Pd-Catalyzed intramolecular oxyalkynylation of alkenes with hypervalent iodine

Article abstract of DOI:10.1021/ol9027286

(Figure presented) The first example of intramolecular oxyalkynylation of nonactivated alkenes using oxidative Pd chemistry is reported. Both phenol and aromatic or aliphatic acid derivatives could be used under operator-friendly conditions (room temperature, technical solvents, under air). The discovery of the superiority of benzlodoxolone-derlved hypervalent iodine reagent 3d as an alkyne transfer reagent further expands the rapidly increasing utility of hypervalent iodine reagents in catalysis and is expected to have important implications for other similar processes.

Full text of DOI:10.1021/ol9027286

ORGANIC
LETTERS
2010
Vol. 12, No. 2
384-387
Pd-Catalyzed Intramolecular
Oxyalkynylation of Alkenes with
Hypervalent Iodine
Stefano Nicolai, Ste´phane Erard, Davinia Ferna´ndez Gonza´lez, and
Je´roˆme Waser*
Laboratory of Catalysis and Organic Synthesis, Ecole Polytechnique Fe´de´rale de
Lausanne, EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne, Switzerland
jerome.waser@epfl.ch
Received November 26, 2009
ABSTRACT
The first example of intramolecular oxyalkynylation of nonactivated alkenes using oxidative Pd chemistry is reported. Both phenol and aromatic
or aliphatic acid derivatives could be used under operator-friendly conditions (room temperature, technical solvents, under air). The discovery
of the superiority of benziodoxolone-derived hypervalent iodine reagent 3d as an alkyne transfer reagent further expands the rapidly increasing
utility of hypervalent iodine reagents in catalysis and is expected to have important implications for other similar processes.
Cyclic structures are ubiquitous in natural products and other
bioactive substances.1 Consequently, the efficient synthesis
of carbo- and heterocycles is an important field of research
in organic chemistry. Metal-catalyzed cyclization reactions,
especially when involving multiple C-C or C-X bond
formations, constitute an efficient pathway to heterocycles.2
One such method is the Wacker cyclization, which is the
Pd-catalyzed cyclization of nucleophiles on double bonds
(Scheme 1, A).2c,3 In place of ꢀ-hydride elimination, further
C-C,2c,4 C-O,5 C-N,6 and C-Cl7 bond formation together
with cyclization have been reported.8
groups; none of these methods reported the use of hyper-
valent iodine reagents.2c,4 It was recently demonstrated that
oxidation of Pd(II) intermediates with aryliodonium salts was
much slower than with PhI(OAc)2, which would make C-C
(3) Pioneering works: (a) Hosokawa, T.; Hirata, M.; Murahashi, S. I.;
Sonoda, A. Tetrahedron Lett. 1976, 1821. (b) Hegedus, L. S.; Allen, G. F.;
Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800. Recent
examples: (c) Uozumi, Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997,
119, 5063. (d) Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem.
Soc. 2001, 123, 2907. (e) Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem.,
Int. Ed. 2002, 41, 164. (f) Kotov, V.; Scarborough, C. C.; Stahl, S. S. Inorg.
Chem. 2007, 46, 1910. (g) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M.
J. Am. Chem. Soc. 2005, 127, 17778.
In particular, C-O and C-N bond formations have
profited tremendously from the use of hypervalent iodine
reagents as oxidants.5,6 In contrast, C-C bond formation has
been limited to SP2 hybridized vinyl, carbonyl, and aryl
(4) (a) Hegedus, L. S.; Allen, G. F.; Olsen, D. J. J. Am. Chem. Soc.
1980, 102, 3583. (b) Tietze, L. F.; Sommer, K. M.; Zinngrebe, J.; Stecker,
F. Angew. Chem., Int. Ed. 2005, 44, 257. (c) Rosewall, C. F.; Sibbald, P. A.;
Liskin, D. V.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 9488. (d) Cernak,
T. A.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 3124. Domino-Heck
C-X bond formation: (e) Wolfe, J. P.; Rossi, M. A. J. Am. Chem. Soc.
