Pd(0)-catalyzed oxy- and aminoalkynylation of olefins for the synthesis of tetrahydrofurans and pyrrolidines

Article abstract of DOI:10.1021/ol2029383

The first Pd(0)-catalyzed intramolecular oxy- and aminoalkynylation of nonactivated olefins is reported. The reaction gives access to important tetrahydrofuran and pyrrolidine heterocycles with high diastereoselectivity. The unique synthetic potential of acetylenes is further exploited to access key building blocks for the synthesis of bioactive natural products.

Full text of DOI:10.1021/ol2029383

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6324–6327
Pd(0)-Catalyzed Oxy- and Aminoalkynylation
of Olefins for the Synthesis of
Tetrahydrofurans and Pyrrolidines
ꢀ ^
Stefano Nicolai and Jerome Waser*
ꢀ ꢀ
Laboratory of Catalysis and Organic Synthesis, Ecole Polytechnique Federale de
Lausanne, EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne, Switzerland
jerome.waser@epfl.ch
Received November 1, 2011
ABSTRACT
The first Pd(0)-catalyzed intramolecular oxy- and aminoalkynylation of nonactivated olefins is reported. The reaction gives access to important
tetrahydrofuran and pyrrolidine heterocycles with high diastereoselectivity. The unique synthetic potential of acetylenes is further exploited to
access key building blocks for the synthesis of bioactive natural products.
Heterocycles are essential structural elements for the
bioactivity of natural and synthetic molecules. Among
them, tetrahydrofurans and pyrrolidines are particularly
important in natural products, such as the antitumoral
annonaceous acetogenins gigantecin (1) and squamostatin
C (2),1 or the antibiotic alkaloid preussin (3) (Figure 1).2
Consequently, the stereoselective synthesis of tetrahydro-
furans and pyrrolidines has been extensively investigated.3
Particularly interesting are methods using cyclization of
alcohols or amines onto nonactivated olefins combined
with a further bond forming event. Iodoetherification or
amination reactions have been often used in the synthesis
of heterocycles.4 Recently, the power of metal catalysis has
been harnessed to achieve multiple functionalizations of
olefins5 for the synthesis of tetrahydrofurans and pyrroli-
dines together with further CÀN,6 CÀO,7 or CÀC bond
formation.8
Impressive progress has been realized in Pd-catalyzed do-
mino reactions involving cyclization on olefins to form a tetra-
hydrofuran or a pyrrolidine followed by carbonylation,8aÀc
vinylation,8d,e or arylation.8fÀj Despite these recent break-
throughs, there are currently no examples of an oxy- or
aminoalkynylation reaction for the synthesis of tetrahy-
drofurans or pyrrolidines.9 Such a process would be highly
useful, as the functionalization of alkynes through cross-
coupling, reduction, addition, cyclization, cycloisomeriza-
tion, or cycloaddition gives access to important building
(1) (a) Crimmins, M. T.; She, J. J. Am. Chem. Soc. 2004, 126, 12790.
(b) Spurr, I. B.; Brown, R. C. D. Molecules 2010, 15, 460.
(2) Johnson, J. H.; Phillipson, D. W.; Kahle, A. D. J. Antibiot. 1989,
42, 1184.
(3) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261.
(4) Mphahlele, M. J. Molecules 2009, 14, 4814.
(5) For reviews, see: (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b)
Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285. (c) Beller, M.;
Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368. (d)
Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. (e) Muniz, K.
Angew. Chem., Int. Ed. 2009, 48, 9412.
(6) Using Pd catalysis: (a) Streuff, J.; Hovelmann, C. H.; Nieger, M.;
Muniz, K. J. Am. Chem. Soc. 2005, 127, 14586. (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) Desai, L. V.; Sanford, M. S.
Angew. Chem., Int. Ed. 2007, 46, 5737. (e) Sibbald, P. A.; Rosewall, C. F.;
Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 15945.
