pyridyl compounds, this insertion pathway is plausibly the
source of small amounts of nonstannylated alkyne dimer
formed as the more reactive organotin species are consumed.
Regarding competition between terminal alkynes and Me3Sn-
functionalized alkynes for insertion (step ii, cycle B, Scheme 7),
it is demonstrated here that despite the increased Me3Sn−
group steric bulk, Me3Sn-functionalized alkyne B preferentially
undergoes insertion into A. In related Cp*2La-mediated
insertive processes, electron-rich TMS−alkynyl species are
found to undergo insertion far more rapidly than terminal
alkynes.41 Similar trends are observed for Cp*2An-catalyzed
(An = Th, U) alkyne insertion processes,42 where the TMS
substituent stabilizes the partial charges in the transition state
−CC unit.43 This preference likely reflects the known ability
of group 14 substituents to stabilize β-positive chargesan
effect which is enhanced for larger group 14 metals (see Figure
4).44 Additional stabilization is doubtless imparted by favorable
monomeric Cp*2Ln(CCR)(base) adducts suppress this
pathway. Thus, the lack of nonstannylated alkyne dimerization
activity in the present system suggests that pyridine (or 1 at the
onset of reaction) acts to inhibit lanthanide−alkynyl dimer
formation.
Initial observations on the final products of the 2b-catalyzed
cyclohexylacetylene + 1 reaction indicate that both (E)-8 and
(Z)-8 product isomers are formed, as well as pyridine. A
plausible catalytic cycle for the (Z)-8 synthesis is shown in
Scheme 11. Here species A, the Cp*2Ln−alkynyl compound,
Scheme 11. One Possible Scenario for (Z)-8 Synthesis
Mediated by an Organolanthanide Catalyst
Figure 4. Potential stabilizing agostic interaction of an electron-rich
−SnMe3 substituent with electrophilic metal ion in the insertive
transition state. For clarity, the arrow indicates a weak intermolecular
stannane/organolanthanide interaction.
undergoes insertion by a second cyclohexylacetylene molecule
(step i). Subsequent σ-bond metathesis (step ii) and
protonolysis (step iii) release the Me3Sn−enyne product.
This scenario requires that free pyridine be produced
concurrently with the Me3Sn−enyne product. However, in
situ NMR monitoring reveals that pyridine is produced
quantitatively within minutes, before either (E)-8 or (Z)-8 is
observed (see Figure 3), suggesting that Scheme 11 is not a
significant contributor to the present catalytic process.
Scheme 7 invokes two distinct cycles, emphasizing that cycle
A may operate independently of cycle B. The initiation of cycle
B necessarily relies on Me3Sn(alkynyl) species B produced by
cycle A. The cycle begins with the thermodynamically favorable
formation of Cp*2Ln−alkynyl species A from the precatalyst
2b, a process known to proceed rapidly at 25 °C.17c In the
present system, A initially undergoes carbostannolysis by 1
substituent−f-center agostic interactions (Figure 4),45 and
similar intermolecular stannane/organolanthanide interactions
are supported by DFT analysis.46
The insertion of the Me3Sn(alkynyl) species B explains the
orientation of the initially formed product double bond. The
data in Table 1 indicate that the kinetic product CC
orientation is predominantly E, and only subsequent heating
yields appreciable quantities of the less hindered Z isomers,
(Z)-8 and (Z)-9. In addition to photoisomerization, vinyl-
stannanes are known to undergo isomerization by thermally or
chemically induced radical pathways.13,27 In the present study,
bond connectivity is established by HSQC and HMBC NMR,
and double-bond orientation is assigned by NOESY NMR.
H
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Observing (trimethylstannyl)alkynyl species B in the 25 °C
reaction mixtures (Figure 5) provides support for the scenario
Figure 5. Plot of ln[Me3Sn(1-hexynyl)] versus time, corresponding to
1
cycle B, Scheme 7. (a) Due to overlapping signals in the H NMR
spectrum, the concentration of Me3Sn(1-hexynyl) could not be
integrated precisely and is determined by eq 8.
Figure 6. Relative concentrations of Me3Sn intermediate B (Me3Sn(1-
hexynyl)) and product (E)-9 during the reaction of 1 + 1-hexyne,
catalyzed by 2b (5 mol %): [1]0 = 294 mM; [1-hexyne]0 = 706 mM;
[2b]0 = 14.7 mM. At 60 °C, [B] is determined by eq 8. The dashed
line indicates the change in reaction temperature from 25 to 60 °C.
proposed in Scheme 7, which allows cycle A to proceed
independently, generating free pyridine and intermediate B.
Indeed, for tert-butylacetylene, only cycle A is populated, while
cycle B is not accessed. Presumably the observed product of
cycle A, (trimethylstannyl)tert-butylethynyl, is too sterically
encumbered for insertion at the Cp*2La− center, thereby
impeding Me3Sn-functionalized enyne formation via cycle B. As
shown in Figure 5, the cycle A process (Scheme 7) is essentially
complete by the initiation of kinetic monitoring. That is, 1 has
reacted quantitatively with 1 equiv of free alkyne to yield 1
equiv of free pyridine and 1 equiv of species B, the
(trimethylstannyl)alkynyl intermediate, before cycle B is
occupied. Therefore, the kinetic data only describe the
processes of Scheme 7, cycle B. Species B is a reactant in
cycle B; however, precise integration of the associated 1H NMR
signals is not possible due to signal overlap. For kinetic analysis,
we assume that during cycle B, cycle A has already proceeded to
quantitative completion and that depletion of species B
corresponds to the simultaneous production of the Me3Sn-
functionalized enyne (8 or 9). For 1-hexyne as the substrate,
the intermediate B concentration is described by eq 8. By
estimating [B] in this manner, further kinetic analysis is then
possible. Thus, plotting ln[B] versus time yields a linear plot,
consistent with first-order rate dependence on [B] (Figure 5),
corresponding to the proposed turnover-limiting insertive step
ii, cycle B, of Scheme 7. Monitoring the Me3Sn-functionalized
intermediate and product concentrations over time at both the
initial temperature of 25 °C and subsequent heating at 60 °C
confirms the rapid formation of intermediate B and subsequent
depletion at 60 °C (Figure 6).
