Novel method for synthesizing spiro[4.5]cyclohexadienones through a Pd-catalyzed intramolecular ipso-Friedel-Crafts allylic alkylation of phenols

Article abstract of DOI:10.1021/ol102190s

The first successful Pd-catalyzed intramolecular ipso-Friedel-Crafts allylic alkylation of phenols, which provided a new access to spiro[4.5]cyclohexadienones, is described. The present method could be applied to catalytic enantioselective construction of

Full text of DOI:10.1021/ol102190s

ORGANIC
LETTERS
2010
Vol. 12, No. 21
5020-5023
Novel Method for Synthesizing
Spiro[4.5]cyclohexadienones through a
Pd-Catalyzed Intramolecular
ipso-Friedel-Crafts Allylic Alkylation of
Phenols
Tetsuhiro Nemoto, Yuta Ishige, Mariko Yoshida, Yuta Kohno,
Mutsumi Kanematsu, and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba UniVersity, 1-33, Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan
hamada@p.chiba-u.ac.jp
Received September 13, 2010
ABSTRACT
The first successful Pd-catalyzed intramolecular ipso-Friedel-Crafts allylic alkylation of phenols, which provided a new access to
spiro[4.5]cyclohexadienones, is described. The present method could be applied to catalytic enantioselective construction of an all-carbon
quaternary spirocenter.
Efficient construction of spirocyclic frameworks is an important
topic in synthetic organic chemistry because of their broad
distribution in biologically active natural products and phar-
maceuticals as well as their usefulness in complex molecule
syntheses. Among the various spirocycles, spirocyclohexadi-
enones are the most important class of compounds in organic
synthesis.1 Extensive effort has been focused on the develop-
ment of an efficient synthetic method based on hypervalent
iodine reagents,2 ipso-halocyclization,3 radical cyclization,4
arene-Ru complex-mediated dearomatization,5 and Cu-cata-
lyzed oxygenation of R-azido-N-arylamides.6 The reported
reactions, however, are difficult to extend to catalytic enanti-
oselective synthesis, and very limited success has been reported
to date.7,8 This background led us to explore a novel method
for synthesizing spirocyclohexadienones that is readily
applicable to catalytic asymmetric synthesis. The present
(3) (a) Appel, T. R.; Yehia, N. A. M.; Baumeister, U.; Hartung, H.;
Kluge, R.; Stro¨hl, D.; Fangha¨nel, E. Eur. J. Org. Chem. 2003, 47. (b) Zhang,
X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 12230. (c) Tang, B.-X.;
Yin, Q.; Tang, R.-Y.; Li, J.-H. J. Org. Chem. 2008, 73, 9008.
(4) (a) Gonza´lez-Lo´pez de Turiso, F.; Curran, D. P. Org. Lett. 2005, 7,
151. (b) Lanza, T.; Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo, P.;
Zanardi, G. Angew. Chem., Int. Ed. 2008, 47, 9439.
(1) For reviews, see: (a) Sannigrahi, M. Tetrahedron 1999, 55, 9007.
(b) Kotha, S.; Deb, A. C.; Lahiri, K.; Manivannan, E. Synthesis 2009, 165.
(2) For recent representative examples, see: (a) Dohi, T.; Maruyama,
A.; Yoshimura, M.; Morimoto, K.; Tohma, H.; Kita, Y. Angew. Chem.,
Int. Ed. 2005, 44, 6193. (b) Dohi, T.; Maruyama, A.; Minamitsuji, Y.;
Takenaga, N.; Kita, Y. Chem. Commun. 2007, 1224. (c) Dohi, Y.;
Minamitsuji, Y.; Maruyama, A.; Hirose, S.; Kita, Y. Org. Lett. 2008, 10,
3559.
(5) (a) Pigge, F. C.; Coniglio, J. J.; Rath, N. P. Org. Lett. 2003, 5, 2011.
(b) Pigge, F. C.; Dhanya, R.; Hoefgen, E. R. Angew. Chem., Int. Ed. 2007,
46, 2887.
(6) Chiba, S.; Zhang, L.; Lee, J.-Y. J. Am. Chem. Soc. 2010, 132, 7266.
