C-H bond functionalization via hydride transfer: Direct coupling of unactivated alkynes and sp3 C-H bonds catalyzed by platinum tetraiodide

Article abstract of DOI:10.1021/ja906480w

We report a catalytic intramolecular coupling between terminal unactivated alkynes and sp³ C-H bonds via through-space hydride transfer (HT-cyclization of alkynes). This method enables one-step preparation of complex heterocyclic compounds by α

Full text of DOI:10.1021/ja906480w

Published on Web 10/23/2009
C-H Bond Functionalization via Hydride Transfer: Direct
Coupling of Unactivated Alkynes and sp3 C-H Bonds
Catalyzed by Platinum Tetraiodide
Paul A. Vadola and Dalibor Sames*
Department of Chemistry, Columbia UniVersity, 3000 Broadway, New York, New York 10027
Received July 31, 2009; E-mail: sames@chem.columbia.edu
Abstract: We report a catalytic intramolecular coupling between terminal unactivated alkynes and sp3 C-H
bonds via through-space hydride transfer (HT-cyclization of alkynes). This method enables one-step
preparation of complex heterocyclic compounds by R-alkenylation of readily available cyclic ethers and
amines. We show that PtI4 is an effective Lewis acid catalyst for the activation of terminal alkynes for
hydride attack and subsequent C-C bond formation. In addition, we have shown that the activity of neutral
platinum salts (PtXn) can be modulated by the halide ligands. This modulation in turn allows for fine-tuning
of the platinum center reactivity to match the reactivity and stability of selected substrates and products.
Scheme 1. Platinum-Catalyzed Coupling of Unactivated Alkynes
and sp3 C-H Bonds via the Through-Space Hydride Transfer
Introduction
C-H bond functionalization provides strategically new
opportunities in the synthesis of complex organic compounds.1
As part of a broad program aimed at the development of new
approaches and methods for the direct functionalization of C-H
bonds, we have been interested in the intramolecular coupling
of sp3 C-H bonds and alkenes to effect R-alkylation and
R-alkenylation of ethers and amines under catalytic, nonbasic
conditions. To complement approaches initiated by transition
metal insertion into a desired C-H bond,2 we explored an
alternative mode of reactivity based on Lewis acid catalyzed
hydride transfer, followed by C-C bond formation (HT-
cyclization). We have demonstrated that a wide range of
substrates containing activated alkenes undergo cyclization under
mild acidic conditions.3,4 Subsequently, other laboratories
demonstrated the feasibility of HT-cyclization with activated
alkynes containing electron-withdrawing groups.5 We here
report that unactivated terminal alkynes serve as hydride
acceptors in the through-space hydride transfer and undergo
catalytic intramolecular hydroalkylation at the R-position of
cyclic ethers and amines, providing rapid access to bicyclic
products (Scheme 1).
The hydroalkylation of terminal alkynes has previously been
limited to aromatic substrates, namely 2-alkyl-1-ethynylben-
zenes, reported to give substituted indenes via an overall 5-endo
cyclization (Scheme 2).6-9 Different mechanistic rationales were
proposed for this transformation including direct insertion of
the metal-vinylidene group into the benzylic C-H bond in the
intermediate II (formed in situ from the alkyne)6 or a 1,5-
sigmatropic hydrogen shift along the π-system.7,8 More recently,
the through-space 1,5-hydride transfer, followed by 6π-elec-
trocyclization and reductive elimination, was proposed as a
viable mechanism for the metal catalyzed cyclization of 2-alkyl-
1-ethynylarenes.8
We here describe a distinct process, the 5-exo alkenylation
of saturated heterocycles, which proceeds via the through-space
hydride transfer, as the other mechanistic pathways (i.e., carbene
insertion or sigmatropic rearrangement) are not plausible. We
also report on the key importance of the platinum-halide bond
in the modulation of the catalyst activity. The catalytic alkeny-
lation of cyclic ethers and cyclic amines affords products of
(1) Godula, K.; Sames, D. Science 2006, 312, 67.
