Pd-catalyzed allylic alkylation cascade with dihydropyrans: Regioselective synthesis of furo[3,2- c ]pyrans

Article abstract of DOI:10.1021/ol400902d

A regioselective palladium-catalyzed allylic alkylation cascade forms furo[3,2-c]pyrans from various cyclic β-dicarbonyl bis-nucleophiles and 3,6-dihydro-2H-pyran bis-electrophiles. The combination of allylic carbonate and anomeric siloxy leaving groups in the dihydropyran substrate allows control of the many regiochemical possibilities in this reaction. Annulation proceeds stereoconvergently to give cis-fused furopyrans from either cis- or trans-substituted starting material.

Full text of DOI:10.1021/ol400902d

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Pd-Catalyzed Allylic Alkylation Cascade
with Dihydropyrans: Regioselective
Synthesis of Furo[3,2‑c]pyrans
Mark J. Bartlett, Claire A. Turner, and Joanne E. Harvey*
School of Chemical and Physical Sciences, Victoria University of Wellington,
P.O. Box 600, Wellington, 6140, New Zealand
Joanne.Harvey@vuw.ac.nz
Received April 2, 2013
ABSTRACT
A regioselective palladium-catalyzed allylic alkylation cascade forms furo[3,2-c]pyrans from various cyclic β-dicarbonyl bis-nucleophiles and
3,6-dihydro-2H-pyran bis-electrophiles. The combination of allylic carbonate and anomeric siloxy leaving groups in the dihydropyran substrate
allows control of the many regiochemical possibilities in this reaction. Annulation proceeds stereoconvergently to give cis-fused furopyrans from
either cis- or trans-substituted starting material.
The construction of complex molecular architectures in
a facile and efficient manner remains an overarching goal
for the chemical sciences. Cascade (or domino) reactions
allow improved atom and step economy in synthesis and
therefore represent significant progress toward this goal.1
Palladium-catalyzed allylic alkylation (Pd-AA) cascades
(1) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134. Newhouse, T.; Baran, P. S.; Hoffmann, R. W.
Chem. Soc. Rev. 2009, 38, 3010. Atom economy: Trost, B. M. Science
1991, 254, 1471. Trost, B. M. Acc. Chem. Res. 2002, 35, 695. Step
economy: Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H Acc.
Chem. Res. 2008, 41, 40.
(2) For selected reviews on Pd-AA, see: Trost, B. M. Acc. Chem. Res.
1980, 13, 385. Tsuji, J. Palladium Reagents and Catalysts: Innovations in
Organic Synthesis; Wiley & Sons: New York, 1996; pp 290À399. Trost, B.
M; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
Figure 1. Generic Pd-AA Cascade Reaction.
involve the sequential addition of a bis-nucleophile (B) to
an allylic bis-electrophile (A) (Figure 1).2 Various combi-
nations of nitrogen, oxygen, and carbon bis-nucleophiles
(B) have been used for the preparation of a variety of vinyl-
substituted ring systems (C).3 A large number of possible
regiochemical outcomes exist for a Pd-AA of a nonsym-
metric allylic bis-electrophile with a nonsymmetric bis-
nucleophile. Therefore, a major challenge of these annula-
tion reactions is in differentiating the two nucleophilic and
electrophilic centers so that a single product is formed
regioselectively. Typically, this challenge has been avoided
by employing symmetric electrophiles or nucleophiles,
thereby obviating the need for regioselectivity. Thus,
despite the synthetic efficiency of the Pd-AA cascade, it
has found limited use in total synthesis.4
(3) For selected examples, see: Piperazines: Tanahashi, A.; Hayashi,
T. J. Org. Chem. 1993, 58, 6826. Massacret, M.; Lhoste, P.; Sinou, D.
Eur. J. Org. Chem. 1999, 129. Morpholines: Thorey, C.; Wilken, J.;
ꢀ
Henin, F.; Martens, J.; Mehler, T.; Muzart, J. Tetrahedron Lett. 1995,
36, 5527. Nakano, H.; Yokoyama, J.; Fujita, R.; Hongo, H. Tetrahedron
Lett. 2002, 43, 7761. Dioxanes: Massacret, M.; Lhoste, P.; Lakhmiri, R.;
Parella, T.; Sinou, D. Eur. J. Org. Chem. 1999, 2665. Oxazolidinones:
Tanimori, S.; Kirihata, M. Tetrahedron Lett. 2000, 41, 6785. Tanimori,
S.; Inaba, U.; Kato, Y.; Kirihata, M. Tetrahedron 2003, 59, 3745.