Selected examples for other methods: (f) Zabawa, T. P.; Kasi, D.;
Chemler, S. R. J. Am. Chem. Soc. 2005, 127, 11250. (g) Muniz, K.;
Streuff, J.; Hoevelmann, C. H.; Nunez, A. Angew. Chem., Int. Ed. 2007,
46, 7125.
(7) Using Pd catalysis: (a) Li, Y.; Song, D.; Dong, V. M. J. Am. Chem.
Soc. 2008, 130, 2962. (b) Jensen, K. H.; Webb, J. D.; Sigman, M. S.
J. Am. Chem. Soc. 2010, 132, 17471. (c) Liskin, D. V.; Sibbald, P. A.;
Rosewall, C. F.; Michael, F. E. J. Org. Chem. 2010, 75, 6294. (d) Kang,
Y. B.; Gade, L. H. J. Am. Chem. Soc. 2011, 133, 3658. Selected examples
for other methods: (e) Donohoe, T. J.; Butterworth, S. Angew. Chem.,
Int. Ed. 2005, 44, 4766. (f) Blanc, A.; Toste, F. D. Angew. Chem., Int. Ed.
2006, 45, 2096. (g) Lovick, H. M.; Michael, F. E. J. Am. Chem. Soc. 2010,
132, 1249. (h) Cheng, H.; Stark, C. B. W. Angew. Chem., Int. Ed. 2010,
49, 1587. (i) de Haro, T.; Nevado, C. Angew. Chem., Int. Ed. 2011, 50,
906.
r
10.1021/ol2029383
Published on Web 11/09/2011
2011 American Chemical Society

blocks used in synthetic chemistry, chemical biology, and
material sciences.10
Scheme 1. Oxy- and Aminoalkynylation of Alkenes
Figure 1. Tetrahydrofuran and pyrrolidine natural products.
Our group has developed the Pd(II)-catalyzed oxy- and
aminoalkynylation of olefins with EBX (ethynyl benzio-
doxolone) reagent 4 for the synthesis of lactones and
lactams (Scheme 1).11 However, the developed methods
could not be used to access tetrahydrofurans or pyrroli-
dines, and CÀC bond formation was limited to primary
positions. Herein, we report a different approach for the
oxy- and aminoalkynylation of olefins using Pd(0) cata-
lysis and triisopropylsilyl ethynyl bromide (5a), which
allowed us to override both limitations (Scheme 1). To
the best of our knowledge, this is the first example of Pd(0)
catalysis for the oxy- and aminoalkynylation of olefins or
for any CÀX/C(SP3)ÀC(SP) domino sequence on alkenes.
Tetrahydrofurans and pyrrolidines were obtained in good
yields and diastereoselectivities, and examples of alkynyla-
tion at secondary positions are also reported. The synthetic
potential of the obtained acetylenes is demonstrated in
further transformations giving access to the core structures
of acetogenin natural products.
halogeno acetylenes. At this point, we decided to reconsi-
der our working model for the reaction (Scheme 2). For
lactonization11a we had used an electron-poor Pd(II)
catalyst I, which would react with the strong oxidant 4 to
form a putative Pd(IV) intermediate III only after oxypal-
ladation to give II had occurred. However, the use of a
Pd(0) catalyst IV with 4 led to fast formation of a diyne
product and to silylation of alcohol 6a (Table 1, entry 1).12
We speculated that a weaker and less electrophilic oxidant,
such as a halogeno acetylene, should be less prone to the
observed side reactions. Instead, oxypalladation and re-
ductive elimination via VI and VII would give the product
7, opening a new Pd(0)/Pd(II) manifold for the reaction.
When Wolfe’s conditions8fÀj were used with phenyl- or
phenylethyl-ethynyl bromides (5b and 5c) (Table 1, entries
2À3), complex mixtures of products were obtained. At this
point, we decided to turn toward triisopropylsilyl acetylenes
derivatives, which had demonstrated exceptional properties
in metal catalysis.11,13 Gratifyingly, whereas chloroacety-
lene 5d displayed only low conversion (entry 4) and iodoa-
cetylene 5e lead to dimerization (entry 5),14 a promising
69% of yield was obtained using 2 mol % Pd2(dba)3 and
DPE-Phos as a ligand with bromoacetylene 5a (entry 6).