(2) (a) DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004,
126, 6556. (b) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.;
Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2001, 123, 10935.
(3) (a) Pastine, S. J.; McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2005,
127, 12180. (b) Pastine, S. J.; Sames, D. Org. Lett. 2005, 7, 5429. (c)
McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2009, 131, 402. (d)
McQuaid, K. M.; Long, J. Z.; Sames, D. Org. Lett. 2009, 11, 2972.
(4) For other recent developments in the area of HT-cyclization, see: (a)
Zhang, C.; Murarka, S.; Seidel, D. J. Org. Chem. 2009, 74, 419. (b)
Ruble, J. C.; Hurd, A. R.; Johnson, T. A.; Sherry, D. A.; Barbachyn,
M. R.; Toogood, P. L.; Bundy, G. L.; Graber, D. R.; Kamilar, G. M.
J. Am. Chem. Soc. 2009, 131, 3991. (c) Zhang, C.; De, C. K.; Mal,
R.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 416.
(6) Bajracharya, G. B.; Pahadi, N. K.; Gridnev, I. D.; Yamamoto, Y. J.
Org. Chem. 2006, 71, 6204.
(7) Odedra, A.; Datta, S.; Liu, R.-S. J. Org. Chem. 2007, 72, 3289.
(8) Tobisu, M.; Nakai, H.; Chatani, N. J. Org. Chem. 2009, 74, 5471.
(9) A related process with substituted alkynes: Yang, S.; Li, Z.; Jian, X.;
He, C. Angew. Chem., Int. Ed. 2009, 48, 3999.
(5) (a) Barluenga, J.; Fañanás-Mastral, M.; Anzar, F.; Valde´s, C. Angew.
Chem., Int. Ed. 2008, 47, 6594. (b) Shikanai, D.; Murase, H.; Hata,
T.; Urabe, H. J. Am. Chem. Soc. 2009, 131, 3166.
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J. AM. CHEM. SOC. 2009, 131, 16525–16528 16525

A R T I C L E S
Vadola and Sames
Scheme 2. Cyclization of 2-Alkyl-1-ethynylbenzenes and Proposed
Mechanistic Rationales
high synthetic value that are not readily accessible via other
approaches.10
Figure 1. Effect of halide ligand on the catalyst activity. Initial rates of
product 2 formation are shown in the plot. The inset lists the yields of
product 2 and remaining starting material 1. Reactions performed at 0.05
M in dry MeCN. Yields were determined by GC, employing tetrachlo-
robenzene as an internal standard. E ) CO2Me.
Results
Identification of the Catalytic System: Platinum versus
Gold. Our approach is based on Lewis acid activation of the
terminal alkyne and the subsequent hydride transfer (Scheme
1). We selected alkyne 1 as the first substrate; it is readily
available in one step by propargylation of the corresponding
malonate (Figure 1). As recent efforts point to the superiority
of gold and platinum catalysts for the activation of alkynes,11
we examined salts of these two metals in detail (see
Supporting Information).12 Surprisingly, substrate 1 gave only
small amounts of the desired product 2 in the presence of a
variety of gold catalysts, leading to complex mixtures of
many products [e.g., (Ph3P)AuCl/AgOTf afforded <10% of
product 2]. In contrast, platinum salts provided promising
leads. For example, PtCl2 (5 mol %, 120 °C, in MeCN)
afforded the desired product 2 in 23% yield (Figure 1).
Although the yield was low, the reaction mixture was clean,
containing the product and the starting material (58% was
recovered) as the two major species. Following this lead, we
examined the effect of silver salt additives that usually lead
to more electrophilic metal centers by generating cationic
complexes in situ. In this case, however, no improvement
was achieved; instead, lower yields of the desired product 2
were obtained in comparison to PtCl2 itself (Table S1 in
Supporting Information provides a complete list of examined
conditions).
