Palladium-catalyzed [4 + 2] cycloaddition of o-(silylmethyl)benzyl esters with ketones: An equivalent to oxo-diels-alder reaction of o-xylylenes

Article abstract of DOI:10.1021/ol101792a

Figure Presented. o-(Silylmethyl)benzyl carbonates reacted with various electron-deficient ketones in the presence of a palladium catalyst, affording the [4 + 2] cycloaddition products, isochromanes, in high yields. The palladium-catalyzed cycloaddition i

Full text of DOI:10.1021/ol101792a

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4332-4334
Palladium-Catalyzed [4 + 2]
Cycloaddition of o-(Silylmethyl)benzyl
Esters with Ketones: An Equivalent to
Oxo-Diels-Alder Reaction of
o-Xylylenes
Satoshi Ueno, Masakazu Ohtsubo, and Ryoichi Kuwano*
Department of Chemistry, Graduate School of Sciences, Kyushu UniVersity,
6-10-1 Hakozaki, Higashi-ku, Fukuoka, Japan
rkuwano@chem.kyushu-uniV.jp
Received August 1, 2010
ABSTRACT
o-(Silylmethyl)benzyl carbonates reacted with various electron-deficient ketones in the presence of a palladium catalyst, affording the [4 + 2]
cycloaddition products, isochromanes, in high yields. The palladium-catalyzed cycloaddition is equivalent to the oxo-Diels-Alder reaction of
o-xylylene with ketones. The regioselectivities were extraordinarily affected by the structures of the o-xylylene precursors and ketones. The
unusual regiochemistry may support two competitive reaction pathways in the catalytic reaction.
The [4 + 2] cycloaddition of o-xylylenes with carbonyl
groups offers an attractive access to isochromane frame-
works, which are often seen in various biologically active
compounds.1 Several methods have been developed to
perform the oxo-Diels-Alder reaction.2,3 However, the
o-xylylene substrates have required an electron-donating
group on their exomethylenes in order to react with the
carbon-oxygen double bonds in good yield. No report has
been made on the successful cycloaddition of electron-neutral
and -deficient o-xylylenes with ketones or aldehydes.4
Previously, we reported that o-(silylmethyl)benzyl carbonates
act as equivalents to o-xylylenes in the presence of a
palladium catalyst, reacting with alkenes5 or imines6 to form
the [4 + 2] cycloaddition products. In this context, we
envisioned that the palladium catalysis might lead to the
successful oxo-Diels-Alder reaction of o-xylylenes.
(1) Examples of biologically active isochromane compounds: (a) Kock,
I.; Draeger, S.; Schulz, B.; Elsasser, B.; Kurtan, T.; Kenez, A.; Antus, S.;
Pescitelli, G.; Salvadori, P.; Speakman, J.-B.; Rheinheimer, J.; Krohn, K.
Eur. J. Org. Chem. 2009, 1427–1434. (b) Shishido, Y.; Wakabayashi, H.;
Koike, H.; Ueno, N.; Nukui, S.; Yamagishi, T.; Murata, Y.; Naganeo, F.;
Mizutani, M.; Shimada, K.; Fujiwara, Y.; Sakakibara, A.; Suga, O.; Kusano,
R.; Ueda, S.; Kanai, Y.; Tsuchiya, M.; Satake, K. Bioorg. Med. Chem. 2008,
16, 7193–7205. (c) Tobe, M.; Tashiro, T.; Sasaki, M.; Takikawa, H.
Tetrahedron 2007, 63, 9333–9337. (d) Chen, G.; Lin, Y.; Vrijmoed, L. L. P.;
Fong, W.-F. Chem. Nat. Compd. 2006, 42, 138–141. (e) Ogawa, A.;
Murakami, C.; Kamisuki, S.; Kuriyama, I.; Yoshida, H.; Sugawara, F.;
Mizushima, Y. Bioorg. Med. Chem. Lett. 2004, 14, 3539–3543.
