Palladium-catalyzed synthesis of 4-oxaspiro[2.4]heptanes via central attack of oxygen nucleophiles to π-allylpalladium intermediates

Article abstract of DOI:10.1021/ol300852v

A palladium-catalyzed decarboxylative cyclopropanation of γ-methylidene-δ-valerolactones with aromatic aldehydes has been developed to give 4-oxaspiro[2.4]heptanes with high selectivity. The site of nucleophilic attack to a π-allylpalladium intermediate h

Full text of DOI:10.1021/ol300852v

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2410–2413
Palladium-Catalyzed Synthesis of
4-Oxaspiro[2.4]heptanes via Central
Attack of Oxygen Nucleophiles to
π-Allylpalladium Intermediates
Ryo Shintani,*,† Tomoaki Ito,† and Tamio Hayashi*,†,‡
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto
606-8502, Japan, and Institute of Materials Research and Engineering, A*STAR, 3
Research Link, Singapore 117602
shintani@kuchem.kyoto-u.ac.jp; tamioh@imre.a-star.edu.sg
Received April 3, 2012
ABSTRACT
A palladium-catalyzed decarboxylative cyclopropanation of γ-methylidene-δ-valerolactones with aromatic aldehydes has been developed to give
4-oxaspiro[2.4]heptanes with high selectivity. The site of nucleophilic attack to a π-allylpalladium intermediate has been controlled with a
sterically demanding phosphine ligand. The course of the reaction is highly dependent on ligands and solvents, and selective formation of
methylenetetrahydropyrans has also been realized.
Palladium-catalyzed cyclopropanation through a nu-
cleophilicattackatthecentralcarbon of aπ-allylpalladium
intermediate represents an interesting way of constructing
cyclopropanes, although it requires suppression of the
competitive allylic substitution process that is usually more
prone to take place.1 Since the first discovery of such a
cyclopropanation by Hegedus and co-workers in stoichio-
metric reactions with ester enolates,2 several effective
catalytic variants have been developed, most of which rely
on the use of enolate-based carbon nucleophiles.3,4 Other
nucleophiles that can be employed for this type of cyclo-
propanation are currently limited to carbonyl-attached
nitrogen nucleophiles in the ring-forming processes.5 In
this context, here we describe the development of a palla-
dium-catalyzed synthesis of 4-oxaspiro[2.4]heptanes from
(3) (a) Formica, M.; Musco, A.; Pontellini, R.; Linn, K.; Mealli, C.
J. Organomet. Chem. 1993, 448, C6. (b) Satake, A.; Nakata, T. J. Am.
Chem. Soc. 1998, 120, 10391. (c) Satake, A.; Koshino, H.; Nakata, T.
Chem. Lett. 1999, 28, 49. (d) Satake, A.; Kadohama, H.; Koshino, H.;
Nakata, T. Tetrahedron Lett. 1999, 40, 3597. (e) Shintani, R.; Park, S.;
Hayashi, T. J. Am. Chem. Soc. 2007, 129, 14866. (f) Liu, W.; Chen, D.;
Zhu, X.-Z.; Wan, X.-L.; Hou, X.-L. J. Am. Chem. Soc. 2009, 131, 8734.
(4) For examples of stoichiometric reactions, see: (a) Hoffmann,
H. M. R.; Otte, A. R.; Wilde, A. Angew. Chem., Int. Ed. Engl. 1992,
31, 234. (b) Wilde, A.; Otte, A. R.; Hoffmann, H. M. R. J. Chem. Soc.,
Chem. Commun. 1993, 615. (c) Otte, A. R.; Wilde, A.; Hoffmann,
H. M. R. Angew. Chem., Int. Ed. Engl. 1994, 33, 1280. (d) Hoffmann,
H. M. R.; Otte, A. R.; Wilde, A.; Menzer, S.; Williams, D. J. Angew.
Chem., Int. Ed. Engl. 1995, 34, 100.
† Kyoto University.
‡ Institute of Materials Research and Engineering.
(1) For reviews on palladium-catalyzed allylic substitutions, see:
(a) Weaver, J. D.; Recio, A.; Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011,
111, 1846. (b) Rios, I. G.; Rosas-Hernandez, A.; Martin, E. Molecules
2011, 16, 970. (c) Norsikian, S.; Chang, C.-W. Curr. Org. Synth. 2009, 6,
264. (d) Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59.
(e) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (f) Negishi,
E., Ed. Handbook of Organopalladium Chemistry for Organic Synthesis;
John Wiley & Sons: Hoboken, NJ, 2002; Vol. 2. (g) Hayashi, T. J. Organomet.
Chem. 1999, 576, 195. (h) Helmchen, G. J. Organomet. Chem. 1999,
576, 203.
(5) (a) Grigg, R.; Kordes, M. Eur. J. Org. Chem. 2001, 707.
(b) Shintani, R.; Park, S.; Shirozu, F.; Murakami, M.; Hayashi, T.
J. Am. Chem. Soc. 2008, 130, 16174. (c) Shintani, R.; Tsuji, T.; Park, S.;
Hayashi, T. J. Am. Chem. Soc. 2010, 132, 7508. (d) Shintani, R.; Moriya,
K.; Hayashi, T. Chem. Commun. 2011, 47, 3057.
(2) Hegedus, L. S.; Darlington, W. H.; Russell, C. E. J. Org. Chem.
1980, 45, 5193.
r
10.1021/ol300852v
Published on Web 04/24/2012
2012 American Chemical Society

γ-methylidene-δ-valerolactones and aldehydes by the suc-
cessful use of oxygen nucleophiles for a central attack to
π-allylpalladium intermediates.6
by the use of L17 as the ligand (5aa/6aa = 87/13; entry 5).
Furthermore, 5aa/6aa = 93/7 was realized in high yield
when the ligand was changed to L28 (entry 6), and the best
result was obtained by conducting the reaction at 85 °C
instead of 50 °C, giving 88% yield of 5aa/6aa in the ratio of
98/2 (entry 7). The relative configuration of the major
diastereomer of 5aa obtained in entry 7 was established by
X-ray crystallographic analysis as shown in Figure 1.9
In 2010, we described a palladium-catalyzed decarboxy-
lative cyclization of γ-methylidene-δ-valerolactone 1a
with 4-methoxyphenyl isocyanate to give piperidone 2
and/or azaspiro[2.4]heptanone 3 (Scheme 1).5c In this
reaction, selective formation of compound 2 was achieved
by the use of electron-rich phosphine ligands such as P(4-
MeOC6H4)3 through a usual allylic substitution pathway
from the π-allylpalladium intermediate, whereas the for-
mation of compound 3 became dominant by employing
electron-deficient phosphine ligands such as P(4-CF3C6H4)3
through a nucleophilic attack at the central carbon of the
same intermediate.
Table 1. Palladium-Catalyzed Decarboxylative Cyclization of
γ-Methylidene-δ-valerolactone 1a with Aldehyde 4a: Ligand
Effect
Scheme 1. Palladium-Catalyzed Decarboxylative Cyclization of
γ-Methylidene-δ-valerolactone 1a with 4-Methoxyphenyl Iso-
cyanate
yield of 5aa
þ6aa (%)a
dr of
5aaa
entry
ligand
5aa/6aaa
1
P(4-MeOC6H4)3
23
39
10
85
82
94
88c
<1/99
30/70
83/17
82/18
87/13
93/7
2
PPh3
26/74
50/50
91/9
3
P(4-CF3C6H4)3
4
P(2-MeC6H4)3
5
L1
L2
L2
78/22
70/30
83/17
6
7b
98/2
a Determined by 1H NMR. b Conducted at 85 °C for 3 h. c Isolated
yield.
On the basis of this reaction, we initially examined a
reaction of γ-methylidene-δ-valerolactone 1a with alde-
hyde 4a in the presence of PdCp(η3-C3H5) (5 mol %) and a
phosphine ligand (10 mol %) in toluene at 50 °C (Table 1).
As was the case for the reaction of 1a with 4-methoxyphe-
nyl isocyanate (Scheme 1),5c the reaction with electron-rich
P(4-MeOC6H4)3 as the ligand gave none of the cyclopro-
panation product 5aa and methylenetetrahydropyran 6aa
was obtained in 22% yield (entry 1). The use of less
electron-rich PPh3 gave a mixture of 5aa and 6aa in a ratio
of 30/70 (entry 2). The selectivity of 5aa became much
higher by employing electron-deficient P(4-CF3C6H4)3 as
the ligand (5aa/6aa = 83/17), but the products were
obtainedonlyin10%combinedyield(entry3). Incontrast,
we were pleased to find that the use of sterically demanding
monophosphine ligands could significantly change the
reactivity as well as the course of the reaction, preferen-
tially producing 4-oxaspiro[2.4]heptane 5aa in high yields.
Thus, 85% yield of cyclization products was obtained with
5aa/6aa = 82/18 under the catalysis of Pd/P(2-MeC6H4)3
(entry 4), and anevenhigher selectivity of5aa was achieved
Under the conditions using L2 as the ligand, compound
1a smoothly reacts with various electron-deficient benzal-
dehydes 4aꢀg regardless of their substitution patterns to
give 4-oxaspiro[2.4]heptanes 5 selectively in high yield with
moderate to good diastereoselectivity (Table 2, entries
1ꢀ7). Unfortunately, unsubstituted benzaldehyde (4h)
shows significantly lower reactivity, but exclusive forma-
tion of spirocyclopropane 5ah was observed with high
diastereoselectivity (entry 8). In addition, heteroaromatic
aldehydes such as 3-pyridinecarboxaldehyde (4i) are also
suitable substrates in the present catalysis (entry 9).10 With
(7) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi,
J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369.
(8) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685.
(9) CCDC-870014 and CCDC-870020 contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
(10) Electron-rich or sterically demanding aldehydes, and ketones
are not reactive substrates, and aliphatic aldehydes give products in
moderate yield with poor diastereoselectivity under the present reaction
conditions.
(6) Central attack of phenoxides to 2-halo(π-allyl)palladium inter-
mediates has been reported: (a) Organ, M. G.; Miller, M. Tetrahedron
Lett. 1997, 38, 8181. (b) Ogran, M. G.; Miller, M.; Konstantinou, Z.
J. Am. Chem. Soc. 1998, 120, 9283. (c) Organ, M. G.; Arvanitis, E. A.;
Hynes, S. J. Tetrahedron Lett. 2002, 43, 8989. (d) Kadota, J.; Katsuragi,
H.; Fukumoto, Y.; Murai, S. Organometallics 2000, 19, 979.
Org. Lett., Vol. 14, No. 9, 2012
2411

allyl ester moiety of 1 to palladium(0), followed by
decarboxylation,11 gives 1,4-zwitterionic species A. The
anionic carbon of A then attacks the electrophilic carbon
of aldehyde 4 to give intermediate B. Ring-closing nucleo-
philic attack of the oxygen atom to the central carbon of
the π-allylpalladium moiety of B leads to palladacyclobu-
tane C. Reductive elimination releases cyclopropanation
product 5 along with regeneration of a palladium(0)
species.2ꢀ5 The site selectivity in the event of nucleophilic
ring closure from intermediate B can be controlled by the
electronic property of the phosphine ligand on palladium
(Table 1, entries 1ꢀ3) as was the case for the nitrogen
nucleophile (Scheme 1),5c,d but the selective formation of
4-oxaspiro[2.4]heptanes 5 by the Pd/L2 catalyst system
shows that this process can also be (more efficiently)
controlled by the steric properties of the ligand.12
Figure 1. X-ray crystal structure of the major diastereomer of 5aa
(hydrogen atoms except at the stereocenter are omitted for clarity).
Scheme 2. Proposed Catalytic Cycle for the Palladium-Cata-
lyzed Decarboxylative Cyclopropanation of 1 with 4
Table 2. Palladium-Catalyzed Synthesis of 4-Oxaspiro-
[2.4]heptanes 5: Scope
yielda
(%) 5/6b
dr of
5b
entry
1 (R)
4 (Ar)
1c 1a (Ph)
2c 1a
3d 1a
4c 1a
5e 1a
6e 1a
7e 1a
8e 1a
9c 1a
4a (4-MeO2CC6H4) 88 98/2 83/17
4b (4-PhCOC6H4) 83 98/2 89/11
4c (4-NCC6H4)
4d (4-F3CC6H4)
4e (4-ClC6H4)
4f (3-ClC6H4)
4g (2-FC6H4)
4h (Ph)
86 88/12 71/29
84 97/3 78/22
82 97/3 88/12
89 94/6 81/19
75 97/3 75/25
31 >99/1 92/8
87 97/3 79/21
82 88/12 81/19
93 97/3 86/14
82 98/2 86/14
82 96/4 87/13
79 98/2 87/13
80 96/4 88/12
97 98/2 96/4
81 80/20 52/48
The above-mentioned steric control is also applicable to
a selective formation of azaspiro[2.4]heptanone 3 by the
reaction of γ-methylidene-δ-valerolactone 1a with 4-meth-
oxyphenyl isocyanate as shown in eq 1 (see also Scheme 1).5c
Thus, in the presence of PdCp(η3-C3H5) (5 mol %) and L2
(10 mol %) in toluene at 50 °C, 90% yield of products 2 and
3 was obtained in the ratio of 10/90.
4i (3-pyridyl)
4a
10c 1b (4-MeOC6H4)
11e 1b
4e
12e 1c (4-MeC6H4)
13c 1d (3-MeC6H4)
14e 1d
15e 1e (3,4-(OCH2O)C6H3) 4e
16c 1f (2-MeC6H4)
17e 1g (CH2Ph)
4e
4a
4e
4a
4e
a Combined isolated yield of 5 and 6. b Determined by 1H NMR.
c Conducted at 85 °C for 3 h. d Conducted at 100 °C for 3 h. e Conducted
at 70 °C for 24 h.
We have also begun to explore the reaction conditions
that can selectively provide methylenetetrahydropyrans
6, rather than 4-oxaspiro[2.4]heptanes 5, in high yield.
On the basis of the ligand effect observed in Table 1,
regard to the substituent of γ-methylidene-δ-valerolac-
tones 1, various aryl groups are tolerated at the R-position
in the reactions with aldehydes 4a and/or 4e to give
cyclopropanation products 5 with high selectivity (entries
10ꢀ16). R-Alkyl lactones such as 1g can also be employed
with somewhat reduced chemoselectivity and low diaster-
eoselectivity (entry 17).
(11) (a) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 21,
3199. (b) Tsuda, T.; Chuji, Y.; Nishi, S.; Tawara, K.; Saegusa, T. J. Am.
Chem. Soc. 1980, 102, 6381. For reviews, see: (c) Reference 1a. (d) Tunge,
J. A.; Burger, E. C. Eur. J. Org. Chem. 2005, 1715. (e) You, S.-L.; Dai,
L.-X. Angew. Chem., Int. Ed. 2006, 45, 5246.
(12) As suggested by one of the reviewers, this steric control could be
attributed to the formation of a PdL1 species, which can be regarded as a
more electron-deficient palladium complex compared to a PdL2 species.
A proposed catalytic cycle of the present catalysis is
illustrated in Scheme 2. Thus, oxidative addition of the
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Org. Lett., Vol. 14, No. 9, 2012