Importance of the Platinum-Halide Bond for the Catalyst
Activity. At this point, we considered other possibilities for
increasing the electrophilicity of the platinum catalyst, focusing
our attention on the nature of the halide ligand and the
platinum-halide bond. As a qualitative hypothesis, we consid-
ered the increasing size and bond length, as well as the trend in
the spectrochemical series, when moving from the chloride to
the iodide ligand. We predicted that platinum iodides in
comparison to other halides should be more electrophilic and
the platinum metal more accessible to the alkyne, resulting in
a more active catalyst.13
Guided by this qualitative rationale, the activity of platinum
halide salts was systematically examined (Figure 1). We found
that, at 5 mol % loading, PtBr2 afforded product 2 in 43% yield,
while PtI2 furnished 2 in even higher yield of 68% (Figure 1,
the inset). In an attempt to further increase the efficiency of the
reaction, we examined PtI4 as we have previously shown the
superiority of PtCl4 to PtCl2 in the hydroarylation of alkynes,
with the rationale that the higher oxidation state renders a more
electrophilic metal center.14 Indeed, PtI4 effected complete
conversion of the starting material and provided the product in
86% yield.
To confirm that the halide effect was due to increased catalyst
activity, and not to catalyst stability, we investigated the initial
rates of product 2 formation under the action of different
(10) During review of this paper, the following report was published that
describes an intramolecular coupling of terminal alkynes and amine-
oxides to afford piperidin-4-ones. Cui, L.; Peng, Y.; Zhang, L. J. Am.
Chem. Soc. 2009, 131, 8394.
(11) Recent reviews: (a) Lee, S. I.; Chatani, N. Chem. Commun. 2009,
371. (b) Patil, N. T.; Yamamoto, Y. Chem. ReV. 2008, 108, 3395. (c)
Li, Z.; Brouwer, C.; He, C. Chem. ReV. 2008, 108, 3239. (d) Fu¨rstner,
A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410. (e) Hashmi,
A. S. K. Chem. ReV. 2007, 107, 3180. (f) Gorin, D. J.; Toste, F. D.
Nature 2007, 446, 395. (g) Nevado, C.; Echavarren, A. M. Synthesis
2005, 167.
(13) Several reports noted that platinum bromides or iodides were better
catalysts than platinum chlorides in the activation of alkynes for attack
by carbon and heteroatom nucleophiles. (a) Fu¨rstner, A.; Szillat, H.;
Gabor, B.; Mynott, R. J. Am. Chem. Soc. 1998, 120, 8305. (b) Hardin,
A. R.; Sarpong, R. Org. Lett. 2007, 9, 4547. (c) Chang, H.-K.; Liao,
Y.-C.; Liu, R.-S. J. Org. Chem. 2007, 72, 8139. (d) Nakamura, I.;
Sato, Y.; Terada, M. J. Am. Chem. Soc. 2009, 131, 4198.
(12) We have examined a broad array of metal complexes in the early
stages of this project, including Rh(I) complexes, but only platinum
salts provided practical yields of the desired products.
(14) (a) Pastine, S. J.; Youn, S. W.; Sames, D. Org. Lett. 2003, 5, 1055.
(b) Pastine, S. J.; Youn, S. W.; Sames, D. Tetrahedron 2003, 59, 8859.
(c) Pastine, S. J.; Sames, D. Org. Lett. 2003, 5, 4053.
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C-H Bond Functionalization via Hydride Transfer
A R T I C L E S
Table 1. Substrate Scope of the Platinum-Catalyzed
platinum catalysts (Figure 1, the plot). Fitting with the observed
trend in yield, the rate of reaction was found to increase from
the chloride to the iodide ligand: PtBr2 afforded the faster initial
rate than PtCl2, while the platinum iodides exhibited far greater
initial rates compared to PtCl2 and PtBr2. Although PtI2 showed
a marginally faster initial rate than PtI4, in terms of the yield,
PtI2 was consistently inferior. The PtI2 catalyzed reactions failed
to proceed to completion most likely due to the lower stability
of this catalyst.
