A new H2O2/acid anhydride system for the iodoarene-catalyzed C-C bond-forming reactions of phenols

Article abstract of DOI:10.1021/ol801321f

(Chemical Equation Presented) We have succeeded in the first versatile iodoarene-catalyzed C-C bond-forming reactions by development of a new reoxidation system at low temperatures using stoichiometric bis(trifluoroacetyl) peroxide A in 2,2,2-trifluoroethanol (TFE). The catalytic system supplies a wide range of substrates and functional availabilities sufficient to be used in the key synthetic process of producing biologically important Amaryllidaceae alkaloids.

Full text of DOI:10.1021/ol801321f

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3559-3562
A New H2O2/Acid Anhydride System for
the Iodoarene-Catalyzed C-C
Bond-Forming Reactions of Phenols
Toshifumi Dohi,† Yutaka Minamitsuji, Akinobu Maruyama, Satoshi Hirose, and
Yasuyuki Kita*,†
Graduate School of Pharmaceutical Sciences, Osaka UniVersity,
1-6 Yamada-oka, Suita, Osaka, 565-0871 Japan
kita@phs.osaka-u.ac.jp
Received June 11, 2008
ABSTRACT
We have succeeded in the first versatile iodoarene-catalyzed C-C bond-forming reactions by development of a new reoxidation system at low
temperatures using stoichiometric bis(trifluoroacetyl) peroxide A in 2,2,2-trifluoroethanol (TFE). The catalytic system supplies a wide range of
substrates and functional availabilities sufficient to be used in the key synthetic process of producing biologically important Amaryllidaceae
alkaloids.
The catalytic utilization of hypervalent iodine reagents is
increasing in importance, with recent growing interest in the
development of environmentally benign synthetic transfor-
mations.1 After the reports of the catalytic reactions using
m-chloroperbenzoic acid (m-CPBA) as the terminal oxi-
dant,2–4 applications of a variety of useful organoiodine
compounds as catalysts that are recyclable2,4a,b and chiral4c
have significantly increased. In this way, the catalytic concept
surely contributes to the progress of hypervalent iodine
chemistry in organic synthesis.5
On the other hand, the most important type of reactions,
the carbon-carbon bond forming reactions, has never been
catalytically accomplished under these conditions. The C-C
bond-forming methods mediated by hypervalent iodine
reagents significantly comprise some key steps in construct-
ing the structures of various biologically active compounds
and natural products.6 To expand the scope of the catalytic
strategy, it is highly important to survey alternative effective
terminal oxidants enabling the generation of active iodine(III)
species under mild conditions. In this paper, the C-C bond-
forming transformations are made catalytic by establishing
† Present address: College of Pharmaceutical Sciences, Ritsumeikan
University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan.
(1) (a) Dohi, T.; Kita, Y. Kagaku 2006, 61, 68. (b) Richardson, R. D.;
Wirth, T. Angew. Chem., Int. Ed. 2006, 45, 4402.
(2) (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, 45,
1224
.
(3) Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamato, K.
J. Am. Chem. Soc. 2005, 127, 12244
.
10.1021/ol801321f CCC: $40.75
Published on Web 07/11/2008
2008 American Chemical Society