Table 3. Palladium-Catalyzed Synthesis of Methylenetetrahy-
dropyrans 6: Examples
entry
1
4
product
yielda (%)
drb
1
1a
1a
1b
1e
1f
4a
4b
4a
4a
4a
6aa
6ab
6ba
6ea
6fa
88
89
91
91
89
74/26
76/24
74/26
72/28
62/38
2
3
4
5c
a Isolated yield of 6. b Determined by 1H NMR. c Conducted with 1.8
equiv of 1f.
Figure 2. X-ray crystal structure of the major diastereomer of
6aa (hydrogen atoms except at the stereocenter are omitted for
clarity).
we reexamined the reaction of 1a with 4a usingP(4-MeOC6H4)3
and PPh3 as the ligand (eq 2) and found that exclusive
formation of 6aa can be achieved when the reactions are
conductedinCH2Cl2 instead of intoluene with higheryield
using PPh3 (66% NMR yield).13 We subsequently identi-
fied that the use of preformed complex Pd(PPh3)4 under
slightly modified conditions gives 6aa in 88% yield (Table
3, entry 1). Under these conditions, several other substrate
combinations can also produce methylenetetrahydropyr-
ans 6 exclusively in high yield (entries 2ꢀ5). The relative
configuration of the major diastereomer of 6aa obtained in
entry 1 was determined by X-ray crystallographic analysis
as shown in Figure 2.9
valerolactones with aldehydes to give 4-oxaspiro[2.4]-
heptanes with high selectivity. The site of nucleophilic
attack to a π-allylpalladium intermediate has been
efficiently controlled by employing sterically demand-
ing phosphine ligand L2. We have found that the course
of the reaction is highly dependent on both ligands and
solvents employed, and selective formation of methy-
lenetetrahydropyrans has also been realized. Future
studies will explore further expansion of the reaction
scope as well as the mechanistic studies of the present
catalysis.
Acknowledgment. Support has been provided in part by
a Grant-in-Aid for Scientific Research, the Ministry of
Education, Culture, Sports, Science and Technology,
Japan (the Global COE Program “Integrated Materials
Science” on Kyoto University), and in part by Taisho
Pharmaceutical Co., Ltd.
Supporting Information Available. Experimental pro-
cedures and compound characterization data and X-ray
data (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, we have described a palladium-catalyzed
decarboxylative cyclopropanation of γ-methylidene-δ-
(13) In comparison, the reaction of 1a with 4a using L2 as the ligand
in CH2Cl2 at 40 °C gave 5aa/6aa = 45/55, confirming that the site
selectivity of the nucleophilic ring closure depends on the reaction
solvent, but we currently have no good explanation for this solvent
effect on the site selectivity.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
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