HT-Cyclizationa
Thus, 5 mol % of PtI4 afforded the desired product 2 in 86%
yield with complete consumption of the starting material after
3 h at 120 °C. With these optimized conditions in hand, we set
out to examine the scope of this new reaction (Table 1).
Substrate Scope of the HT-Cyclization. We first explored the
cyclic amine substrates owing to their considerable synthetic
importance. The methyl carbamate substrate 3 was synthesized
to enable direct comparison to the corresponding ether 1. As
expected, the carbamate substrate, proceeding through an
alkoxycarbonyl-iminium intermediate, was less reactive than the
ether 1. Nevertheless, the bicyclic product 4 was obtained in
67% after 5 h at 120 °C. To expand the synthetic utility of this
reaction, we investigated the compatibility of frequently used
carbamate protecting groups. The Fmoc- and CBz-protected
compounds 5 and 7 are good substrates, affording the desired
products in 56% and 68% yield, respectively. The piperidine-
derived substrate 9 gave incomplete conversion under the
standard conditions. The lower reactivity of R-C-H bonds of
six-membered heterocycles has previously been observed by
us and others in reactions that proceed via different mechanisms
(e.g., metal insertion).2 Increasing the catalyst loading to 10
mol % led to full conversion of the starting material and
formation of the annulated product 10 in 63% isolated yield
(Table 1, entry 5).
We next investigated the spirocyclization of ether substrates
11 and 13 (Table 1, entries 6 and 7). Although we expected
higher reactivity of these substrates due to the greater hydride
donor ability of the tertiary center, 5 mol % PtI4 led to complete
decomposition of the starting material under the optimized
conditions. Monitoring the reaction by GC revealed that although
the product was formed, it was rapidly decomposed prior to
complete conversion of the starting material. Consequently, we
turned to the less active platinum chlorides and found that
K2PtCl4 was the optimal catalyst for these substrates, affording
spirocycles 12 and 14 in 70% and 40% isolated yield,
respectively. It appears that the higher Lewis acidity of PtI4
promotes the decomposition of the product via C-O bond
cleavage, to afford a tertiary allylic carbocation and subsequent
decomposition of this reactive intermediate. However, modula-
tion of the catalyst activity by the choice of the halide ligand
enabled us to expand the substrate scope. The less reactive
pyrrolidine substrate 15 required the most active PtI4 catalyst,
furnishing interesting spiro-pyrrolidine product 16 in good yield
(Table 1, entry 8). Presumably, spirocycle 16 is less prone to
C-N bond cleavage, resulting in greater stability of this product
under the catalytic conditions.
a Reactions performed at 0.05 M in dry MeCN, employing PtI4 5 mol
% at 120 °C. b E ) CO2Me. c Isolated yield as an average of three runs.
d PtI4 10 mol %. e K2PtCl4 used in place of PtI4. f Relative geometry
determined by NOESY NMR experiments.
10), showing the sensitivity of this reaction to electron-
withdrawing substituents, particularly in the para- and ortho-
position, due to destabilization of the oxocarbenium intermediate.
The HT-cyclization has a good substrate scope and enables
the R-alkenylation of cyclic ethers and cyclic carbamates (with
five- and six-membered rings), furnishing both the annulation
and spirocyclization products. Also, formation of new hetero-
cyclic rings, namely tetrahydrofurans, from the corresponding
benzyl ethers was demonstrated. The reactivity of neutral
platinum salts can be modulated by the choice of the halide
ligand, which expands the scope to those substrates that yield
We have previously demonstrated the hydride-donating ability
of benzyl ethers.3 We therefore prepared substrates 17 and 19,
which are readily available from the cyclohexene oxide and in
one step would provide complex bicyclic tetrahydrofurans.