Dihydrofurans: Yoshida, M.; Nakagawa, T.; Kinoshita, K.; Shishido,
K. J. Org. Chem. 2013, 78, 1687. Clavier, H.; Giordano, L.; Tenaglia, A.
Angew. Chem., Int. Ed. 2012, 51, 8648. Tanimori, S.; Kato, Y.; Kirihata,
M. Synthesis 2006, 865. Yoshizaki, H.; Satoh, H.; Sato, Y.; Nukui, S.;
Shibasaki, M.; Mori, M. J. Org. Chem. 1995, 60, 2016. Cyclopropanes:
Burgess, K. Tetrahedron Lett. 1985, 26, 3049. Gaucher, A.; Dorizon, P.;
€
Ollivier, J.; Salaun, J. Tetrahedron Lett. 1995, 36, 2979.
r
10.1021/ol400902d
XXXX American Chemical Society

We have discovered that certain dihydropyran sub-
strates serve as nonsymmetric bis-electrophiles for Pd-
AA cascades with cyclic β-dicarbonyl compounds. This
methodology provides rapid access to unsaturated furo-
[3,2-c]pyran ring systems with excellent regio- and diaste-
reoselectivity. The Pd-AA cascade was investigated using
cis-1, which was prepared in four steps from furfuryl
alcohol via known alcohol 25 (Scheme 1).
Table 1. Optimization of the Pd-AA Cascade with cis-1
entry
catalyst (mol %)
solvent
equiv 3 yielda
1
Pd2(dba)3/PPh3 (10)b CH2Cl2
Pd2(dba)3/PPh3 (10)b CH3CN
Pd2(dba)3/PPh3 (10)b THF
Pd2(dba)3/PPh3 (10)b CH2Cl2
Pd2(dba)3/PPh3 (10)b CH3CN/NEt3
Pd2(dba)3/PPh3 (10)b CH3CN/NEt3
Pd2(dba)3/PPh3 (10)b toluene
1.0
1.0
1.0
2.2
2.2
1.0
1.0
1.0
1.0
1.0
1.0
30%
12%
44%
5%c
Scheme 1. Synthesis of Pyran Substrates, cis-1 and trans-1
2
3
4
d
d
5
42%
40%
65%
71%
83%
71%
56%e
6
7
8
Pd(PPh3)4 (10)
Pd(PPh3)4 (5)
Pd(PPh3)4 (5)
Pd(PPh3)4 (1)
toluene
9
toluene
toluene/NEt3
toluene
d
10
11
a Isolated yield. b 2:1 ratio of P/Pd was used. c 39% recovered cis-1
and 4% O-alkylation product cis-5 were also isolated. d 1.0 equiv of NEt3
was added. e 9% O-alkylation product cis-5 was also isolated.
Initial solvent screening experiments employed 4-hydroxy-
6-methyl-R-pyrone (3) as the β-dicarbonyl compound and
provided modest yields of furopyran 4 (Table 1, entries
1À3). Interestingly, the use of excess 3 was detrimental
to the reaction (entry 4), leaving unreacted cis-1 and
producing the undesired O-alkylation side product, cis-5
(Scheme 2). The negative effects of excess 4-hydroxy-R-
pyrone could be countered by adding triethylamine to the
reaction mixture (entry 5). Toluene was found to be the
optimal reaction solvent, and when used in conjunction
with 5 mol % of Pd(PPh3)4, the desired product 4 was
obtained in 83% yield (entry 9).