(7) (a) Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.; Minamitsuji,
Y.; Fujioka, H.; Caemmerer, S. B.; Kita, Y. Angew. Chem., Int. Ed. 2008,
47, 3787. (b) Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed.
2010, 49, 2175
.
10.1021/ol102190s  2010 American Chemical Society
Published on Web 10/11/2010

paper describes a new access to spiro[4.5]cyclohexadienone
frameworks through a Pd-catalyzed intramolecular ipso-
Friedel-Crafts allylic alkylation of phenols that can be
applied to catalytic enantioselective construction of an all-
carbon quaternary spirocenter.
Phenols are generally utilized as oxygen nucleophiles in
transition metal-catalyzed allylic alkylation,9 with very few
exceptions of C-allylation.10 In contrast to the general reactivity,
we found that Pd-catalyzed intramolecular allylic alkylation of
meta-substituted phenol derivative 1 occurred on the aromatic
carbons to afford the corresponding Friedel-Crafts-type adducts
2a and 2b in good conversion (Scheme 1).11 This surprising
Table 1. Optimization of the Reaction Conditions Using 3aa
entry
catalyst
ligand (mol %)
solvent yield of 4a (%)b
1
2
3
4
5
6
7
8
9
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
dppm (6)
dppe (6)
dppp (6)
dppf (6)
PPh3 (12)
P(o-tol)3 (12)
P(4-Cl-Ph)3 (12)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
33 (84)c
16
trace
5
94 (1)d
76
94
P(4-MeO-Ph)3 (12) CH2Cl2
30 (93)c
trace
95
P(cHex)3 (12)
P(OPh)3 (12)
PPh3 (12)
CH2Cl2
CH2Cl2
CH3CN
THF
10 Pd(dba)2
11 Pd(dba)2
12 Pd(dba)2
90
88
PPh3 (12)
Scheme 1
13 [allylPdCl]2 PPh3 (12)
14 Pd(OAc)2 PPh3 (12)
15 [Ir(cod)Cl]2 PPh3 (6)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
84
trace
0
16 [Ir(cod)Cl]2 P(OPh)3 (6)
0
a Reaction conditions: metal catalyst (5 mol %), solvent (0.2 M), rt, 3 h.
b Isolated yield. c Yield in 24 h. d Isolated yield of 4a′.
phosphite were suitable ligands for this reaction, and the desired
product 4a with a spiro[4.5]cyclohexadienone framework was
obtained in 94-95% yield. For practical reasons, triphenylphos-
phine was used for further optimization. There was no noticeable
solvent effect in this reaction. No reaction occurred when
Pd(OAc)2 and [Ir(cod)Cl]2 were used as the catalyst source.
When the reaction was performed under the reaction conditions
shown in entry 5, 3a was completely consumed. Careful
purification of the reaction mixture revealed the formation of
cyclic trimer 4a′ via O-alkylations in 1% yield (3% of 3a was
incorporated).
Having developed efficient conditions, we next examined the
scope and limitations of different substrates (Table 2). Intramo-
lecular ipso-Friedel-Crafts allylic alkylation of 3a could be
performed even in the presence of 1 mol % of the Pd catalyst,
giving 4a in 89% yield (entries 1-3). Secondary alcohol
derivatives 3b and 3c were also applicable to this reaction, and
the corresponding spiro[4.5]cyclohexadienones with a trans-
olefin 4b and 4c were obtained in 84% yield and 89% yield,
respectively (entries 4 and 5). Moreover, intramolecular ipso-
Friedel-Crafts allylic alkylation of 3d and 3e, bearing a
dimethyl acetal tether or an N-Ts tether connecting the phenol
and allyl carbonate moiety, proceeded smoothly to give the
corresponding spirocyclic adducts in good yield (entries 6 and
7). In contrast, the use of oxygen-tethered substrate 3f resulted
in a messy reaction, and the desired product 4f was not obtained
at all using the Pd(dba)2-PPh3 catalyst system. This result
indicates that the present spirocyclization process would be
facilitated by the Thorpe-Ingold effect. Optimization of the
reaction conditions revealed that the reactivity was dramatically
affected by the properties of the phosphorus ligand. Spirocyclic
adduct 4f was obtained in 63% yield when triphenyl phosphite
was utilized instead of triphenylphosphine (entry 8). Multisub-
result led us to hypothesize that para-substituted phenol
derivatives such as 3a could be utilized as substrates for
intramolecular ipso-Friedel-Crafts allylic alkylation, which
would provides a new access to spirocyclohexadienones. We
initially optimized the reaction conditions using allyl carbonate
3a as a model substrate (Table 1). First, we investigated the
effect of a phosphorus ligand using 5 mol % of Pd(dba)2 in
CH2Cl2 at room temperature. Compared with bidentate phos-
phorus ligands, the use of monodentate phosphorus ligands
increased the reactivity. Among the examined ligands, triph-
enylphosphine, tris(4-chlorophenyl)phosphine, and triphenyl
(8) For recent representative examples of catalytic asymmetric construc-
tion of a spirocenter, see: (a) Teng, X.; Cefalo, D. R.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 10779. (b) Hatano, M.;
Mikami, K. J. Am. Chem. Soc. 2003, 125, 4704. (c) Tsuchikama, K.;
Kuwata, Y.; Shibata, T. J. Am. Chem. Soc. 2006, 128, 13686. (d) Trost,
B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem. Soc. 2007, 129, 12396.
(e) Zhang, E.; Fan, C.-A.; Tu, Y.-Q.; Zhang, F.-M.; Song, Y.-L. J. Am.
Chem. Soc. 2009, 131, 14626. (f) Shintani, R.; Isobe, S.; Takeda, M.;
Hayashi, T. Angew. Chem., Int. Ed. 2010, 49, 3795. (g) Yao, W.; Pan, L.;
Wu, Y.; Ma, C. Org. Lett. 2010, 12, 2422. (h) Wu, Q.-F.; He, H.; Liu,
W.-B.; You, S.-L. J. Am. Chem. Soc. 2010, 132, 11418.
(9) For reviews, see: (a) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003,
103, 2921. (b) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258.
(10) (a) Malkov, A. V.; Davis, S. L.; Baxendale, I. R.; Mitchell, W. L.;
Kocovsky, P. J. Org. Chem. 1999, 64, 2751. (b) Ferna´ndez, I.; Hermatsch-
weiler, R.; Breher, F.; Pregosin, P. S.; Veiros, L. F.; Calhorda, M. J. Angew.
Chem., Int. Ed. 2006, 45, 6386. For an example of Pd-catalyzed C-allylation
of phenols via an O-allylation-Claisen rearrangement sequence, see: (c)
Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 815.
(11) For examples of catalytic intramolecular Friedel-Crafts-type
allylations using aromatic nucleophiles, see: (a) Ma, S.; Zhang, J. Tetra-
hedron 2003, 59, 6273. (b) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi,
R.; Tommasi, S.; Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424.
(c) Cook, G. R.; Hayashi, R. Org. Lett. 2006, 8, 1045. (d) Namba, K.;
Yamamoto, H.; Sasaki, I.; Mori, K.; Imagawa, H.; Nishizawa, M. Org. Lett.
2008, 10, 1767. (e) Bandini, M.; Elchholzer, A.; Kotrusz, P.; Tragni, M.;
Troisi, S.; Umani-Ronchi, A. AdV. Synth. Catal. 2009, 351, 319.
Org. Lett., Vol. 12, No. 21, 2010
5021

Table 2. Scope and Limitations
entry
substrate
X
R1
R2
R3
catalyst (mol %)
product
time (h)
yield (%)a
drb
1
3a
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
C(COOMe)2
C(COOMe)2
C(COOMe)2
C(COOMe)2
C(COOMe)2
C(OMe)2
NTs
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
Ph
H
H
H
H
H
H
H
5
2
1
5
5
5
5
5
5
5
5
5
5
4a
4a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
3
6
24
6
6
6
6
6
6
8
94
96
89
84
89
93
86
-
-
-
-
-
-
-
-
2c
3d
4
5
6
7
8e
9
O
0 (63)f
97
92
89
97
95
C(COOMe)2
C(COOMe)2
NTs
NTs
C(COOMe)2
CH3
Cl
CH3
13.4:1
11.0:1
7.5:1
3.0:1
1.1:1
10
11
12g
13
9
24
24
-CHdCH-CHdCH-
CH3
H
H
a Isolated yield. b Determined by 1H NMR analysis of the crude mixture. c [3a] ) 0.33 M. d [3a] ) 0.5 M. e [3f] ) 0.05 M. f Isolated yield using
triphenyl phosphite as the ligand. g (R)-Monophos was used as the ligand. Solvent: CH3CN.
stituted phenol derivatives were also examined using 5 mol %
of the catalyst. Dimethyl malonate-tethered substrates with a
methyl group (3g) or a chloride group (3h) on the meta-position
to the phenol proceeded under the same reaction conditions,
affording the corresponding products with contiguous chiral
centers in excellent yield with high diastereoselectivity (entries
9 and 10). The relative stereochemistry of 4g was determined
by the NOE experiment. Similarly, N-Ts-tethered-type substrate
3i was an effective substrate, resulting in the formation of 4i in
89% yield with relatively high diastereoselectivity (entry 11).
Although diastereoselectivity decreased, naphthol-type substrate
3j was also applicable to this reaction, giving naphthoquinone
derivative 4j in excellent yield (entry 12). On the other hand,
there was no significant diastereoselectivity when compound
3k, bearing a methyl group on the ortho-position to the phenol,
was utilized as the substrate. To the best of our knowledge,
this is the first example of Pd-catalyzed intramolecular ipso-
Friedel-Crafts allylic alkylation of phenols, which provides new
access to spiro[4.5]cyclohexadienones.
When compound 5, an anisole variant of 1, was treated
with the optimized reaction conditions, diene 6 was
obtained in 21% yield, accompanied by the recovery of 5
(58%) (eq 1). It is noteworthy that no bicyclic compounds
were produced by an intramolecular Friedel-Crafts allylic
alkylation of 5, based on an 1H NMR analysis of the crude
reaction sample.12 In addition, there was a significant
decrease in the reactivity when 1,1,1,3,3,3-hexafluoro-2-
propanol (HFIP) was added to the spirocyclization of 3a
(eq 2). Compared with a control experiment using
methanol (pKa 15.5) as the additive (95% yield), 4a was
obtained in 7% yield with the use of 1 equiv of HFIP
(pKa 9.3) as the additive (recovery of 3a: 89%). These
results indicate the importance of phenol deprotonation
by the methoxide anion, which was generated during the
formation of the π-allylpalladium species, to promote this
reaction.13
Furthermore, when phenol derivative 7, a substrate bearing
a CH2 unit-longer tether than 3a, was reacted under the
optimized reaction conditions, conventional O-alkylations
occurred dominantly to afford cyclic dimer 8 as the major
product (16% yield: 32% of 7 was incorporated) (Scheme
3). Cyclic trimer, tetramer, and pentamer were also observed
To gain preliminary insight into the reaction mechanism,
we performed the following experiments (Scheme 2).
Scheme 2
(12) Reaction of an anisole derivative prepared from 3a also gave a
similar diene adduct in 88% yield under the same reaction conditions. No
bicyclic compounds derived from the postulated spirocyclic oxonium cation
intermediate were detected by 1H NMR analysis of the crude reaction
mixture.
(13) Base-promoted intramolecular alkylation of phenols to form spi-
rocyclohexadienones is a classical transformation. See: (a) Baird, R.;
Winstein, S. J. Am. Chem. Soc. 1962, 84, 788. (b) Kropp, P. J. Tetrahedron
Lett. 1965, 21, 2183. 4a was not produced through a SN2′ substitution,
however, when 3a was treated with 1 equiv of KOt-Bu in CH2Cl2 at room
temperature in the absence of Pd catalyst. In contrast, 4a was obtained in
good yield when an allyl bromide derivative corresponding to 3a was
refluxed in t-BuOH in the presence of KOt-Bu.
5022
Org. Lett., Vol. 12, No. 21, 2010

Scheme 3
Scheme 5
in ESI-MS analysis. In contrast, spirocyclic adduct 9 was
isolated in only 5% yield, indicating that the tether length
between the phenol and π-allylpalladium unit was a crucial
factor for the present spirocyclization.