2004, 126, 1620. (f) Wolfe, J. P. Synlett 2008, 2913.
(1) Clardy, J.; Walsh, C. Nature 2004, 432, 829.
(2) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115. (b) Nakamura, I.;
Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (c) Zeni, G.; Larock, R. C.
Chem. ReV. 2004, 104, 2285. (d) Zeni, G.; Larock, R. C. Chem. ReV. 2006,
106, 4644.
(5) (a) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc.
2005, 127, 7690. (b) Desai, L. V.; Sanford, M. S. Angew. Chem., Int. Ed.
2007, 46, 5737. (c) Li, Y.; Song, D.; Dong, V. M. J. Am. Chem. Soc. 2008,
130, 2962.
10.1021/ol9027286  2010 American Chemical Society
Published on Web 12/10/2009

Scheme 1
.
Wacker Cyclization and Alkoxyalkynylation
Reaction
Table 1. Optimization of the Alkoxyalkynylation Reaction
entry
catalyst
reagent solvent/additive
yielda
1
2
3
4
5
6
7
8
9
PdCl2(CH3CN)2
PdCl2(CH3CN)2
Pd(TFA)2
3a
3c
3d
3d
3d
3d
3c
3e
3d
3d
Toluene, baseb 6% (<20%)
Toluene, baseb traces (<20%)
Toluene, baseb 19% (73%)
Pd(TFA)2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
17% (100%)
40% (93%)
73% (100%)
20% (84%)
43%c (>90%)
71%c
PdCl2(CH3CN)2
Pd(hfacac)2
Pd(hfacac)2
Pd(hfacac)2
Pd(hfacac)2
10 Pd(hfacac)2
73%c,d
bond formation unable to compete with other side reactions.8b
Herein,wereportaPd-catalyzedWackercyclization-alkynyla-
tion domino process using a benziodoxolone-derived reagent
3d (Scheme 1, B).
a Reaction conditions: 0.069 mmol 1a, 0.014 mmol catalyst, 0.083 mmol
reagent in 5 mL dry solvent under N2 at 23 °C for 12-16 h. Yield was
determined via GC-MS. Conversion is given in parentheses. b K2CO3 (2
equiv) and 0.20 equiv pyridine were used as base. c Isolated yield using
0.40 mmol 1a, 0.48 mmol 3d and 0.040 mmol catalyst in 10 mL CH2Cl2.
d As Entry 9, but using technical solvent under air.
Acetylenes have broad utility in organic chemistry,
biological chemistry, and material sciences.9 Furthermore,
the direct addition of acetylenes to nonactivated olefins is
challenging and has been successful only for strained
olefins10 or using radical methods.11 The Pd-catalyzed C-C
bond formation between a SP3 and a SP center is also a
difficult process, which was successful only in rare cases.12
Our report constitutes the first example of intramolecular
oxyalkynylation of nonactivated alkenes, which represents
an important breakthrough in the area of oxidative Pd
chemistry. The discovery of the unique superiority of
benziodoxolone derived reagents 3c-3e for alkynyl transfer
when compared with established alkynyliodonium salts (3a,
3b) constitutes an important advance in the burgeoning field
of hypervalent iodine chemistry13 and opens new perspective
for the development of more efficient reagents in Pd-
mediated C-C bond formation and other acetylene transfer
processes. Indeed, we recently discovered in our group that
benziodoxolone derivatives were also unique acetylene-
transfer reagents in a completely different process, namely
the Au-catalyzed alkynylation of heterocycles.14
Alkynyliodonium salts are known as oxidative/electrophilic
alkynylation reagents,13c-f but they have been used only
rarely for the metal-mediated introduction of acetylene
groups.15 Preliminary results using Stoltz’ conditions3g with
phenol 1a and alkynyliodonium salts 3a were disappointing,
leading mostly to acetylene dimerization and low conversion
(Table 1, Entry 1). However, using neutral benziodoxolone
reagents 3c and 3d, which have been largely ignored as
acetylene transfer reagents, a 19% yield of the desired
product was obtained with 3d (Entries 2-3).16 Bases were
not required and CH2Cl2 was the best solvent (Entry 4).17
At this point, full conversion was obtained, but a noniden-
tified decomposition pathway consumed the starting materi-
(6) (b) Muniz, K. J. Am. Chem. Soc. 2007, 129, 14542. (c) Muniz, K.;
Hovelmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130, 763. (d) Sibbald,
P. A.; Michael, F. E. Org. Lett. 2009, 11, 1147.
(7) (a) Manzoni, M. R.; Zabawa, T. P.; Kasi, D.; Chemler, S. R.