The oxyalkynylation of penten-5-ol (6a) with TIPS-
EBX (4) as reagent and a Pd(II) catalyst gave only low
yields (<25%), and no conversion was observed with
(8) Using Pd catalysis: Carbonylation: (a) Hegedus, L. S.; Allen,
G. F.; Olsen, D. J. J. Am. Chem. Soc. 1980, 102, 3583. (b) Semmelhack,
M. F.; Zhang, N. J. Org. Chem. 1989, 54, 4483. (c) Cernak, T. A.;
Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 3124. Vinylation: (d)
Semmelhack, M. F.; Epa, W. R. Tetrahedron Lett. 1993, 34, 7205. (e)
Ney, J. E.; Hay, M. B.; Yang, Q. F.; Wolfe, J. P. Adv. Synth. Catal. 2005,
347, 1614. Arylation: (f) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc. 2004,
126, 13906. (g) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43,
3605. (h) Wolfe, J. P.; Rossi, M. A. J. Am. Chem. Soc. 2004, 126, 1620. (i)
Mai, D. N.; Wolfe, J. P. J. Am. Chem. Soc. 2010, 132, 12157. (j) Neukom,
J. D.; Perch, N. S.; Wolfe, J. P. J. Am. Chem. Soc. 2010, 132, 6276.
Synthesis of epoxides or aziridines: (k) Hayashi, S.; Yorimitsu, H.;
Oshima, K. J. Am. Chem. Soc. 2009, 131, 2052. (l) Hayashi, S.;
Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2009, 48, 7224.
Selected examples for other methods: (m) Zhang, G. Z.; Cui, L.; Wang,
Y. Z.; Zhang, L. M. J. Am. Chem. Soc. 2010, 132, 1474. (n) Brenzovich,
W. E.; Benitez, D.; Lackner, A. D.; Shunatona, H. P.; Tkatchouk, E.;
Goddard, W. A.; Toste, F. D. Angew. Chem., Int. Ed. 2010, 49, 5519.
(9) With the exception of conjugate addition of alkynes on Michael
acceptors, the alkynylationof olefins has only been achievedin a few rare
cases in the past. See for a few selected examples: (a) Catellani, M.;
Chiusoli, G. P. Tetrahedron Lett. 1982, 23, 4517. (b) Larock, R. C.;
Narayanan, K. Tetrahedron 1988, 44, 6995. (c) Shirakura, M.; Suginome,
M. J. Am. Chem. Soc. 2008, 130, 5410. (d) Shirakura, M.; Suginome, M.
J. Am. Chem. Soc. 2009, 131, 5060. (e) Kohno, K.;Nakagawa, K.; Yahagi,
T.; Choi, J. C.; Yasuda, H.; Sakakura, T. J. Am. Chem. Soc. 2009, 131,
2784. (f) Li, Y. B.; Liu, X. H.; Jiang, H. F.; Liu, B. F.; Chen, Z. W.; Zhou,
P. Angew. Chem., Int. Ed. 2011, 50, 6341.
Scheme 2. Working Models for the Oxyalkynylation of Penten-
5-ol (6a)
(10) Diederich, F.; Stang, P. J.; Tykwinski, R. R.; Acetylene Chemistry:
Chemistry, Biology and Material Science; Wiley-VCH: Weinheim, 2005.
Further optimization studies allowed us to identify
toluene as the optimal solvent and confirmed DPE-Phos
as the ideal ligand (entry 7).15 Under these conditions, 7a
ꢀ
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(11) (a) Nicolai, S.; Erard, S.; Gonzalez Fernandez, D.; Waser, J.
Org. Lett. 2010, 12, 384. (b) Nicolai, S.; Piemontesi, C.; Waser, J. Angew.
Chem., Int. Ed. 2011, 50, 4680.