These findings led us to propose a plausible reaction pathway
for this reaction (Scheme 4). First, oxidative addition of allylic
of Pd catalyst, 6 mol % of chiral ligand (+)-10,16 and 1 equiv
of Li2CO3, catalytic asymmetric ipso-Friedel-Crafts allylic
alkylation of 3l proceeded in a diastereoselective manner (dr
) 9.2:1), providing (S,S)-4l in 80% yield with 89% ee (major
diastereomer).17 Although there is still room for improvement
in the enantioselectivity, the asymmetric transformation
constitutes a proof of concept and provides a blueprint for
the development of a more efficient catalytic system.
In conclusion, we developed a novel method for synthesiz-
ing spiro[4.5]cyclohexadienones using a Pd-catalyzed in-
tramolecular ipso-Friedel-Crafts allylic alkylation of phe-
nols. Moreover, the potential applicability to catalytic
asymmetric synthesis of spirocyclic compounds bearing two
contiguous chiral centers was demonstrated for the first time.
Further investigations into the catalytic asymmetric version
of this process, as well as more detailed studies of the
reaction mechanism, are in progress.
Scheme 4
Acknowledgment. This work was supported by a Grant-
in Aid for Encouragement of Young Scientists (B) from the
Ministry of Education, Culture, Sports, Science, and Tech-
nology, Japan.
carbonates to the Pd(0) catalyst forms a π-allylpalladium
species. Subsequent deprotonation of the phenol by the endog-
enous methoxide anion proceeds to increase the nucleophilicity
of the para-position to the phenol. The carbon-carbon bond
formation occurs via transition states TS-1 or TS-2, where the
proximal arrangement of both reactive centers is facilitated by
the chairlike transition state structure.14 The observed diaste-
reoselectivity could be explained by steric repulsion between
the π-allyl unit and the ortho-substituent (R1) in TS-1.
Supporting Information Available: Experimental pro-
cedures, supplementary data, compound characterization, and
NMR charts. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL102190S
(16) For examples of asymmetric reactions using 10, see: (a) Trost,
B. M.; Tsui, H.-C.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 3534. (b)
Trost, B. M.; Tang, W. J. Am. Chem. Soc. 2003, 125, 8744. (c) Trost, B. M.;
Frederiksen, M. U. Angew. Chem., Int. Ed. 2005, 44, 308. (d) Trost, B. M.;
Xu, J. J. Am. Chem. Soc. 2005, 127, 2846. (e) Trost, B. M.; Xu, J. J. Am.
Chem. Soc. 2005, 127, 17180. (f) Trost, B. M.; Xu, J.; Reichle, M. J. Am.
Chem. Soc. 2007, 129, 282. (g) Trost, B. M.; Thaisrivongs, D. A. J. Am.
Chem. Soc. 2008, 130, 14092. (h) Trost, B. M.; Thaisrivongs, D. A. J. Am.
Chem. Soc. 2009, 131, 12056. (i) Trost, B. M.; Lehr, K.; Michaelis, D. J.;
Xu, J.; Buckl, A. K. J. Am. Chem. Soc. 2010, 132, 8915.
Preliminary attempts to extend the developed reaction to
enantioselective construction of an all-carbon quaternary
spirocenter were promising (Scheme 5).15 Using 5 mol %
(14) There might be π-orbital interactions between the electron-deficient
cationic π-allylpalladium unit and the electron-rich phenoxide ring in the
transition states. Phosphorus ligands with π-acidic properties, such as
triphenyl phosphite, could enhance the intramolecular charge transfer
interaction, facilitating the carbon-carbon bond formation.
(15) For reviews on catalytic asymmetric construction of quaternary
stereocenters, see: (a) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed.
2001, 40, 4591. (b) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (c)
Shibasaki, M.; Kanai, M. Org. Biomol. Chem. 2007, 5, 2027.
(17) Enantiomeric excess of the minor isomer was 21% ee. For the
determination of the absolute configuration of the major isomer, see the
Supporting Information. When the reaction was performed in the absence
of Li2CO3, the product was obtained in 88% yield (dr ratio ) 9.2:1; ee:
major diastereomer 87% ee, minor diastereomer 18% ee).
Org. Lett., Vol. 12, No. 21, 2010
5023