Organometallics 2004, 23, 5618. (b) Michael, F. E.; Sibbald, P. A.; Cochran,
B. M. Org. Lett. 2008, 10, 793.
19
al.18 A catalyst screen (Entries 4-6) identified Pd(hfacac)2
as the most efficient Pd source for preventing the decomposi-
tion of the substrates (73% yield, Entry 6). To the best of
our knowledge, the use of this complex has not been reported
yet for oxidative Pd catalysis.
A sterically hindered silyl group is important to obtain
good yields, (Entries 6-8), but it is the benziodoxolone
(8) Review :(a) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocor-
nola, S. Chem. ReV. 2007, 107, 5318. For a discussion of high oxidation
states of Pd, see: (b) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc.
2009, 131, 11234. (c) Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302.
(9) Diederich F.; Stang, P. J.; Tykwinski, R. R. Acetylene Chemistry:
Chemistry, Biology and Material Science; Wiley-VCH: Weinheim, 2005.
(10) (a) Shirakura, M.; Suginome, M. J. Am. Chem. Soc. 2008, 130,
5410. (b) Shirakura, M.; Suginome, M. J. Am. Chem. Soc. 2009, 131, 5060.
(c) Kohno, K.; Nakagawa, K.; Yahagi, T.; Choi, J. C.; Yasuda, H.; Sakakura,
T. J. Am. Chem. Soc. 2009, 131, 2784.
(14) Brand, J. B.; Charpentier, J.; Waser, J. Angew. Chem., Int. Ed. 2009,
48, 9346.
(11) (a) Gong, J. C.; Fuchs, P. L. J. Am. Chem. Soc. 1996, 118, 4486.
(b) Schaffner, A. P.; Darmency, V.; Renaud, P. Angew. Chem., Int. Ed.
2006, 45, 5847.
(15) (a) Kang, S. K.; Lee, H. W.; Jang, S. B.; Ho, P. S. J. Org. Chem.
1996, 61, 4720. (b) Huang, X. A.; Zhong, P. J. Chem. Soc., Perkin Trans.
1 1999, 1543. (c) Yu, C. M.; Kweon, J. H.; Ho, P. S.; Kang, S. C.; Lee,
G. Y. Synlett 2005, 2631. (d) Canty, A. J.; Rodemann, T.; Skelton, B. W.;
White, A. H. Organometallics 2006, 25, 3996. (e) Canty, A. J.; Gardiner,
M. G.; Jones, R. C.; Rodemann, T.; Sharma, M. J. Am. Chem. Soc. 2009,
131, 7236. (f) Chaudhuri, P. D.; Guo, R.; Malinakova, H. C. J. Organomet.
Chem. 2008, 693, 567.
(12) Altenhoff, G.; Wurtz, S.; Glorius, F. Tetrahedron Lett. 2006, 47,
2925.
(13) (a) Wirth, T. HyperValent iodine chemistry: modern deVelopments
in organic synthesis, Vol. 224; Springer: New York, 2003. (b) Zhdankin,
V. V.; Stang, P. J. Chem. ReV. 2008, 108, 5299. (c) Beringer, F. M.; Galton,
S. A. J. Org. Chem. 1965, 30, 1930. (d) Ochiai, M.; Ito, T.; Takaoka, Y.;
Masaki, Y.; Kunishima, M.; Tani, S.; Nagao, Y. J. Chem. Soc., Chem.
Commun. 1990, 118. (e) Stang, P. J.; Arif, A. M.; Crittell, C. M. Angew.