Disubstituted Alkynes and Alkenes as Substrates. The
successful activation of the heterocycle−SnMe3 bond in 1 and
subsequent ethylene insertion raises the question of whether
other C−C unsaturated groups might exhibit similar reactivity.
In previous work with Cp*2Y(2-pyridyl), it was reported that
stoichiometric amounts of 2-pentyne react over the course of 2
days at 75 °C, producing a mixture of products that includes
the 2,3- and 3,2-insertion products.14i However, in the present
[Cp*2LaH]2 system with excess 1, no catalytic insertive
reactivity with the internal alkyne is observed, even at 120 °C
over 2 days. While H2 is not observable by NMR in reactions
1
with internal alkynes, Me3SnH is observed as characteristic H
NMR spectral features at δ 4.65 ppm and a doublet at δ 0.13
ppm, suggesting C−SnMe3 bond activation at the onset of
reaction (eq 9).48 Furthermore, the presence of a Lewis base
appears to inhibit cyclic disubstituted alkyne dimerization,
known to be catalyzed by Cp*2LaCH(SiMe3)2.47g The lack of
typical insertive reactivity in the present system is rationalized
by considering the inhibitory effects of pyridine on
lanthanocene insertion chemistry (vide supra).14i Under
identical conditions, attempted reactions using methylenecy-
clopentane as the unsaturated substrate similarly failed to effect
turnover. These observations, as well as the observation that
even sterically slender terminal alkynes (e.g., 1-hexyne) do not
undergo insertion at La-[2-(6-Me3Sn)pyridyl] centers, argue
that the high reactivity observed for terminal alkynes results
from σ-bond metathesis involving the acidic terminal H−C
C− moiety.
Effect of Varying Heterocycles. While regioselective
pyridine C−H activation is generally challenging in other parts
of the periodic table,49 advances in this area have recently been
reviewed by Nakao.14b However, compound 1 is known to
undergo transmetalation exclusively at the 2-pyridyl−Sn bond
in typical palladium-catalyzed Stille coupling processes.50 In the
present system, the reactivity of cyclohexylacetylene with Het−
[B] = [1]0 − [8]
(8)
Primary, secondary, and tertiary alkynes were also examined
as substrates for catalytic Me3Sn-functionalized enyne synthesis
(Table 1). The general trend observed is that the less sterically
hindered alkynes are more reactive, consistent with the steric
demands of the insertive transition state (Figure 4)a
ubiquitous trend in organo-f-element alkyne insertion chemis-
try.9d,17a,c,26b,38b,39,42,47 Note that the most encumbered
substrate, tert-butylacetylene, completely resists insertion, even
at elevated temperatures. That these rates are dominated by the
alkyne substituent bulk is consistent with other data supporting
the insertion step as turnover limiting.
I
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SnMe3 species (Het = non-pyridine heterocycle) stands in
marked contrast to the results with 1. Thus, when 2-
(trimethylstannyl)thiophene, 2-(trimethylstannyl)furan, or tri-
methylphenyltin is used, rapid (<15 min) alkyne disappearance
the grants CHE-1048773 (NMR) and CHE-0923236 (GC-
TOF). We also thank Ms. E. Rabinovich for substrate synthesis.
REFERENCES
■
1
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CONCLUSIONS
■
The 2-(trimethylstannyl)pyridine C−Sn bond is found to be
highly reactive with respect to Cp*2La−R activation (R = H,
alkynyl), to catalytically deliver the Me3Sn− group. While the
Cp*2La−pyridyl product does not catalyze ethylene polymer-
ization after the initial insertion, likely due to strong chelation
in Cp*2LaCH2CH2(2-NC5H4), a rich small-molecule chemistry
has been discovered. Similar to the activation of unfunctional-
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can be inserted at the 2-position. Insertion at the 2-SnMe3
position of 1 is found to be strongly preferred over the 6-C−H
position. In contrast to the reaction of unfunctionalized
pyridine with terminal alkynes, the present system initiates a
catalytic cycle using 2-(trimethylstannyl)pyridine which gen-
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monosubstituted and α-disubstituted alkynes are effective
substrates, while α-trisubstituted alkynes appear to be too
sterically encumbered to undergo efficient insertion. This work
should provide a tool for accessing synthetically valuable tin-
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ASSOCIATED CONTENT
* Supporting Information
Figures giving NMR and GC spectra of reaction products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
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AUTHOR INFORMATION
Corresponding Author
*E-mail: m-delferro@northwestern.edu (M.D.); t-marks@
northwestern.edu (T.J.M.).
Author Contributions
The manuscript reflects the contributions of all authors. All
authors have given approval to the final version of the
manuscript.
■
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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We thank the National Science Foundation (NSF, grants CHE-
0809589 and CHE-1213235) for financial support. Use was
made of the IMSERC facility at Northwestern University,
supported by the National Science Foundation (NSF) under
J
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K
dx.doi.org/10.1021/om301031e | Organometallics XXXX, XXX, XXX−XXX