Palladium-catalyzed alkyne insertion/reduction route to trisubstituted olefins

Article abstract of DOI:10.1021/ol4018694

A new route to trisubstituted olefins through a palladium-catalyzed alkyne insertion/reduction reaction with unactivated alkyl iodides is reported. The reaction proceeds under mild conditions and tolerates a range of functional groups and substitution patterns. Preliminary mechanistic inquiry suggests that the transformation may proceed through a hybrid radical/organometallic pathway.

Full text of DOI:10.1021/ol4018694

ORGANIC
LETTERS
2013
Vol. 15, No. 17
4362–4365
Palladium-Catalyzed Alkyne Insertion/
Reduction Route to Trisubstituted Olefins
Erin R. Fruchey, Brendan M. Monks, Andrea M. Patterson, and Silas P. Cook*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington,
Indiana 47405-7102, United States
sicook@indiana.edu
Received July 3, 2013
ABSTRACT
A new route to trisubstituted olefins through a palladium-catalyzed alkyne insertion/reduction reaction with unactivated alkyl iodides is reported.
The reaction proceeds under mild conditions and tolerates a range of functional groups and substitution patterns. Preliminary mechanistic inquiry
suggests that the transformation may proceed through a hybrid radical/organometallic pathway.
Aryl and vinyl halides account for the vast majority of
electrophiles employed in palladium-catalyzed cross-
coupling reactions.1 However, the use of alkyl halides as
electrophiles in these reactions is relatively rare.2 The rarity
of these reactions stems in part from the difficulty of
preventing the facile β-hydride elimination inherent to
alkyl palladium species.3 The alkyl-Heck reaction, where
an olefin undergoes migratory insertion into an alkyl palla-
dium species, remains relatively underdeveloped, but the
reaction offers an attractive method to functionalize
alkenes.
migratory insertion of the pendant olefin. The use of the
N-heterocyclic carbene ligand SIMes was critical to the
success of this reaction, presumably due to the disruption
of β-agostic interactions by the sterically encumbered
ligand. The authors propose an SN2 oxidative addition
based on a deuterium-labeling study that revealed inver-
sion of stereochemistry at the carbon site of oxidative
addition. A later iteration of an alkyl-Heck-type reaction
by Alexanian et al. demonstrated a significantly broader
substrate scope for primary iodide substrates (Figure 1b).2b
The synthetic potential of the alkyl-Heck reaction has
motivated researchers to explore the reaction in greater
detail. For example, Fu et al. reported a successful alkyl-
Heck reaction using alkyl bromides and chlorides as
electrophiles.2a The reaction was made possible by con-
trolling the rate of β-hydride elimination relative to
(1) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062–5085.
(2) For recent examples, see: (a) Firmansjah, L.; Fu, G. C. J. Am.
Chem. Soc. 2007, 129, 11340–11341. (b) Bloome, K. S.; McMahen, R. L.;
Alexanian, E. J. J. Am. Chem. Soc. 2011, 133, 20146–20148. (c) Monks,
B. M.; Cook, S. P. J. Am. Chem. Soc. 2012, 134, 15297–15300. For
relevant reviews, see: (d) Rudolph, A.; Lautens, M. Angew. Chem., Int.
Ed. 2009, 48, 2656–2670. (e) Frisch, A. C.; Beller, M. Angew. Chem., Int.
Ed. 2005, 44, 674–688.
(3) (a) Ozawa, F.; Ito, T.; Yamamoto, A. J. Am. Chem. Soc. 1980,
102, 6457. (b) Hartwig, J. F.; Richards, S.; Baranano, D.; Paul, F. J. Am.
Chem. Soc. 1996, 118, 3626. (c) Tanaka, D.; Romeril, S. P.; Myers, A. G.
J. Am. Chem. Soc. 2005, 127, 10323–10333. (d) Bissember, A. C.; Levina,
A.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 14232–14237.
Figure 1. Palladium-catalyzed (a) alkyl-Heck reaction with un-
activated alkyl bromide and (b) Heck-type reaction with unac-
tivated alkyl iodide.
r
10.1021/ol4018694
Published on Web 08/19/2013
2013 American Chemical Society

Interestingly, the authors provide evidence for a hybrid
radical/organometallic process under tetrakis(triphenyl-
phosphine)palladium(0) catalysis.
Table 1. A Sample of Hydrides Employed in the Formation of
Trisubstituted Olefin 8
The relative scarcity of reactions reported for alkyl
palladium species, along with our interest in discovering
fundamental organometallic processes with rates compar-
able or faster than β-hydride elimination,4 inspired our
group to investigate the migratory insertion of alkynes.
These studies led to the recently reported tandem alkyne
insertion/Suzuki reaction of unactivated iodides.2c Initial
work on the alkyne insertion/Suzuki reaction revealed the
formation of trisubstituted olefin 8 in 7% yield (Figure 2).2c
The formation of 8 offers a unique palladium-catalyzed
route to trisubstituted olefins.5 Since such exocyclic tri-
substituted olefins represent important structural motifs
in natural products,6 we sought to optimize conditions
favorable for its formation. Here we offer a new approach
to trisubstituted olefins through a tandem alkyne insertion/
reduction reaction.
entry
hydride
NaO2CH
conv (%)
yield (%)a
1
2
3
4
5
6
7
8
100
100
100
100
50
35
23
29
29
25
8
Hantzsch ester
NaBH4
n-Bu3SnH
proton sponge
Ph3SiH
51
Ph2SiH2
100
100
62
77
PhSiH3
a Yields determined by 1H NMR with 1,3,5-trimethoxybenzene as an
internal standard.
To ascertain the scope of the reaction, a variety of
alkynyl iodide substrates were prepared and subjected to
the optimized conditions (Table 2). When aryl alkynes
were employed, both electron-rich and electron-deficient
aryl substituents provided high yields (entries 1À8 and 12,
Table 2). Furthermore, the reaction proceeds on >700 mg
scale (2.3 mmol) with comparable yield (84% isolated yield
of8, 90%BORSM, seeSI). While alkylsubstitutedalkynes
generally performed well in the reaction (entries 9 and 11,
Table 2), the sterically encumbered tert-butyl alkyne 25
only provided product 26 in 50% yield (entry 10, Table 2).
Heterocycle-substituted alkynes such as thiophene 17 and
quinoline 19 provided trisubstituted olefins 18 and 20 in
71% and 78% yield, respectively (entries 6 and 7, Table 2).
Since the formation of six-membered rings is rare in
palladium-catalyzed alkyl-Heck-type reactions,2a,b we
were pleased when substrate 21 formed trisubstituted
olefin 22 in 61% yield (entry 8, Table 2). Since migratory
insertion proceeds through a syn addition to an alkyne,8
the formation of product 30 in a 1:3 ratio of E/Z isomers
came as a surprise (entry 12, Table 2).
The lack of stereospecificity for the presumptive migra-
tory insertion step of the reaction raises an interesting
question with regard to the mechanism of isomerization.
Recent work by Lipshutz et al. demonstrates that vinyl
palladium species can isomerize through a proposed pal-
ladium carbene intermediate.9 If such an isomerization
pathway is operable here (Scheme 1a), then vinyl palla-
dium species 31 could isomerize to vinyl palladium 34. This
isomerization would occur through the formation of pal-
ladium carbene 32, which allows for a bond rotation event
Figure 2. Unoptimized reaction conditions for an alkyne inser-
tion/Suzuki reaction provides trisubstituted olefin 8 as a side
product.
While all the pertinent reaction parameters were exam-
ined during the course of optimization (see Supporting
Information (SI)), the hydride source had the most sig-
nificant impact on the formation of trisubstituted olefin
product 8 (Table 1). When the reaction was conducted in
the presence of sodium formate, the desired trisubstituted
olefin 8 was obtained in 35% yield (entry 1, Table 1).
Interestingly, there was little difference in yield between a
strong hydride donor (NaBH4) or hydrogen atom donor
n-Bu3SnH, both providing a 29% yield (entries 3À4,
Table 1). Tertiary amines also functioned as hydride
donors. For example, proton sponge produced the desired
product in 25% yield (entry 5, Table 1).7 However, silanes
proved the most effective in the formation of desired
trisubstituted olefin 8, with phenylsilane providing the
highest yield at 77% (entry 8, Table 1). Further substitu-
tion of the silane, such as diphenylsilane and triphenylsi-
lane, provided lower yields (entries 6À7, Table 1).
(4) Gao, P.; Cook, S. P. Org. Lett. 2012, 14, 3340–3343.
(5) For examples of tin-based reductions of alkynes to form trisub-
stituted olefins, see: (a) Chatgilialoglu, C.; Ferreri, C. Chem. Triple-
Bonded Funct. Groups 1994, 917–944. (b) Martinez-Grau, A.; Curran,
D. P. Tetrahedron 1997, 53, 5679–5698. (c) Curran, D. P. Synthesis 1988,
7, 489–513. For an example of a nickel-catalyzed reduction to form
trisubstituted olefins, see: (d) Kim, H.; Lee, C. Org. Lett. 2011, 13, 2050–
2053.
(8) (a) Hartwig, J. F. Organotransition Metal Chemistry: From
Bonding to Catalysis; Murdzek, J., Eds.; University Science Books: Mill
Valley, CA, 2010; p 379. (b) Thorn, D. L.; Hoffman, R. J. Am. Chem. Soc.
1978, 100, 2079–2090.
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Tetrahedron Lett. 2000, 41, 2401–2404.
(7) Minatti, A.; Zheng, X.; Buchwald, S. L. J. Org. Chem. 2007, 72,
9253–9258.
(9) (a) Krasovskiy, A.; Lipshutz, B. H. Org. Lett. 2011, 13, 3818–
3821. (b) Lu, G.-P.; Voigtritter, K. R.; Cai, C.; Lipshutz, B. H. J. Org.
Chem. 2012, 77, 3700–3703. (c) Lu, G.-P.; Voigtritter, K. R.; Cai, C.;
Lipshutz, B. H. Chem. Commun. 2012, 48, 8661.
Org. Lett., Vol. 15, No. 17, 2013
4363

both the electronic and steric properties of the phosphine
ligands on palladium should have an influence on the E/Z
ratio. For example, electron-deficient phosphines would
likely destabilize the formally cationic palladium carbene
32, thereby preventing isomerization and favoring forma-
tion of the Z isomer. Conversely, electron-rich phosphines
would stabilize cationic palladium carbenes 32 and 33 and
allow Z to E isomerization. If palladium carbenes 32 and
33 establish an equilibrium, the Keq will depend on the
relative steric repulsion between ligated palladium and the
phenyl substituent.
Table 2. Substrate Scope of Alkyl Iodides
Scheme 1. Potential Mechanisms for Olefin Isomerization:
(a) Vinyl Palladium Isomerization and (b) Vinyl Radical
Isomerization
To examine the role of the ligand in isomerization,
several isosteric aryl phosphines with varying degrees of
σ donicity were examined for their effects on E/Z product
ratios (Table 3). Interestingly, both electron-rich and
-deficient triaryl phosphines produced identical 1:3 E/Z
ratios (entries 1À5, Table 3).
Next the steric properties of the ligand were evaluated
for their effect on selectivity. Isomerization to the E isomer
should be disfavored by phosphines with larger cone or
bite angles due to steric interactions between the bulky
phosphine and the aryl substituent fused to the five-
membered ring 33 (Figure 2a). However, while triphenyl-
phosphine (cone angle = 145°) provided an E/Z ratio of
1:3, the use of tri-o-tolylphosphine (cone angle = 194°)
produced product 30 in only an E/Z ratio of 1:4 (entries 1
and 6, Table 3).10 Furthermore, the ratio did not improve
by increasing the cone angle to 212° with the use of
trimesitylphosphine (entry 7, Table 3).10 Bidentate ligands
dppe and dppf, with bite angles of 78.1° and 99.1°,
respectively, also provided the products in a 1:3 E/Z ratio
(entries 8À9, Table 3).11 These results indicate that either
the palladium carbene isomerization pathway is inoper-
able under our conditions or the phosphine ligand is likely
not influencing the isomerization event.
a Yields determined by 1H NMR with 1,3,5-trimethoxybenzene as an
internal standard; isolated yields in parentheses. b The low boiling
product was isolated as a mixture with hexanes. c The product produced
was a 1:3 E/Z mixture of stereoisomers.
(10) Tolman, C. A. Chem. Rev. 1977, 77, 313–348.
(11) Kranenburg, M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
Eur. J. Inorg. Chem. 1998, 25–27.
(12) (a) Fessenden, R. W.; Schuler, R. H. J. Chem. Phys. 1963, 39,
2147–2195. (b) Galli, C.; Gentili, P.; Guarnieri, A.; Zvi, R. J. Org. Chem.
1996, 61, 8878–8884. (c) Jenkins, P. R.; Symons, M. C. R.; Booth, S. E.;
Swain, C. J. Tetrahedron Lett. 1992, 33, 3543–3546.
to form carbene isomer 33. Palladium carbene 33 could then
isomerize to vinyl palladium 34, which eventually forms
the E trisubstituted olefin. According to this mechanism,
4364
Org. Lett., Vol. 15, No. 17, 2013

palladium radicals,17 this result may not be relevant to
the optimized reaction conditions. Furthermore, BHT, an
efficient radical inhibitor, has no effect on the yield when
included under the optimized reaction conditions. More-
over, the rate appears linear throughout the course of the
reaction (i.e., no induction period indicative of radicals),
and no dimeric products from radical termination were
observed. Consequently, a completely free-radical me-
chanism appears unlikely, and the hybrid radical/organo-
metallic mechanism (presumably via Pd(I) species)18
remains consistent with these results.
Table 3. Variation in Electronic and Steric Properties of the
Phosphine
entry
phosphine
PPh3
E/Z
yield (%)a
1
2
3
4
5
6
7
8
9
1:3
1:3
1:3
1:3
1:3
1:4
1:4
1:3
1:3
84
85
84
86
90
87
85
70
70
(4-MeOPh)3P
(4-MePh)3P
(4-CF3Ph)3P
(4-FPh)3P
(o-tol)3P
Scheme 2. TEMPO Reacts with the Substrate under the
Optimized Reaction Conditions
(mes)3P
dppe
dppf
a Yields determined by 1H NMR with 1,3,5-trimethoxybenzene as an
internal standard.
Since vinylic radicals have a low barrier to inversion
(Scheme 1b),12 a free-radical mechanism could explain the
lack of stereospecificity in the reaction. To test for the
intermediacy of radicals, the radical scavenger 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO) was included with
the optimized conditions (Scheme 2).13 Interestingly, the
reaction produced primary TEMPO product 38 in 63%
yield along with trisubstituted olefin 8 in 13% yield
(Scheme 2). A completely free-radical mechanism would
predict the formation of primary TEMPO product 38 since
the rate of intramolecular primary radical addition to an
In summary, we have developed a palladium-catalyzed
alkyne/insertion reduction reaction of alkyl iodides for
the production of trisubstituted olefins. The reaction
proceeds under mild conditions and tolerates a range of
functional groups. While additional mechanistic studies
areneeded, the reaction maybeoperating througha hybrid
radical/organometallic mechanism. Further experiments
to examine these mechanistic possibilities are currently
underway.
Acknowledgment. We acknowledge generous start-up
funds from Indiana University in partial support of this
work. We also gratefully acknowledge the American Che-
mical Society Petroleum Research Fund (PRF 52233-
DNI1) and NSF-CAREER Award (CHE-1254783) for
partial support of this work. Additionally, we thank Luke
Kurowski for aiding in the preparation of several
substrates.
alkyne (104À105 MÀ1 sÀ1 14
)
is slower than the rate of
recombination with TEMPO (109 MÀ1 sÀ1).15 The forma-
tion of trisubstituted olefin 8 would suggest that radical
recombination with phenylsilane is faster than with TEM-
PO. This is surprising since the rate constant for hydrogen
atom abstraction from phenylsilane by a tert-butoxyl
radical is on the order of 107 MÀ1 sÀ1 16 thereby implying
,
hydrogen atom abstraction by a vinylic radical is signifi-
cantly faster than the tert-butoxyl radical. However, since
TEMPO can react with palladium hydrides to form
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds are
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) (a) Matyjaszewski, K. Macromolecules 1998, 31, 4710–4717. (b)
~
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and Excited States; DeMayo, P., Ed.; Academic: New York, 1980; Vol. 1,
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I. Org. Lett. 2006, 8, 1383–1386. (b) Jahn, U. Top. Curr. Chem. 2012, 320,
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1982, 1, 466–469.
The authors declare no competing financial interest.
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