a new reoxidation system using the H2O2/acid anhydride, in
which the active hypervalent iodine(III) species is rapidly
generated in situ at low temperatures. The catalytic reactions
of phenols 2a-g furnished the key spiro C-C bonds of the
galanthamine-type Amaryllidaceae alkaloids,6a,b and hence,
it is, we believe, the first successful example utilizing this
catalytic concept for the key steps of natural product
syntheses (eq 1).
Table 1. Effect of the Oxidant, Solvent, and TFAA
entry
oxidanta
solvent
TFAA (equiv)
yieldb (%)
1c,d
2d
3d
4
5
6
m-CPBA
m-CPBA
m-CPBA
urea·H2O2
urea·H2O2
urea·H2O2
CH2Cl2
CH2Cl2
TFE
TFE
TFE
TFE
TFE
TFE
none
none
none
4
6
8
8
8
36
17
45
8
60
70
16
28
e
7
8
H2O2 (35%)
Na2O2
Amaryllidaceae alkaloids are known to have diverse
pharmacologic actions and potentially new biological activi-
ties.7,8 Our challenge was the realization of the catalytic
oxidative spirocyclization of 2a to 3a, as a landmark and
versatile catalytic C-C bond-forming process (Table 1, eq
2). Relying on our previous reoxidation conditions of
iodoarenes using m-CPBA as the terminal oxidant,2 we first
developed the reaction at room temperature in CH2Cl2 which
only resulted in the low yield of 3a along with the
decomposition of a large amount of 2a (Table 1, entry 1).
Since the conversion of iodobenzene to the corresponding
iodine(III) forms was possible, we assumed that the decom-
position of 2a was due to the involvement of some unstable
intermediates for 3a, which are too reactive at ambient
temperature.9 By lowering the reaction temperature the yield
a 2 equiv relative to 2a. b Isolated yield. c Reaction was performed at
room temperature. d CF3CO2H (1 equiv) was added. e 4 equiv of urea·H2O2
was used.
may be improved, but m-CPBA is not the best oxidant for
the generation of iodine(III) species from iodoarenes at low
temperatures due to issues of reactivity and solubility
regarding the solvents (Table 1, entries 2 and 3).
Trifluoroperacetic acid, CF3CO3H, is a powerful oxidant
that can oxidize iodoarenes to the corresponding iodine(III)
at lower temperatures.10 On the basis of the recent reports
on the in situ preparation method of CF3CO3H,10c we
investigated the catalytic reactions at low temperature under
several modified conditions. In this screening, CF3CO3H
itself was also not suitable for the catalytic process in 2,2,2-
trifluoroethanol (TFE) (Table 1, entry 4). Meanwhile, we
noted that the increasing ratio of TFAA relative to H2O2 led
to an improvement in the yield of 3a, even though the amount
of the oxidant decreased (Table 1, entries 5 and 6). This
interesting outcome is rationalized by considering the forma-
tion of the alternative oxidant, bis(trifluoroacetyl) peroxide
A (Scheme 1).11 Thus, the treatment of H2O2 with excess
(4) Other examples: (a) Yamamoto, Y.; Kawano, Y.; Toy, P. H.; Togo,
H. Tetrahedron 2007, 63, 4680. (b) Akiike, J.; Yamamoto, Y.; Togo, H.
Synlett 2007, 2168. (c) Richardson, R. D.; Page, T. K.; Altermann, S.;
Paradine, S. M.; French, A. N.; Wirth, T. Synlett 2007, 538
.
(5) For recent reviews of hypervalent iodine chemistry, see: (a) Stang,
P. J.; Zhdankin, V. V. Chem. ReV. 1996, 96, 1123. (b) Kita, Y.; Takada,
T.; Tohma, H. Pure Appl. Chem. 1996, 68, 627. (c) Varvoglis, A.
HyperValent Iodine in Organic Synthesis; Academic Press: San Diego, 1997.
(d) Ochiai, M. In Chemistry of HyperValent Compounds; Akiba, K., Ed.;
Wiley-VCH: New York, 1999; Chapter 12. (e) Koser, G. F. Aldrichim. Acta
2001, 34, 89. (f) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002, 102, 2523.
(g) HyperValent Iodine Chemistry; Wirth, T., Ed,; Springer-Verlag: Berlin,
Heidelberg, 2003. (h) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656. (i)
Moriarty, R. M. J. Org. Chem. 2005, 70, 2893
.
(6) (a) Studies in our laboratory: Kita, Y.; Takada, T.; Gyoten, M.;
Tohma, H.; Zenk, M. H.; Eichhorn, J. J. Org. Chem. 1996, 61, 5857. (b)
Kita, Y.; Arisawa, M.; Gyoten, M; Nakajima, M.; Hamada, R.; Tohma, H.;
Takada, T. J. Org. Chem. 1998, 63, 6625. (c) Kita, Y.; Tohma, H.; Inagaki,
M.; Hatanaka, K.; Yakura, T. J. Am. Chem. Soc. 1992, 114, 2175. (d)
Tohma, H.; Harayama, Y.; Hashizume, M.; Iwata, M.; Egi, M.; Kita, Y.
Scheme 1. Formation of Bis(trifluoroacetyl) Peroxide A
Angew. Chem., Int. Ed. 2002, 41, 348
.
(7) Recent reports: (a) Marco-Contelles, J.; Carreiras, M. C.; Rodriguez,
C.; Villarroya, M.; Garcia, A. G. Chem. ReV. 2006, 106, 116. (b) McNulty,
J.; Nair, J. J.; Codina, C.; Bastida, J.; Pandey, S.; Gerasimoff, J.; Griffin,
C. Phytochemistry 2007, 68, 1068. (c) Unver, N. Phytochem. ReV. 2007, 6,
125
.
(8) For synthetic studies using hypervalent iodine reagents, see ref
6a,b and others: (a) Kodama, S.; Takita, H.; Kajimoto, T.; Nishide, K.;
Node, M Tetrahedron 2004, 60, 4901. (b) Kodama, S.; Hamashima, Y.;
Nishide, K; Node, M. Angew. Chem., Int. Ed. 2004, 43, 2659. (c) Baxendale,
I. R.; Deeley, J.; Griffiths-Jones, C. M.; Ley, S. V.; Saaby, S.; Tranmer,
TFAA led to the exclusive formation of anhydride A, which
was also supported by the calculations.11b Other screenings
(10) Preparation of PhI(OCOCF3)2 using trifluoroperacetic acid: (a)
Yagupolskii, L. M.; Maketina, I. I.; Kondratenko, N. V.; Orda, V. V.
Synthesis 1978, 835. (b) Zhdankin, V. V.; Scheuller, M. C.; Stang, P. J.
Tetrahedron Lett. 1993, 34, 6853. (c) Page, T. K.; Wirth, T. Synthesis 2006,
3153.
G. K. Chem. Commun. 2006, 24, 2566
.
(9) Formation of reactive phenoxenium ions was proposed in iodine(III)-
induced oxidations of phenols: (a) Moriarty, R. M.; Prakash, O. Org. React.
2001, 57, 327. (b) Ku¨rti, L.; Herczegh, P.; Visy, J.; Simonyi, M.; Antus,
S.; Pelter, A. J. Chem. Soc., Perkin Trans. 1 1999, 379. (c) Pelter, A.; Ward,
(11) (a) Sawada, H. Chem. ReV. 1996, 96, 1779. (b) Krasutsky, P. A.;
Kolomitsyn, I. V.; Carlson, R. M. Org. Lett. 2001, 3, 2997.
R. S. Tetrahedron 2001, 57, 273
.
3560
Org. Lett., Vol. 10, No. 16, 2008

of oxidants (Table 1, entries 7 and 8), solvents, and
temperatures did not lead to a further improvement in the
yield.
Table 3. C-C Bond-Forming Spirocyclization of Phenols 2a
Once the basic conditions were established, we next tried
to determine the appropriate iodoarene catalyst for the
transformations (Table 2). For the loading of iodobenzene
Table 2. Comparison of the Catalytic Activitiesa
a Reactions were performed under the conditions of entry 6 in Table 1.
The percentages indicate the isolated yield of 3a.
ranging from 10 mol % to 1 mol %, the catalyst turnover
numbers (TONs) were 7-16 times (Table 2, entry 1).
4-Iodotoluene 1a, the most efficient catalyst for the C-O
and C-N bond-forming spirocyclizations of the phenols,2
was an inferior catalyst in this case because of the low
solubility of 1a in TFE at the lower temperature (Table 2,
entry 2). Therefore, the use of an affinity catalyst 1b to TFE
is critical for enhancing the TON (Table 2, entry 3). The
para-substituted 1b well maintained the catalytic activities
during the reactions over iodobenzene, and the TON of the
catalyst reached 44 s.
The optimized catalytic conditions with 1b allowed the
versatile C-C bond-forming method for constructing a wide
range of spirodienone structures (Table 3).12 The catalytic
reactions successfully offered a family of valuable nitrogen-
containing seven-membered ring products 3a-g in moderate
to good yields (Table 3, entries 1-7). In these cases,
compatibility of the highly functionalized substrates should
be noted. Even substrate 2g8b having an oxidizable poly
oxygenated ring and active benzyl position afforded the
tetracyclic 3g in a moderate yield, despite the need for
the higher loading of 1b (Table 3, entry 7). Similar to the
Amaryllidaceae alkaloid precursors, the alkyl-tethered prod-
a Performed using 1b (10 mol %), urea·H2O2 (2 equiv), and TFAA (8
equiv) in TFE at -40 to -10 °C otherwise noted. b 20 mol % of 1b was
used. c Isolated yield based on the reacted 2j.
ucts 3h and 3i were obtained using the catalytic method
(Table 3, entries 8 and 9). Thus, it is a general method for
the production of five- to seven-membered spirodienones by
forming spiro C-C bonds. Moreover, the enamino ketone
structures also work as the nucleophilic partner. The phenol
2j, having an enamino ketone tether, under these conditions
afforded 3j, a model substrate of the discorhabdin marine
alkaloids,6c,d in 46% yield with the 53% recovery of 2j (Table
3, entry 10). In all cases, the successful transformations
depended on both the selection of the terminal oxidant, TFE
solvent, and the temperatures.
(12) General Experimental Procedure. To a stirred solution of
urea·H2O2 (94 mg, 1 mmol) in TFE (5 mL) was added TFAA (0.60 mL, 4
mmol) at -40 °C. After 30 min, 4-fluoroiodobenzene 1b (11.1 mg, 0.05
mmol) and phenol 2a (191.7 mg, 0.5 mmol) were quickly added, and the
temperature was allowed to warm slowly toward -10 °C. After addition
of AcOEt, the reaction mixture was quenched with aqueous satd sodium
thiosulfate and washed with satd NaHCO3 aqueous. The aqueous layer was
extracted using AcOEt, and the combined organic phase was washed with
brine and then dried over anhydrous Na2SO4. After evaporation of the
solvent, the residue was purified by column chromatography on silica gel
(eluent: hexane/AcOEt ) 1/1, ca. 300 mL) to give 3a in 76% yield (144.6
mg, 0.38 mmol) as colorless crystals. The spectroscopic data (1H and 13C
NMR, IR) and mp were consistent with the values from a previous report.6a
Org. Lett., Vol. 10, No. 16, 2008
3561

When the reaction was performed in the absence of the
phenols 2, detection of the active catalytic species in the
reactions was anticipated. After the reaction of 1b at -10
°C for 2 h in TFE, the solvent was removed and the resulting
residue was subjected to a 1H NMR analysis in CDCl3. The
1H NMR observation indicated the presence of
4-FC6H4I(OCOCF3)2 B13 as the major species.14 At this stage,
we assumed that the active catalytic species in TFE is B
itself or its derivatives including the solvent as a ligand
(Scheme 2).15
causing any undesired substrate oxidation. The selection of
bis(trifluoroacetyl) peroxide A seems to be best suited for
the selective oxidation of iodine(I) to the iodine(III) states
at low temperatures. The formed iodine(III) species B then
reacts with the phenolic oxygen of 2a to produce the type C
phenoxy iodine(III) intermediates. The liberation of 1b results
in the formation of the phenoxenium ion D,9 which is
stabilized by the polar cation-stabilizing solvent, TFE. At
low temperatures, the reactive cationic intermediate would
be selectively trapped by the internal π-nucleophile at the
ipso-carbon, to give the final spirocyclized product 3a.
Therefore, the appropriate choices of the terminal oxidant,
solvent, and reaction temperature are of considerable
significance.
Scheme 2. A Plausible Catalytic Cycle
In conclusion, we have established new catalytic conditions
at low temperatures involving the bis(trifluoroacetyl) per-
oxide A as a real stoichiometric oxidant for the first effective
iodoarene-catalyzed C-C bond forming reactions of phenols
2 that form a series of spirocyclic dienones 3 including the
key intermediates for the biologically active Amaryllidaceae
alkaloids.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research (A) and for Encour-
agement of Young Scientists and a grant for Scientific
Research on Priority Areas “Advanced Molecular Transfor-
mations of Carbon Resources” from the Ministry of Educa-
tion Culture, Sports, Science, and Technology, Japan. T.D.
also acknowledges support from the Industrial Technology
Research Grant Program from the New Energy and Industrial
Technology Development Organization (NEDO) of Japan
and the Japan Chemical Innovation Institute (JCII).
Supporting Information Available: The experimental
1
procedures and detailed spectroscopic data containing H
The catalytic cycle should be initiated by the generation
of the catalytic iodine(III) species B from 1b by the action
of a stoichiometric oxidant under suitable conditions not
NMR charts of the new compounds and products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL801321F
(13) Kazmierczak, P.; Skulski, L. Molecules 2002, 7, 810.
(14) In the control experiment, 4-FC6H4I(OCOCF3)2 B was isolated in
a nearly quantitative yield after evaporation of TFE, although a trace amount
of the µ-oxo-bridged iodine(III) dimer [4-FC6H4I(OCOCF3)]2O B′ was also
detected. See the Supporting Information, Chart 1.
(15) On the iodine(III) species including alcohol solvents as ligands:
(a) Schardt, B. C.; Hill, C. L. Inorg. Chem. 1983, 22, 1563. (b) Silva, L. F.,
Jr.; Lopes, N. P. Tetrahedron Lett. 2005, 46, 6023. See also ref 5i.
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