(3) For reports on the intermolecular reactions, see: (a) Griesbeck, A. G.;
Stadtmu¨ller, S. Chem. Ber. 1993, 126, 2149–2150. (b) Chino, K.; Takata,
T.; Endo, T. Synth. Commun. 1996, 26, 2145–2154. (c) Hentemann, M. F.;
Allen, J. G.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2000, 39, 1937–
1940. (d) Benda, K.; Regenhardt, W.; Schaumann, E.; Adiwidjaja, G. Eur.
J. Org. Chem. 2009, 1016–1021.
(4) Oppolzer attempted the intramolecular oxo-Diels-Alder reaction of
o-xylylene without an electron-donating group but obtained the desired
product in only 25% yield; see: Oppolzer, W. Angew. Chem., Int. Ed. Engl.
1972, 11, 1031–1032.
(2) For reports on the intramolecular reactions, see: (a) Funk, R. L.;
Vollhardt, K. P. C. J. Am. Chem. Soc. 1976, 98, 6755–6757. (b) Funk,
(5) Kuwano, R.; Shige, T. J. Am. Chem. Soc. 2007, 129, 3802–3803.
(6) Ueno, S.; Ohtsubo, M.; Kuwano, R. J. Am. Chem. Soc. 2009, 131,
12904–12905.
R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1980, 102, 5245–5253
.
10.1021/ol101792a  2010 American Chemical Society
Published on Web 09/02/2010

A mixture of o-[(trimethylsilyl)methyl]benzyl carbonate
1 and phenylglyoxylate 2a was heated at 120 °C in the
presence of Pd(η3-allyl)Cp-DPPPent,7 which is the most
effective catalyst for our previous [4 + 2] cycloaddition of
1 with imines (Scheme 1).6 The desired isochromane 3a was
2d showed reactivity comparable to 2b (entry 3). The ortho-
substituent in 2e hindered the catalytic cycloaddition (entry
4). The reactions of poly- and heterocyclic aromatic sub-
strates 2g and 2h produced isochromanes 3g and 3h in high
yields, while 2f reacted with 1 in moderate yield because of
the steric hindrance of its 1-naphthyl group (entries 5-7).
As with the R-keto esters, isatin 2i or 1,2-diketone 2j also
served as a dienophile in the palladium-catalyzed [4 + 2]
cycloaddition (entries 8 and 9). Furthermore, the palladium
catalysis is effective for the reaction of trifluoromethyl ketone
2k (entry 10). However, acetophenone and methyl pyruvate
remained intact in the reactions with 1. The observations
indicate that the ketonic substrate requires an aryl and
electron-withdrawing group on each side of its carbonyl
carbon in order to react with 1 to form the desired
isochromane product.
Scheme 1. Cycloaddition of 1 with 2a
Next, we directed our attention to the regiochemistry in
the catalytic cycloadditions of substituted o-(silylmethyl)-
benzyl carbonates 4a-e (Table 2). The reactions of 4a and
formed in 42% GC yield after 1 h. The activity of the
palladium catalyst was enhanced using DPEphos8 in place
of DPPPent. The DPEphos-palladium catalyst completed
the desired reaction within 3 h and produced 3a in 90%
isolated yield. No formation of 3a was detected when the
mixture of 1 and 2a was treated with potassium fluoride in
the absence of DPEphos-palladium, although the fluoride
source was known to generate o-xylylene from 1 with no
palladium.9,10 In the reaction, 1 completely disappeared at
3 h and was converted into o-xylylene oligomers. The
observation may suggest that free o-xylylene fails to undergo
the oxo-Diels-Alder reaction. The palladium catalysis would
be crucial for the formation of the isochromane skeleton
through the reaction of 1 with ketones.
Table 2. Cycloaddition of Substituted o-(Silylmethyl)benzyl
Carbonates 4 with Ketones 2a
entry
R3 (4)
2
time, h
product
5a, 6a
5b () 6a), 16:84
6b () 5a)
5/6b yield,c %
The DPEphos-palladium catalyst allows a variety of
arylglyoxylates 2b-h to react with the o-xylylene equivalent
1 (Table 1, entries 1-7). The electron-donating methoxy
1
2
6-Ph (4a)
3-Ph (4b)
2k
2k
24
6
85:15
82
92
3
4
6-Me (4c)
3-Me (4d)
2k
2k
24
6
5c, 6c
5d () 6c), 68:32
6d () 5c)
5e, 6e
5f, 6f
5g () 6f),
6g () 5f)
5h, 6h
5i, 6i
35:65
86
80
Table 1. Cycloaddition of 1 with Ketones 2a
5
6
7
4b
4c
4d
2a
2a
2a
4
24
20
52:48
13:87
90:10
63d
74
75
8
9
10
4d
4d
2i
2j
24
6
9
91: 9
88:12
>99:1
69
73
70
entry
R1
R2
2
time, h product (3) yield,b
%
4-MeO (4e) 2k
5j
a All reactions were conducted in DMF (3.0 mL). The ratio of 1/2 (0.45
mmol)/Pd(η3-C3H5)Cp/DPEphos was 150:100:3.0:6.6. b Determined by the
1H NMR analyses of crude products. c Isolated yield of a mixture of 5 and
6 unless otherwise noted. d Combined yield of 5e and 6e, which were isolated
in 30% and 33% yields, respectively.
1
2
3
4
5
6
7
8
9
Ph
CO2Et 2b
3
12
3
24
3
3
4
24
6
24
3b
3c
3d
3e
3f
3g
3h
3i
93
41
81
35
67
93
93
92
85
93
4-MeOC6H4 CO2Et 2c
4-CF3C6H4 CO2Et 2d
2,4-Me2C6H3 CO2Me 2e
1-naphthyl CO2Et 2f
2-naphthyl CO2Et 2g
2-furyl
-C6H4N(Bn)C(O)- 2i
Ph C(O)Ph 2j
CF3 2k
CO2Me 2h
4b with trifluoromethyl ketone 2k were similar in regiose-
lectivity to the corresponding reactions with N-tosylimine
in our previous report (entries 1 and 2).6 Both reactions
afforded the mixture of two regioisomers 5a and 6a with
the same molar ratio. The observed regioselectivities suggest
that 4a and 4b were transformed into identical intermediates
in the course of the cycloaddition. The substrates 4c and 4d,
which have a methyl group at the 6- or 3-position, also
underwent the cycloaddition with 2k in good yields (entries
3j
3k
10 Ph
a All reactions were conducted in DMF (3.0 mL). The ratio of 1/2 (0.45
mmol)/Pd(η3-C3H5)Cp/DPEphos was 150:100:3.0:6.6. b Isolated yield.
group in 2c caused a decrease in the reactivity of the carbonyl
substrate (entry 2). In contrast, the electron-deficient substrate
Org. Lett., Vol. 12, No. 19, 2010
4333

3 and 4). The decrease in the size of the 6- or 3-substituent
brought about the reversed regioselectivities as well as the
lower ratios of 5 to 6. Furthermore, the reversed regiose-
lectivities rose to 16:84 or 86:14 when R-keto ester 2a was
used in place of 2k (entries 6 and 7). Preferential formation
of 5 from 4d was observed in the reactions with 2i and 2j,
which have a 1,2-dicarbonyl skeleton (entries 8 and 9). It is
noteworthy that 4-methoxy-substituted 4e was transformed
into 5j with no formation of 6j (entry 10).
The formation of regioisomeric C′ is hindered by the
repulsion between R3 and palladium. The benzylic anion in
zwitterionic C attacks on the carbonyl carbon of 2 to form
intermediate D. The intramolecular nucleophilic attack of
the alkoxide on the η3-benzyl in D forms the regioisomeric
product E. The regioselectivities in the reactions of 4c or
4d with R-keto ester 2a indicate that these cycloadditions
would proceed through path b in preference to path a. The
o-phenyl group in 4a or 4b may obstruct the nucleophilic
attack of C on 2, allowing these substrates to react with 2a
through path a. Hence, the reaction of 4b with 2a gave an
equimolar mixture of 5e and 6e. Furthermore, the trifluoro-
methyl group in 2k may be advantageous to path a because
its bulkiness makes the ketonic substrate less reactive to the
nucleophilic attack of C.13 Synergistic effects of the triflu-
oromethyl in 2k and the phenyl group in 4a or 4b would
lead to the selective formation of 5a in entries 1 and 2 of
Table 2. In the reaction of 4e, the benzylic anion would be
preferentially generated at the meta position of the methoxy
substituent in zwitterionic C due to resonance effects. The
resulting intermediate would lead to the exclusive formation
of 5j.
In order to rationalize the unexpected correlation of
regioselectivity with substrate structure, we envision two
competitive reaction pathways as shown in Figure 1. One is
In conclusion, electron-deficient ketones 2 react with (o-
silylmethyl)benzyl carbonates in the presence of the
DPEphos-palladium catalyst, affording 3,3-disubstituted
isochromanes in high yields. The catalytic cycloaddition is
equivalent to the oxo-Diels-Alder reaction of o-xylylenes
with ketones. The regioselectivity of the cycloaddition was
extraordinarily sensitive to the structures of both substrates.
The observations suggest that the present catalytic cycload-
dition may proceed through two competitive reaction path-
ways.
Figure 1. Two competitive pathways for the cycloaddition of 4
with 2.
similar to the pathway proposed for the cycloaddition of 1
or 4 with imine in our previous report (path a).6 An
o-(silylmethyl)benzyl ester reacts with palladium(0) to form
2-palladaindan A. The 1,2 insertion of 2 occurs at one of
the C-Pd bonds as the ketone avoids the steric hindrance
of R3, leading to the preferential formation of cycloaddition
product B.11 In another pathway (path b), A is in equilibrium
with (η3-benzyl)palladium C through η1-η3 isomerization.12
Acknowledgment. This work was partly supported by a
Grant-in-Aid for the Global COE Program “Science for
Future Molecular Systems” from MEXT.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(7) DPPPent ) 1,5-bis(diphenylphosphino)pentane: Sacconi, L.; Gel-
somini, J. Inorg. Chem. 1968, 7, 291–294.
(8) DPEphos ) bis[2-(diphenylphosphino)phenyl] ether: Kranenburg,
M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.;
Goubitz, K.; Fraanje, J. Organometallics 1995, 14, 3081–3089.
(9) Kuwano, R.; Shige, T. Chem. Lett. 2005, 34, 728–729.
(10) (a) Yoshida, H.; Nakano, S.; Yamaryo, Y.; Ohshita, J.; Kunai, A.
Org. Lett. 2006, 8, 4157–4159. (b) Yoshida, H.; Nakano, S.; Mukae, M.;
Ohshita, J. Org. Lett. 2008, 10, 4319–4322.
OL101792A
(13) The A values of the trifluoromethyl and alkoxycarbonyl groups
indicate that the former is sterically bulkier than the latter; see: (a) Della,
E. W. J. Am. Chem. Soc. 1967, 89, 5221–5224. (b) Eliel, E. L.; Reese,
M. C. J. Am. Chem. Soc. 1968, 90, 1560–1566.
(11) (a) Krug, C.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 1674–
1679. (b) Krug, C.; Hartwig, J. F. Organometallics 2004, 23, 4594–4607.
(12) Kuwano, R. Synthesis 2009, 1049–1061.
4334
Org. Lett., Vol. 12, No. 19, 2010