Chem., Int. Ed. Engl. 1990, 29, 287. (f) Zhdankin, V. V.; Stang, P. J.
Tetrahedron 1998, 54, 10927. (g) Ochiai, M.; Masaki, Y.; Shiro, M. J.
Org. Chem. 1991, 56, 5511. (h) Zhdankin, V. V.; Kuehl, C. J.; Krasutsky,
A. P.; Bolz, J. T.; Simonsen, A. J. J. Org. Chem. 1996, 61, 6547.
(16) Previous to our work, the only report of benziodoxolone reagents
for C-C bond formation concerned CF3-transfer: (a) Eisenberger, P.;
Gischig, S.; Togni, A. Chem.sEur. J. 2006, 12, 2579. (b) Kieltsch, I.;
Eisenberger, P.; Togni, A. Angew. Chem., Int. Ed. 2007, 46, 754. (c) Koller,
R.; Stanek, K.; Stolz, D.; Aardoom, R.; Niedermann, K.; Togni, A. Angew.
Chem., Int. Ed. 2009, 48, 4332.
Org. Lett., Vol. 12, No. 2, 2010
385

structure that is essential for success, as the use of alkynyli-
odonium salts 3a or 3b or simple iodoacetylenes under the
optimized conditions were not successful (results not shown).
On a 0.40 mmol scale with 10 mol % catalyst, 71% of 4b
was isolated after purification (Entry 9). Using technical
grade CH2Cl2 in a flask open to air, 73% of product was
obtained, demonstrating the tolerance of the reaction to air
and moisture (Entry 10). On a 2.4 mmol scale, 68% of
product was isolated and 65% of 2-iodobenzoic acid was
recovered through basic extraction. This acid can then be
recycled to prepare reagent 3d in 2 steps and 76% overall
yield.
Table 2. Scope of the Oxyalkynylation Reaction
The scope of the reaction with phenols was examined next
(Table 2, Entries 1-10). A 4-methyl group led to a lower
yield (Entry 2) and more electron-rich derivatives could not
be used.20 Apart from this limitation, the reaction displayed
good functional group tolerance, including bromo, cyano,
nitro and ketone groups (Entries 3-6). The bromo tolerance
makes the method orthogonal to Pd(0) chemistry. The
reaction was also successful for 5-Br and 6-Br substituted
substrates (Entries 7 and 8). Promising preliminary results
were obtained for allyl phenol 1i (Entry 9) and for the
formation of 6-membered rings (Entry 10). The former result
demonstrates that alkynylation can be efficient even in the
presence of a ꢀ-hydrogen atom. Although full conversion
was observed, no compound was isolated in significant
amount beside the desired product and optimization of the
reaction conditions was not successful to improve the yield.
As we hypothesized, the limitation of the scope observed
with phenols was due to the sensibility of the substrate under
oxidative conditions, we thus decided to examine benzoic
acid derivatives next (Table 1, Entries 11-15).
Indeed, excellent results were obtained and an electron-
donating group on the benzene ring (Entry 12) or a diaryl
olefin (Entry 13) were now tolerated in the reaction. Even a
trisubstituted olefin could be used (Entry 14). In this case
the 1,3 addition product was obtained, probably via isomer-
ization of the formed Pd-alkyl intermediate. Formation of a
6-membered ring was also possible in 80% yield (Entry 15).
A single example of nitrogen nucleophile gave a useful
amount of product, but further control of the chemoselectivity
will be needed (Entry 16).
Although aliphatic alcohols could not be used (not shown),
aliphatic acids worked well in the reaction and full conver-
sion and good yields were obtained after 3 h (Entries 17-20).
In this case, the presence of ꢀ-hydrogen on the double bond
was not deleterious to the yield (Entries 19-20) and even
simple commercially available 4-pentenoic acid could be
(17) See Supporting Information for a complete list of tested reaction
conditions and catalysts.
(18) Beside the desired product, no low-molecular weight compound
was isolated from the reaction mixture. That would indicate that the main
pathway for decomposition is polymerization, either via the alkene, or via
the aromatic nucleus, for example through hypervalent iodine mediated
oxidation.
(19) hfacac ) hexafluoroacetonate.
a Reaction conditions: 0.40 mmol substrate, 0.48 mmol reagent and 0.040
mmol Pd(hfacac)2 in 10 mL CH2Cl2 at 23 °C for 12 h. b In 10 mL CHCl3.
c No full conversion was observed. d Reaction time was 3 h.
(20) Excepted when stated otherwise, full conversion was observed for
all substrates in Table 2. In the case of electron-rich substrates, decomposi-
tion was observed and no defined low-molecular weight product could be
isolated. We speculate that this class of substrates is not compatible with
the oxidative conditions of the reaction.
386
Org. Lett., Vol. 12, No. 2, 2010

cyclized in good yield (Entry 20). The obtained γ-lactones
bearing an acetylene group are important building blocks
for the synthesis of bioactive compounds.21
Scheme 2. Speculative Mechanism
As the oxyalkynylation process involves several bond
forming steps, understanding the mechanism is challenging.
Nucleophilic attack on alkynyliodonium salts proceeds via
ꢀ-addition followed by 1,2 shift.13d However, when a 13C-
label was introduced next to Si in 3d, no shift was observed
(eq 1), eliminating the possibility of this pathway. At least
two mechanisms could still be envisaged (Scheme 2): (1)
oxidative addition of 3d to PdII to form a PdIV intermediate
II,22 followed by oxy-palladation to form V and reductive
elimination to give 4a or (2) initial oxy-palladation to give
IV, either via phenolate complex III or directly from 1a;
oxidative reaction with 3d to form V and reductive elimina-
tion. Currently, we tend to favor the latter, as oxidation to
form a PdIV from PdII-alkyl intermediate should be easier,
electron-deficient catalysts worked best and the intramolecu-
lar oxy-palladation of olefins with PdII catalysts is well-
precedented.3g Furthermore, a fast reaction was not observed
when mixing the reagent and the catalyst.
acetylene incorporation to olefins using oxidative Pd chem-
istry. It is operatively simple and was successful both in the
case of phenol and acid derivatives. With phenols, good
yields were obtained only for substrates with a geminally
disubstituted double bond and electron-donating groups on
the benzene ring were not tolerated. With acids, the scope
was more general, and good yields were obtained, even for
the monosubstituted double bond and in the case of aliphatic
substrates. The unprecedented use of benziodoxolone-derived
hypervalent iodine was essential for success. Further work
on the reaction mechanism, an asymmetric method and the
use of hypervalent iodine reagents in other catalytic alky-
nylation reactions is currently ongoing in our group.
Finally, we think that the basicity of the 2-iodo benzoate
formed in the reaction could be important to promote reaction
turnover by accelerating proton transfer from 1a in the oxy-
palladation step (conversion of VI to III or IV in Scheme
2). The generation of a basic carboxylate upon reaction is
again specific to the benziodoxolone derivative 3d, and could
further contribute to the exceptional performance of this
reagent when compared with more often used alkynyliodo-
nium salts.
Acknowledgment. EPFL and SNF (grant number
200021_119810) are acknowledged for financial support,
Dr. Tom Woods (Chemical Synthesis Laboratory, EPFL)
for proofreading, and Dr. Laure Menin and Mr. Francisco
Sepulveda (Mass Spectrometry Services, ISIC, EPFL) for
HIRES mass spectra.
In summary, we have reported a novel oxyalkynylation
reaction of olefins. Our work represents the first example of
(21) (a) Jones, E. R. H.; Jones, J. B.; Skattebol, L.; Whiting, M. C.
J. Chem. Soc. 1960, 3489. (b) Doad, G. J. S.; Barltrop, J. A.; Petty, C. M.;
Owen, T. C. Tetrahedron Lett. 1989, 30, 1597. (c) Braukmuller, S.;
Bruckner, R. Eur. J. Org. Chem. 2006, 2110. (d) Habel, A.; Boland, W.
Org. Biomol. Chem. 2008, 6, 1601.
Supporting Information Available: Experimental details
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(22) See reference 15d for an example of a PdIV-acetylene complex.
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