Synthesis of 3,3-disubstituted oxindoles by palladium-catalyzed tandem reaction of 2-(alkynyl)aryl isocyanates with benzylic alcohols

Article abstract of DOI:10.1021/ol101892b

A palladium complex sequentially promoted two mechanistically distinct reactions, the first, cyclization of 2-(alkynyl)aryl isocyanates with benzylic alcohols, and the second, [1,3] rearrangement of a benzyl group from oxygen to carbon, furnishing 3,3-dis

Full text of DOI:10.1021/ol101892b

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4584-4587
Synthesis of 3,3-Disubstituted Oxindoles
by Palladium-Catalyzed Tandem
Reaction of 2-(Alkynyl)aryl Isocyanates
with Benzylic Alcohols
Takeharu Toyoshima, Yusuke Mikano, Tomoya Miura, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto UniVersity,
Katsura, Kyoto 615-8510, Japan
murakami@sbchem.kyoto-u.ac.jp
Received August 12, 2010
ABSTRACT
A palladium complex sequentially promoted two mechanistically distinct reactions, the first, cyclization of 2-(alkynyl)aryl isocyanates with
benzylic alcohols, and the second, [1,3] rearrangement of a benzyl group from oxygen to carbon, furnishing 3,3-disubstituted oxindoles
in one pot.
Tandem reactions involving multistep transformations in
sequence reduce synthetic steps and incidental wastes to
greatly improve synthetic efficiency.1,2 There has been a
growing interest in the development of multifunctional
catalytic processes, wherein a single catalyst promotes two
or more transformations in a single flask. Such catalytic
systems have been named as “auto-tandem catalysts
(ATCs)”.3 Palladium catalysts are most promising for this
purpose because they are so versatile to promote a large
number of reactions of different patterns.4 Elegant examples
of palladium ATCs have appeared over the past several
years.5,6 2-Iodophenol reacted with methyl bromomethyl-
acrylate and phenylboronic acid in the presence of a
palladium catalyst to give a dihydrobenzofuran derivative
through a sequence of O-allylation/Heck/Suzuki coupling
processes.5a A tandem Buchwald-Hartwig coupling/cycliza-
tion reaction afforded indole derivatives starting from 2-alky-
nylhaloarenes and amines.5c Fagnou developed a tandem
Heck/C-H arylation reaction, and employed this strategy
for the construction of cytotoxic carbazoles.5d We describe
herein a new palladium-catalyzed tandem reaction of 2-(alky-
(5) (a) Szlosek-Pinaud, M.; Diaz, P.; Martinez, J.; Lamaty, F. Tetrahe-
dron Lett. 2003, 44, 8657. (b) Gruber, M.; Chouzier, S.; Koehler, K.;
Djakovitch, L. Appl. Catal., A 2004, 265, 161. (c) Ackermann, L. Org.
Lett. 2005, 7, 439. (d) Leclerc, J.-P.; Andre´, M.; Fagnou, K. J. Org. Chem.
2006, 71, 1711. (e) Gabriele, B.; Plastina, P.; Salerno, G.; Mancuso, R.;
Costa, M. Org. Lett. 2007, 9, 3319. (f) Meyers, C.; Rombouts, G.; Loones,
K. T. J.; Coelho, A.; Maes, B. U. W. AdV. Synth. Catal. 2008, 350, 465.
(g) Lu, Y.; Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010,
132, 5916.
(1) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, Germany, 2006
.
(2) For recent reviews, see: (a) Ajamian, A.; Gleason, J. L. Angew.
Chem., Int. Ed. 2004, 43, 3754. (b) Wasilke, J.-C.; Obrey, S. J.; Baker,
R. T.; Bazan, G. C. Chem. ReV. 2005, 105, 1001. (c) Shindoh, N.; Takemoto,
Y.; Takasu, K. Chem.sEur. J. 2009, 15, 12168. (d) Nicolaou, K. C.; Chen,
J. S. Chem. Soc. ReV. 2009, 38, 2993. (e) Poulin, J.; Grise´-Bard, C. M.;
(6) For recent examples catalyzed by transition metal complexes except
palladium, see: (a) Chen, J.-R.; Li, C.-F.; An, X.-L.; Zhang, J.-J.; Zhu, X.-
Y.; Xiao, W.-J. Angew. Chem., Int. Ed. 2008, 47, 2489. (b) Kelly, B. D.;
Allen, J. M.; Tundel, R. E.; Lambert, T. H. Org. Lett. 2009, 11, 1381. (c)
He, H.; Liu, W.-B.; Dai, L.-X.; You, S.-L. Angew. Chem., Int. Ed. 2010,
Barriault, L. Chem. Soc. ReV. 2009, 38, 3092
.
(3) For taxonomy of auto-tandem catalyst, see ref 2c. For alternative
classifications/terms, see: Suga, S.; Yamada, D.; Yoshida, J. Chem. Lett.
2010, 39, 404.
´
49, 1496. (d) Fructos, M. R.; Alvarez, E.; D´ıaz-Requejo, M. M.; Pe´rez,
P. J. J. Am. Chem. Soc. 2010, 132, 4600. (e) Wender, P. A.; Stemmler,
R. T.; Sirois, L. E. J. Am. Chem. Soc. 2010, 132, 2532. (f) Fuwa, H.; Noto,
K.; Sasaki, M. Org. Lett. 2010, 12, 1636.
(4) Tsuji, J. Palladium Reagents and Catalysis: New perspectiVes for
the 21st Century; Wiley: Weinheim, Germany, 2004.
10.1021/ol101892b  2010 American Chemical Society
Published on Web 09/10/2010

nyl)aryl isocyanates with benzylic (or allylic) alcohols.7 3,3-
Disubstituted oxindoles are synthesized in one pot through
a sequence of cyclization and [1,3] rearrangement of a benzyl
(or allyl) group from oxygen to carbon.8
We have previously reported a stereoselective synthesis
of 3-(alkoxyalkylidene)oxindoles by the palladium-catalyzed
cyclization of 2-(alkynyl)aryl isocyanates with alcohols.9 The
scope of this reaction was examined in more detail, leading
to the use of benzyl alcohol. Thus, 2-(1-hexynyl)phenyl
isocyanate (1a, 1.0 equiv) was treated with benzyl alcohol
(2a, 3.0 equiv) in the presence of Pd2(dba)3·CHCl3/dppf (5.0
mol % of Pd; dppf )1,1′-bis(diphenylphosphino)ferrocene)
in THF at 40 °C for 12 h. After an extractive workup
followed by chromatographic isolation, 3-(1-(benzyloxy)-
pentylidene)oxindole (3aa) was obtained as the sole product
in 81% isolated yield (Z:E ) >20:1), being in accordance
with the results we reported9 (Table 1, entry 1). When the
On the other hand, no [1,3] rearrangement of 3aa was observed
in the absence of the palladium catalyst even at 100 °C. These
results indicated that 3aa is initially formed by the palladium-
catalyzed cyclization reaction of 1a with 2a, as we previously
reported,9 and that the benzyl group bound to an enol oxygen
subsequently undergoes 1,3-rearrangement onto an enol carbon,
probably via a (η3-benzyl)palladium(II) complex C, to furnish 4aa
(Scheme 1).12,13 The involvement of a (η3-benzyl)palladium(II)
Scheme 1. Proposed Mechanism for the Pd(0)-Catalyzed
Tandem Reaction from 1a and 2a to 4aa
Table 1. Optimization of Reaction Conditionsa
yield of
yield of
entry
[Pd]
t (°C) solvent
3aa (%)b 4aa (%)
1
2
3
4
5
6
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
CpPd(π-allyl)
40
80
80
80
80
80
THF
THF
DME
dioxane 54 (7:1)
toluene 41 (1:2)
81 (>20:1)
56 (9:1)
57 (13:1)
0
13
13
16
31
69
complex was supported by the result of an analogous reaction with
1-naphthylmethanol (2b). The reaction of 1a with 2b proceeded
more rapidly than that with 2a to afford the product 4ab in 74%
yield (eq 2). It has been reported that the formation of (η3-
benzyl)palladium(II) intermediate from a benzyl ester through
oxidative addition onto palladium(0) is slower than the forma-
tion of (η3-naphthylmethyl)palladium(II) intermediate from a
toluene
0
a Reactions conducted on a 0.2 mmol scale. b Isomer ratios (Z/E) given
in parentheses.
reaction was carried out at an elevated temperature of 80
°C, however, another minor product was formed in addition
to 3aa (entry 2). The structure of the new product was
determined to be 3-benzyl-3-pentanoyloxindole (4aa) by 1H
and 13C NMR spectrometry. Careful examination of the
reaction conditions revealed that 4aa was selectively formed
when toluene was used as the solvent and CpPd(π-allyl) as
the catalyst (entry 6).
naphthylmethyl ester because the former process suffers
from disruption of aromaticity.13a,f Therefore, the slower
reaction rate observed with 2a accords with the involvement
of (η3-benzyl)palladium(II) intermediate. Thus, the palladium
catalyst mediates two distinct transformations in sequence,
the first, alkyne/isocyanate cyclization, and the second, 1,3-
The isolated oxindole 3aa was subjected to the same
reaction conditions. Conversion of 3aa took place smoothly
to afford 4aa in 97% yield in 12 h (eq 1).10,11
(7) For examples of tandem reactions including a rearrangement step,
see: (a) Waetzig, S. R.; Tunge, J. A. J. Am. Chem. Soc. 2007, 129, 4138.
(b) Tanaka, K.; Okazaki, E.; Shibata, Y. J. Am. Chem. Soc. 2009, 131,
10822.
(11) For examples of palladium-catalyzed [1,3] rearrangement, see: (a)
Trost, B. M.; Runge, T. A.; Jungheim, L. N. J. Am. Chem. Soc. 1980, 102,
2840. (b) Tsuji, J.; Kobayashi, Y.; Kataoka, H.; Takahashi, T. Tetrahedron
Lett. 1980, 21, 1475. (c) Evans, P. A.; Brandt, T. A.; Robinson, J. E.
Tetrahedron Lett. 1999, 40, 3105. (d) Langer, P.; Holtz, E. Angew. Chem.,
Int. Ed. 2000, 39, 3086. (e) Ghobsi, A.; Hacini, S.; Wavrin, L.; Gaudel-
Siri, A.; Corbe`res, A.; Nicolas, C.; Bonne, D.; Viala, J.; Rodriguez, J. Eur.
(8) For reviews of 3,3-disubstituted oxindole synthesis, see: (a) Marti,
C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209. (b) Zhou, F.; Liu, Y.-
L.; Zhou, J. AdV. Synth. Catal. 2010, 352, 1381.
(9) Miura, T.; Toyoshima, T.; Ito, Y.; Murakami, M. Chem. Lett. 2009,
38, 1174.
J. Org. Chem. 2008, 4446
.
(10) For reviews of [1,3] rearrangement from oxygen to carbon, see:
(a) Meek, S. J.; Harrity, J. P. A. Tetrahedron 2007, 63, 3081. (b)
(12) For reviews on palladium-catalyzed transformations of benzylic
derivatives, see: (a) Lie´gault, B.; Renaud, J.-L.; Bruneau, C. Chem. Soc.
ReV. 2008, 37, 290. (b) Kuwano, R. Synthesis 2009, 1049.
Nasveschuk, C. G.; Rovis, T. Org. Biomol. Chem. 2008, 6, 240
.
Org. Lett., Vol. 12, No. 20, 2010
4585

rearrangement of a benzyl group. We also carried out a
crossover experiment using the isolated 3-(alkoxyalkylide-
ne)oxindoles 3aa and 3dc, which was prepared from 4-
chloro-2-(1-hexynyl)phenyl isocyanate (1d) and 4-methyl-
benzyl alcohol (2c) (Scheme 2). Thus, a mixture of 3aa and
Table 2. Pd(0)-Catalyzed Cyclization/[1,3] Rearrangement
Reaction of 1 with Benzylic Alcohols 2a
Scheme 2. Crossover Experiment with 3aa and 3dc
entry
1
R1
2
Ar
4
yield (%)b
1
2
3
4
5
6
7
8
9
1a n-Bu
1a n-Bu
1a n-Bu
1a n-Bu
1a n-Bu
1a n-Bu
1b Ph
2c 4-Tol
2d 3-Tol
2e 2-Tol
4ac
4ad
4ae
75
73
73
76
63c
67d
68
74
76
2f
4-MeO-C6H4 4af
2g 4-NO2-C6H4
2h 3-pyridyl
2d 3-Tol
4ag
4ah
4bd
1b Ph
1c 3-thienyl 2a Ph
2f
4-MeO-C6H4 4bf
4ca
a Reactions conducted on a 0.2 mmol scale. b Isolated yield. c With 7.5
mol % of CpPd(π-allyl)/dppf. d With 2 equiv of 2h at 65 °C.
3dc was subjected to the same reaction conditions, and the
formation of the crossover products 4ac and 4da was
observed in addition to 4aa and 4dc.14 This result indicates
that facile dissociation and/or exchange of the stabilized
enolate anion occur with the intermediary (η3-benzyl)palla-
dium(II) complex C.
to the reaction with 1a in the presence of CpPd(π-allyl)/
dppf (toluene, 40 °C, 10 min), only the tandem product 6aa
was obtained in 59% yield (entry 1). The expected 3-(1-
(allyloxy)pentylidene)oxindole was not detected at all, sug-
gesting that the [1,3] rearrangement step of an allyl group
was considerably faster than the cyclization step. This is
probably because the formation of (η3-allyl)palladium(II)
intermediate through oxidative addition onto palladium(0)
is much faster than the formation of (η3-benzyl)palladium(II)
intermediate. Various substituted allylic alcohols 5b-d were
suitable for the reaction with 1a and 1b, and the correspond-
ing products were produced in yields ranging from 71% to
79% (entries 2-5). It was noteworthy that the reactions with
5c and 5d proceeded regioselectively and the formation of
[3,3] rearrangement products (Claisen rearrangement prod-
ucts) was not observed. (E)- and (Z)-isomers of 2-hexen-1-
ol (5e) gave the same product 6ae having (E) configuration,
being supportive of a common (η3-allyl)palladium(II) inter-
mediate (entries 6 and 7). In the case of secondary alcohol
5f, allylation took place regioselectively at the less substituted
position to produce the product 6af (entry 8).
The results obtained with various combinations of 2-(alky-
nyl)aryl isocyanates 1 and benzylic alcohols 2 are listed in
Table 2. All three isomeric methylbenzyl alcohols (2c-e)
gave the corresponding products 4ac-ae in good yield
(entries 1-3). Benzylic alcohols 2f and 2g having electron-
donating and -withdrawing substituents as well as 3-pyridi-
nylmethanol (2h) were competent substrates for the tandem
reaction (entries 4-6). Aryl groups were also tolerated as
the R1 substituent at the alkyne terminus of 1 (entries 7-9).
The asymmetric version was attempted by using 1b and
2d as the substrates. Although various chiral ligands were
examined, only moderate chiral induction was attained. For
example, (+)-4bd was obtained in 61% isolated yield with
38% ee when the ferrocene-type ligand (S,S)-f-Binaphane15
was used (eq 3).
Interestingly, when the reaction of 1a with allyl alcohol
(5a, 20 equiv) was carried out for a longer period of time
(12 h), N-allylated oxindole 7aa was formed as the major
product (Table 4). The isolated oxindole 6aa was subjected
to a reaction with allyl alcohol (5a) in the presence of the
same palladium catalyst, and 7aa was obtained in 94%
yield.16 This reaction involved three mechanistically distinct
transformations (cyclization/[1,3] rearrangement/N-allyla-
tion), all catalyzed by a single palladium complex. The
reaction of 1a with allylic alcohols 5b and 5c for 12 h gave
We next used allylic alcohols instead of benzylic alcohols
(Table 3). When allyl alcohol (5a, 10 equiv) was subjected
(13) For examples of benzylation reactions through (η1-benzyl or η3-
benzyl)palladium(II) intermediates, see: (a) Legros, J.-Y.; Fiaud, J.-C.
Tetrahedron Lett. 1992, 33, 2509. (b) Kuwano, R.; Kondo, Y.; Matsuyama,
Y. J. Am. Chem. Soc. 2003, 125, 12104. (c) Narahashi, H.; Shimizu, I.;
Yamamoto, A. J. Organomet. Chem. 2007, 693, 283. (d) Fields, W. H.;
Chruma, J. J. Org. Lett. 2010, 12, 316. (e) Mukai, T.; Hirano, K.; Satoh,
T.; Miura, M. Org. Lett. 2010, 12, 1360. (f) Torregrosa, R. R. P.;
Ariyarathna, Y.; Chattopadhyay, K.; Tunge, J. A. J. Am. Chem. Soc. 2010,
132, 9280.
(16) For catalytic substitution reactions of allylic alcohols, see: (a) Qu¨,
J.; Ishimura, Y.; Nagato, N. Nippon Kagaku Kaishi 1996, 256. (b) Ozawa,
F.; Okamoto, H.; Kawagishi, S.; Yamamoto, S.; Minami, T.; Yoshifuji, M.
J. Am. Chem. Soc. 2002, 124, 10968. (c) Ohshima, T.; Miyamoto, Y.;
Ipposhi, J.; Nakahara, Y.; Utsunomiya, M.; Mashima, K. J. Am. Chem.
Soc. 2009, 131, 14317, and references cited therein.
(14) See the Supporting Information for details.
(15) (S,S)-f-Binaphane ) 1,1′-bis[(S)-4,5-dihydro-3H-binaphtho[2,1-c:
1′,2′-e]phosphepino]ferrocene, see: Xiao, D.; Zhang, X. Angew. Chem., Int.
Ed. 2001, 40, 3425.
4586
Org. Lett., Vol. 12, No. 20, 2010

Table 3. Pd(0)-Catalyzed Cyclization/[1,3] Rearrangement
Reaction of 1 with Allylic Alcohols 5a
Table 4. Pd(0)-Catalyzed Cyclization/[1,3] Rearrangement/
Allylation Reaction of 1a with Allylic Alcohols 5a
a Reactions conducted on a 0.2 mmol scale. b Isolated yield. c With 20
equiv of 5a. d With 10 equiv of 5b and 5c.
In summary, a new tandem process integrating a
cyclization step and a [1,3] rearrangement step has been
developed. The produced 3,3-disubstituted oxindoles are
an important class of heterocycles often found in naturally
occurring and biologically active molecules. Furthermore,
three steps of cyclization/[1,3] rearrangement/N-allylation
are sequentially catalyzed by a single catalyst system.
Acknowledgment. This work was supported in part by
MEXT (Grant-in-Aid for Scientific Research on Innovative
Areas, No. 22106520). T.T. is grateful for a Research
Fellowship from JSPS for Young Scientists.
Supporting Information Available: Experimental details
and spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Reactions conducted on a 0.2 mmol scale. b Isolated yield. c E:Z )
>20:1. d E:Z ) 1:17. e With 20 equiv of 5f for 3 h.
the corresponding N-allylated products 7ab and 7ac in 71%
OL101892B
and 70% yield, respectively.
Org. Lett., Vol. 12, No. 20, 2010
4587