Scheme 2. Conversion of cis-5 into 4 and ORTEP Drawing of 4
with Thermal Ellipsoids at 50% Probability
Pd-AA with soft nucleophiles typically proceeds through
a double inversion of configuration;6 however, the Pd-AA
cascade of trans-1 with 3 also produced the cis-fused
furopyran, 4 (Table 2). The cis-stereochemistry of 4 was
confirmed by X-ray crystallographic analysis (Scheme 2).7
This is presumably a consequence of the prohibitively
large amount of strain energy present in the trans-fused
furopyran product, 6,8 since the relative energy difference
between the cis- and trans-fused products was calculated to
be 51 kJ/mol.9 While an inner-sphere process could be
invoked to explain the overall retention of configuration,
the higher catalyst loading required for efficient transfor-
mation of trans-1 into 4 (Table 2, entry 3) suggests that the
initial syn-palladium complex, 7, is isomerized by intermolec-
ular nucleophilic attack of a transient Pd(0) species (step VI,
Scheme 3).10 To validate this hypothesis we investigated
the Pd-AA cascade of cyclohexene-based substrate trans-
811(Scheme 4). This substrate provides an opportunity to
evaluate the putative π-allyl-Pd isomerization without the
possibility of the reaction proceeding through an oxonium
intermediate, as may be the case for trans-1. Ultimately,
(4) Agelastatin A: Trost, B. M.; Dong, G. Chem.;Eur. J 2009, 15,
6910. Huperzine A: Campiani, G.; Sun, L.-Q.; Kozikowski, A. P.;
Aagaard, P.; McKinney, M. J. Org. Chem. 1993, 58, 7660. Kaneko, S.;
Yoshino, T.; Katoh, T.; Terashima, S. Tetrahedron 1998, 54, 5471. He,
X.-C.; Wang, B.; Yu, G.; Bai, D. Tetrahedron: Asymmetry 2001, 12,
3213. Neosarpagine: Liao, X.; Huang, S.; Zhou, H.; Parrish, D.; Cook,
J. M. Org. Lett. 2007, 9, 1469. Carbovir/Aristeromycin: Trost, B. M.; Li,
L.; Guile, S. D. J. Am. Chem. Soc. 1992, 114, 8745.
(5) Achmatowicz, O., Jr.; Buckowski, P.; Szechner, B.; Zierchowska,
A.; Zamojski, A. Tetrahedron 1971, 27, 1973. Sugawara, K.; Imanishi,
Y.; Hashiyama, T. Tetrahedron: Asymmetry 2000, 11, 4529.
(10) The isomerization of π-allyl-Pd complexes by Pd(0) has been
previously implicated in the loss of stereospecificity in Pd-AA reactions:
Takahashi, T.; Jinbo, Y.; Kitamura, K.; Tsuji, J. Tetrahedron Lett. 1984,
25, 5921. Granberg, K. L.; Backvall, J. E. J. Am. Chem. Soc. 1992, 114,
6858.
(6) Trost, B. M.; Verhoeven, T. R. J. Org. Chem. 1976, 41, 3215.
(7) Crystal data: monoclinic, space group P21/c (No. 14), (a)
˚
˚
˚
€
7.7627(3) A, (b) 11.0574(4) A, (c) 11.2765(4) A, (β) 103.614(2)°, (V)
940.73(6) A , (Z) 4.
3
˚
(8) For examples of strain energy in 5,6-ring systems, see: Velluz, L.;
ꢀ
(11) Tsarev, V. N.; Wolters, D.; Gais, H.-J. Chem.;Eur. J. 2010, 16,
2904.
(12) The relative stereochemistry of 9 was assigned using NOE
Valls, J.; Nomine, G. Angew. Chem., Int. Ed. 1965, 4, 181.