Org. Lett., Vol. 13, No. 23, 2011
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could be isolated in 92% yield using only 1.33 equiv of
bromide 5a (Table 2, entry 1).
Table 2. Scope of the Alkynylation Reaction
Table 1. Optimization of the Oxyalkynylation Reaction
a Reaction conditions: 0.15 mmol of 6a, 0.20 mmol of 5, 0.20 mmol of
NaOtBu, 0.003 mmol of Pd2(dba)3, 0.006 mmol of ligand, 0.8 mL of dry
solvent under N2 at 65À70 °C. Yield determined via GC-MS. b Complex
mixture of nonseparable products.
We then examined the scope of the reaction (Table 2).
The cyclization of primary alcohols proceeded in 80À92%
yield (entries 1À3). We then turned to the use of secondary
alcohols in the cyclization reaction (entries 4À7). This class
of substrates is particularly interesting, as trans 2,5-disub-
stituted tetrahydrofurans are often represented in natural
products, such as acetogenins (Figure 1). The reaction
worked in 60À80% yield and excellent trans diastereo-
selectivity (>95:5) (entries 5À7), with the exception of
the small Me substituent (entry 4). The reaction tolerated
a second double bond in the molecule (entry 6) and gave
access to bicyclic heterocycles (entry 7). Useful yields
could be obtained with tertiary alcohols (entries 8À9),
including for the formation of a spiro-bicyclic hetero-
cycle 7i (entry 9).
In our previous work, completely different condi-
tions had to be used when going from lactonization to
lactamization.11 However, thiswas not thecase when using
(12) On a 0.40 mmol scale, 1,4-bis(triisopropylsilyl)buta-1,3-diyne
and triisopropyl(pent-4-enyloxy)silane were obtained in 8 and 84% yield
respectively using the conditions of entry 1, Table 1. See Supporting
Information.
(13) (a) Rucker, C. Chem. Rev. 1995, 95, 1009. (b) Nishimura, T.;
Sawano, T.; Hayashi, T. Angew. Chem., Int. Ed. 2009, 48, 8057. (c) Ano,
Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 12984. (d)
Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem., Int. Ed. 2009, 48,
9346. (e) Brand, J. P.; Waser, J. Angew. Chem., Int. Ed. 2010, 49, 7304. (f)
a Reaction conditions: 0.40 mmol of 6, 0.53 mmol of alkyne 5a,
0.53 mmol of NaOtBu, 0.008 mmol of Pd2(dba)3, 0.016 mmol of
DPE-Phos, 2.1 mL of toluene under N2 at 65À70 °C for 3 h. Isolated
yield after column chromatography. b At 110 °C.
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ꢀ
Brand, J. P.; Gonzalez Fernandez, D.; Nicolai, S.; Waser, J. Chem.
Commun. 2011, 47, 102.
(14) On a 0.40 mmol scale, 1,4-bis(triisopropylsilyl)buta-1,3-diyne
and tetrahydrofuran 7a were both obtained in 34% yield using the
conditions of entry 5, Table 1. See Supporting Information.
(15) See Supporting Information for further tested conditions.
(16) (a) Altenhoff, G.; Wurtz, S.; Glorius, F. Tetrahedron Lett. 2006,
47, 2925. (b) de Carne-Carnavalet, B.; Archambeau, A.; Meyer, C.;
Cossy, J.; Folleas, B.; Brayer, J. L.; Demoute, J. P. Org. Lett. 2011, 13,
956. (c) Thaler, T.; Guo, L. N.; Mayer, P.; Knochel, P. Angew. Chem.,
Int. Ed. 2011, 50, 2174.