Substrate 17 led to the formation of product 18 in 62% yield,
and although the yield is moderate, this reaction affords a single
diastereomer of an attractive product. The brominated derivative
19 gave a lower yield of compound 20 (33%, Table 1, entry
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J. AM. CHEM. SOC. VOL. 131, NO. 45, 2009 16527

A R T I C L E S
Vadola and Sames
Scheme 3. HT-Cyclization of Deuterium Labeled Compounds 21
and 23
Scheme 4. Proposed Mechanisms for the Platinum-Catalyzed
HT-Cyclization
sensitive products (e.g., substrates 11 and 13). The scope is
limited by the requirement for a relatively rigid linker between
the terminal alkyne and the R-position and by the electronic
effects that disfavor the hydride transfer by destabilizing the
oxocarbenium intermediate. Attempts to cyclize nonactivated
internal alkynes failed to provide the desired products. For
example, the methyl-substituted derivative of substrate 1 proved
to be largely unaffected by any of the platinum catalysts, even
after prolonged heating at 150 °C.
Deuterium Labeling Studies and Proposed Mechanisms. To
provide experimental support for the hydride transfer mecha-
nism, we prepared the deuterium-labeled substrates 21 and 23
(Scheme 3). As expected, the benzyl deuterium was transferred
to the vinyl position of product 22 with no loss of the label.
However, the H and H NMR showed that a mixture of two
isotopic stereoisomers was formed with the deuterium present
in both vinylic positions (in a ratio close to 1:1; see Supporting
Information). In the cyclization of 23, the label in the acetylenic
position is retained in the vinyl position of the product. In
analogy to the previous case, with respect to the deuterium
position in the alkene, the reaction is not stereoselective (Scheme
3). Some deuterium label was lost (62% deuterium incorporation
in 24), most likely due to the deuterium/hydrogen exchange at
the acetylenic position, which is frequently observed with
terminal alkynes.8
These results can be rationalized by two related mechanistic
pathways, illustrated with substrate 21 in Scheme 4. In pathway
A, coordination of the catalyst activates the alkyne and triggers
the hydride transfer, leading to the zwitterionic alkenyl inter-
mediate VIII. The alkenyl-platinum moiety then attacks the
oxocarbenium ion, thereby forming the new C-C bond and the
platinum carbene intermediate IX. This species then undergoes
a 1,2-hydrogen shift to furnish the product and the regenerated
catalyst. The labeling results indicate that the last step, the 1,2-
hydrogen migration and platinum salt elimination, is not
stereospecific. Alternatively, the reaction may proceed via
pathway B where the platinum vinylidene X is formed first,6,7
followed by the through-space 1,6-hydride transfer to afford
intermediate XI, which affords the product via the sequence of
C-C bond formation, nonstereospecific 1,2-hydrogen migration,
and platinum salt elimination. Similarly, conversion of the
labeled substrate 23 to the product 24 can be explained by either
pathway (not shown). Although the results with the labeled
substrates support the hydride transfer mechanism, they do not
distinguish between the two mechanisms, owing to, most
probably, the lack of stereospecificity of the alkene formation
step.
1
2
Conclusions
In summary, we have demonstrated that PtI4 is an efficient
Lewis acid catalyst for the hydroalkylation of unactivated
alkynes with sp3 C-H bonds in the context of saturated
substrates. This method enables one-step preparation of complex
heterocyclic compounds from readily available cyclic ethers and
amines. In addition, we have shown that the activity of neutral
platinum salts (PtXn) can be modulated by the halide ligands.
This modulation in turn allows for fine-tuning of the platinum
center reactivity to match the reactivity and stability of chosen
substrates and products. The scope of the through-space hydride
transfer reactions has been expanded to include terminal alkynes
as the hydride acceptors.
Acknowledgment. This work was supported by the National
Institute of General Medical Sciences (GM060326). We thank Dr.
J. M. Joo, Dr. K. M. McQuaid, Dr. S. J. Pastine, and W. Sattler for
helpful discussions.
Supporting Information Available: Experimental procedures
and spectroscopic data for starting materials and products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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16528 J. AM. CHEM. SOC. VOL. 131, NO. 45, 2009