(9) DFT calculations (B3LYP/6-31G*) were performed with
Spartan ’08. See Supporting Information for computational details.
correlation and comparison to the 3JHH values of 4.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Proposed Mechanism for the Palladium-AA Cascade of trans-1 with Pyrone 3a
a (I) Selective ionization of the allylic carbonate, giving a π-allyl Pd complex. (II) C-3 alkylation with net retention of configuration. (III) Reversion
of the O-alkylation product trans-5 to a π-allyl Pd complex. (IV) Formation of the second π-allyl Pd complex. (V) Deprotonation of the 4-hydroxy-
R-pyrone nucleophile by tert-butyldimethylsiloxide. (VI) Isomerization of the π-allyl Pd complex by Pd(0). (VII) Annulative O-attack at C-5 to form the
cis-fused product and regenerate the Pd(0) catalyst.
Table 2. Pd-AA Cascade with trans-1
Scheme 4. Mechanistic Validation Using trans-8
entry
catalyst (mol %)
solvent
equiv 3 yielda
anomeric siloxy group is key to the success of this chem-
istry as the relatively low reactivity of the OTBS group
allows preferential ionization of the allylic carbonate.15
The resulting π-allyl-Pd species is regioselectively alkylated
at C-3 as a result of both steric and electronic factors
inherent to pyran-based substrates.16
Pd2(dba)3/PPh3 (10)b CH3CN/NEt3
1.0
1.0
1.0
38%
10%
74%
c
1
2
3
Pd(PPh3)4 (5)
Pd(PPh3)4 (20)
toluene
toluene
a Isolated yield. b 2:1 ratio of P/Pd used. c 1.0 equiv of NEt3 added.
The scope of this reaction was explored withcis-1 using a
variety of cyclic β-dicarbonyl bis-nucleophiles 3, 11À20
(Table 3). In general, nucleophiles with high enol content,
such as R-pyrones, 3, and coumarins, 11À14, produced the
highest yields of the desired furopyrans (i.e., 4, 21, 22, 31,
32). In contrast, substrates that are predisposed to the keto
form, such as 1,3-indandione (19) and Meldrum’s acid
(20), are prone to the formation of R-disubstituted
β-dicarbonyl side products (e.g., 29). The Pd-AA cascade
with 20 produced the ring-opened lactone 30, which
presumably results from extrusion of acetone from the
initial dioxinone, followed by trapping of the resulting
acylketene intermediate with methanol liberated from the
carbonate.17 While only a 39% yield of 30 was obtained
trans-8 was also found to provide cis-fused 9, adding
weight to the proposed inversion by Pd(0).12
Throughout these investigations, double alkylation was
observed in almost all instances. Single O-alkylation was
only observed in two cases where reactivity was impaired,
either through low catalyst loading (Table 1, entry 11) or
by the presence of excess pyrone 3 (Table 1, entry 4).
4-Hydroxy-6-methyl-R-pyrone (3) has a pKa of 6.83 (80%
(w/w) DMSO/H2O),13 and therefore, under effective reac-
tion conditions, the O-alkylation product, 5, can act as an
allyl acetate equivalent, reacting with Pd(0) to reform the
previous π-allyl complex (Scheme 3, step III).14 Indeed, the
O-alkylated byproduct cis-5 was converted into 4 upon
treatment with 10 mol % palladium catalyst (see Scheme 2).
This suggests that the excellent regioselectivity observed
in most cases is a consequence of the first substitution
operating under thermodynamic control. The use of an
(15) In contrast, the analogous hemiacetal substrate produced a
complex mixture of undesired products. See Supporting Information
for details.
(16) Brescia, M.-C.; Shimshock, Y. C.; DeShong, P. J. Org. Chem.
1997, 62, 1257.
(17) Related processes have been noted previously: (a) Fillion, E.;
ꢀ
ꢀ
Carret, S.; Mercier, L. G.; Trepanier, V. E. Org. Lett. 2008, 10, 437. (b)
Basson, M. M.; Holzapfel, C. W.; Verdoorn, G. H. Heterocycles 1989,
29, 2261.