Pd(0) catalysis, and no further optimization was required
in the case of Boc-protected amines as substrates (entries
10À13). Excellent cis selectivity was observed in the for-
mation of 2,5-disubstituted pyrrolidines (entries 12À13),
which is the same relative stereochemistry as observed in
preussin (3) (Figure 1). Up to now, we had examined only
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Org. Lett., Vol. 13, No. 23, 2011

Scheme 3. Functionalization of the Products
monosubstituted olefins involving most probably a pri-
mary Pd-alkyl intermediate. The use of 1,2 disubstituted
olefins would require a challenging SP3ÀSP reductive
elimination at a secondary position. Such processes are
difficult in Pd catalysis.16 Gratifyingly, the reaction also
worked well for disubstituted olefins, in the case of both
alcohols and amines (entries 14À16). Preorganization
through rigidification was not required, and even simple
acyclic substrate 6o could be used (entry 15). In the case of
bicyclic products 7n and 7p, an all-cis relationship of the
substituents was observed. This is in accordance with the
mechanism we proposed in our working model (Scheme 2)
involving binding of the heteroatom to Pd, followed by syn
oxypalladation and reductive elimination.
allylicester 13wasobtainedin34% yield and 73:27dr. This
preliminary result is highly interesting, especially when
considering that the reaction had been reported for the
acid as a limiting agent, and no effort has yet been done to
improve the reaction with only 1 equiv of alkyne. Building
blocks for the synthesis of acetogenins were accessed
starting from enantioenriched alcohol 14 (Scheme 3,
(3)).22 High diastereoselectivity for the desired trans pro-
duct 15 was observed, giving an asymmetric entry to the R-
monohydroxylated tetrahydrofuran ring of gigantecin (1)
or squamostatin C (2) (Figure 1). A second hydroxy group
could be introduced using Breit’s method to access the bis
R-hydroxylated tetrahydrofuran ring.
In summary, we have reported the first oxy- and ami-
noalkynylation reactions of alkenes catalyzed by a Pd(0)
catalyst. Tetrahydrofurans and pyrrolidines were obtained
in good yield and diastereoselectivity with simultaneous
installation of a triple bond. The utility of the alkyne was
demonstrated through its transformation in other func-
tional groups and into key building blocks for the synthesis
of acetogenin natural products. Principles applied in aryla-
tion chemistry could be transferred to alkynylation reac-
tions if a triisopropylsilyl protecting group was present. This
discovery will probably be of broad use in the development
of other reactions involving acetylenes. Further investiga-
tions along this line, as well as the development of asym-
metric methods, are currently ongoing in our group.
We then shortly investigated the transformation of the
obtained acetylenes into important building blocks
(Scheme 3). TIPS deprotection and Sonogashira coupling
on 7a can be done in one pot to give aryl acetylene 8 in 87%
yield (Scheme 3, (1)).17 A Larock annulation18 gave indole
9 with perfect regioselectivity, albeit in moderate yield
(43%). With 7e, deprotection proceeded in good yield,
and the terminal alkyne could be converted in two steps to
known 11,19 which allowed us to confirm definitively the
trans relationship of the substituents (Scheme 3, (2)).
Hydration using the method developed by Hintermann20
gave access to versatile aldehyde 12 in 87% yield, resulting
in an overall addition of an oxygen atom and acetaldehyde
to an olefin. We then introduced an oxygen group in the
propargylic position using Breit’s method.21 The desired
Acknowledgment. EPFL, F. Hoffmann-La Roche Ltd.,
and SNF (Grant No. 200021_119810) are acknowledged
for financial support.
(17) Sun, J.; Conley, M. P.; Zhang, C.; Kosmin, S. A. J. Am. Chem.
Soc. 2006, 128, 9705.
(18) Grunenthal GMBH, Patent: US2009/247505 A1, 2009.
(19) Shi, H.; Liu, H.; Bloch, R.; Mandville, G. Tetrahedron 2001, 57,
9335.
(20) Labonne, A.; Kribber, T.; Hintermann, L. Org. Lett. 2006, 8,
5853.
Supporting Information Available. Experimental de-
tails and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) Lumbroso, A.; Koschker, P.; Vautravers, N. R.; Breit, B. J. Am.
Chem. Soc. 2011, 133, 2386.
(22) Zhao, H.; Gorman, J. T.; Pagenkopf, B. L. Org. Lett. 2006, 8, 4379.
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