(13) Tan, S. F.; Ang, K. P.; Jayachandran, H. J. Chem. Soc., Perkin
Trans. 1 1983, 471. The pKa of 6-methyl-4-hydroxy-R-pyrone in H2O is
4.94: Ang, K.; Tan, S. J. Chem. Soc., Perkin Trans. 1 1979, 1525.
(18) For related processes with sugar-derived bis-electrophiles,
see ref 17b and: Al-Tel, T. H. Z. Naturforsch., B: Chem. Sci. 2000,
55, 657.
~
(14) Moreno-Manas and coworkers have shown this experimentally,
by reacting a 4-allyloxy-6-methyl-R-pyrone with a Pd(0) catalyst to
~
obtain a C-3 alkylated 4-hydroxy-R-pyrone: Moreno-Manas, M.; Ribas,
J.; Virgili, A. J. Org. Chem. 1988, 53, 5328.
Org. Lett., Vol. XX, No. XX, XXXX
(19) See Supporting Information for details of these experiments.
C

Table 3. Pd-AA Cascade Substrate Scope
Scheme 5. Synthetic Utility of Furopyrans
23, 24, and 28in reasonable yield. Additionally, the use of a
sugar-derived bis-electrophile, 10, provided good yields of
the more substituted furopyrans 31 and 32.18 In these
cases, the dihydropyran starting material contained a
mixture of anomers; thus a higher catalyst loading was
used to facilitate these stereoconvergent reactions. The
latter examples serve to probe the impact of steric factors
on the excellent regiochemical control of these Pd-cata-
lyzed reactions.16 Overall, the parameters that define an
effective bis-nucleophile proved relatively complex, and
enol content alone does not seem to guarantee high yield.
For example, tetronic and tetramic acids, which both exist
predominantly in the enol form, provided complex mix-
tures devoid of the desired products.19
The synthetic utility of the furopyran products was
demonstrated through the bromohydroxylation of 4
(Scheme 5).20 Treatment of the resulting bromohydrin 33
with sodium borohydride effected both hemiacetal reduc-
tion and cyclization, forming the fused bis-furan 34. This
bicyclic motif is present in a number of bioactive natural
products.21
In summary, a palladium-catalyzed allylic alkylation
cascade of cyclic β-dicarbonyl bis-nucleophiles with non-
symmetric pyran-based bis-electrophiles was used to re-
gioselectively and stereoconvergently prepare a range of
cis-fused furo[3,2-c]pyrans. This methodology affords a
number of versatile chemical structures, whose exploita-
tion in several synthetic endeavors is currently being
pursued.
Acknowledgment. Victoria University is gratefully
acknowledged for funding, the provision of a Ph.D. scho-
larship (M.J.B.) and a Curtis-Gordon Scholarship
(C.A.T.). We also thank Dr. Jan Wikaira (University of
Canterbury) for obtaining the X-ray data for 4 and Ian
Vorster, Dr. Robert Keyzers, and Assoc. Profs. Paul
Teesdale-Spittle and Peter Northcote (VUW) for NMR
assistance and helpful discussions.
a Isolated yields are quoted. b 10 mol % Pd(PPh3)4 was used.
c Toluene/DMF (3:1) was used as solvent. d ca. 14:1 dr. e 53% of the
R-disubstituted side product was also obtained. f 5 equiv of Meldrum’s
acid and THF/MeOH (10:1) were used. g 15 mol % Pd(PPh3)4 was used.
under the previously optimized conditions, the use of
excess 20 and a THF/MeOH (10:1) solvent mixture re-
duced the formation of the R-disubstituted side product
and provided an improved 69% yield of 30. Bis-nucleo-
phile solubility is an important consideration, and the use
of DMF as a cosolvent was required for the generation of
Supporting Information Available. Experimental proce-
dures, spectroscopic data and spectra for all new compounds.
X-ray crystallographic data (CIF) for 4. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) The 6-epi diastereomer of 33 was also isolated (19% yield).
(21) For example: Atienza, J.; Hernandez, E.; Primo, J. Appl. Micro-
biol. Biotechnol. 1992, 37, 298.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX