New synthesis of spirocycles by utilizing in situ forming hypervalent iodine species

Article abstract of DOI:10.1039/c1ob06199b

A very effective spirocyclization procedure for installing nucleophiles (Nu = N₃, NO₂, SCN, SO₂Tol, and halogens) via iodonium(iii) salts has been developed using the combination of iodoarene and mCPBA. The high-yielding s

Full text of DOI:10.1039/c1ob06199b

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New synthesis of spirocycles by utilizing in situ forming hypervalent iodine
species†‡
Toshifumi Dohi, Tomofumi Nakae, Yohei Ishikado, Daishi Kato and Yasuyuki Kita*
Received 19th July 2011, Accepted 16th August 2011
DOI: 10.1039/c1ob06199b
A very effective spirocyclization procedure for installing
nucleophiles (Nu = N3, NO2, SCN, SO2Tol, and halogens) via
iodonium(III) salts has been developed using the combination
of iodoarene and mCPBA. The high-yielding syntheses of
the cyclohexadienone-type spirocyclic compounds 2 having
varied functionalities in the skeletons have been achieved from
the aryl alkynes 1 with the optimized bis(iodoarene) 3h.
There exists a number of spirocyclic compounds in nature, and
these consist of classes that have received significant interest in
recent years as the privileged structures of some pharmaceuticals,
organic materials for optoelectronics and other applications,
chiral ligands and catalysts for synthetic uses, etc.1 Due to their
useful biological activities and physical properties in combination
with their unique structural aspects, many synthetic chemists
inspired by biosynthetic hypotheses devoted themselves to develop
valuable routes to these spirocyclic compounds focusing on the
spiroannulation processes,2,3 among which the ipso-cyclization of
aryl alkynes triggered by electrophiles, such as NBX (where X = I,
Br, Cl), X2 (X = I, Br) and CuX (X = I, Br, SCN) combined
with oxidants, has been reported by several groups.4 These are
attractive as one of the expeditious approaches to construct
the functionalized spirocyclohexadienone-type structures. These
known methods, namely, the electrophilic ipso-cyclizations, can
indeed furnish the desired spiro carbon–carbon bonds with the
accompanying introduction of halogens4 or thiocyanate (up to
59%)4d to the products. However, the limitation of the electrophiles
that can be used to induce effective spirocyclizations restricted the
kind of functionalities installed in the final spirocyclic skeletons.
Herein, this paper describes a very effective and facile method
for synthesizing spirocyclic compounds with functionality from
aryl alkynes by the continuous involvement of hypervalent iodine
chemistry during the course of the reaction.
Scheme 1 Strategy to functionalized spirocycles 2 from aryl alkynes 1 via
iodonium salts (L = ligand).
m-chloroperbenzoic acid (mCPBA) in the presence of acid (HA),5
(ii) alkyne activation by the electrophilic iodines6 for inducing ipso-
cyclization of aryl alkynes 1 directed by their methoxy group at
the aryl ring, forming the spirocyclized iodonium(III) salts, and
(iii) final installation of nucleophiles by reductive coupling7 of the
formed salts to produce the functionalized spirocyclic compounds
2. The introduction of the hypervalent onium salts as intermediates
for both the effective spirocyclization and facile attachment of
the functionalities is a significant characteristic of the strategy.
Only the successful completion of all steps should furnish two
new bonds to the alkyne groups of the substrates 1, forming
the spiro carbon–carbon and carbon–nucleophile bonds of the
spirocyclic products 2 in good yield. This approach was, in fact,
partially realized using the prepared hypervalent iodine reagent,
but the yields were sometimes unsatisfactory (for example, 77%
yield at best for azidative spirocyclization) except for producing
iodinated spirocycles.8 Further elaboration to the onium salt-
mediated approach is possible, thus we present the idea utilizing
Our approach to the spirocyclization of aryl alkynes 1 which can
permit installation of various functionalities is depicted in Scheme
1. It contains the following three key steps: (i) in situ generation
of cationic hypervalent iodine species from iodoarene 3 using
College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihi-
gashi, Kusatsu, Shiga, 525-8577, Japan. E-mail: kita@ph.ritsumei.ac.jp
† This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
‡ Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob06199b
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Org. Biomol. Chem., 2011, 9, 6899–6902 | 6899
©

Table 1 Optimization of the Strategya
in situ forming hypervalent iodine species and the results of
the evaluation of iodoarenes for producing the functionalized
spirocycles 2.
We initially evaluated the synthetic strategy using the simple
iodobenzene 3a, mCPBA, p-TsOH monohydrate, and butyl-
ammonium azide (Bu4N+N3 ) for the aryl alkyne 1a4b–d (eqn 1),
-
which gave an unsatisfactory result regarding the formation of
2a/N3 having the azide functionality (Table 1, entry 1), despite
consumption of the starting 1a. Other typical iodoarenes 3b–g
(Fig. 1) were also treated using the same procedure, only yielding
the desired spirocyclic compound 2a/N3 at best with a 67% yield
(entries 2–7), even when testing other acids, azide sources, and
modified conditions. The NMR observations and TLC monitoring
of the reaction mixtures revealed that these iodoarenes 3a–g
had some problems regarding the alkyne activation for the ipso-
cyclization step (Scheme 1, step (ii) and/or the generation of the
hypervalent iodine species by the action of mCPBA (step (i)). Thus,
further candidates for the spirocyclization of 1a could not be found
in our attempts to use mono-iodoarenes.
Entry
Iodoarene (3)
Product
Yieldb (%)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
2a/N3
2a/N3
2a/N3
2a/N3
2a/N3
2a/N3
2a/N3
37
66
67
n.d.
n.d.
n.d.
n.d.
3g
8
9
10
11
12
13
3h
3h
3i
2a/N3
2b/N3
2b/N3
2b/N3
2b/N3
2b/N3
92
99
82
33
n.d.
90
3j
3k
3l
a Each reaction was performed at room temperature by adding 1a or 1b to
a pre-mixed trifluoroethanol solution including iodoarene 3a–g (1.1 equiv.
relative to 1a) or bis(iodoarene) 3h–l (0.55 equiv. relative to 1a or 1b), wet
mCPBA (1.1 equiv.), and p-TsOH·H2O (2 equiv.) for 3 h, then treated with
Bu4N+N3- (1.1 equiv.) in chloroform overnight. b Isolated yield of the pure
product 2a/N3 or 2b/N3. n.d. = not determined (less than 5% yield of
2a/N3 or 2b/N3 formation).
Fig. 1 Screened iodoarenes 3a–l.
The optimized iodoarene 3h obtained by this screening could
expand the versatility of the strategy in terms of the range
of the nucleophiles and usable substrates 1.12 Table 2 includes
the results of using an extensive number of ring- and tether-
modified aryl alkynes 1c–k that could verify the generality of
the new synthetic method. As well as the construction of five-
and six-membered para-spirocyclized cyclohexadienones 2a–h/N3
(Tables 1 and 2), application to the valuable ortho-spirolactone
structures that are frequently seen in some natural products13 is
acceptable based on the demonstrations of the aryl alkynes 1i–k
(entries 7–9). In addition to the azide functionality, a series of
nitrogen, sulfur, and halogen nucleophiles participated effectively
in the spirocyclization of 1b and its analogues 1l and 1m having
different alkynes (Scheme 2).14,15 The yields were dramatically
increased when compared to the previous results8 using the
prepared reagent based on the bis(iodoarene) 3i.
Regarding the iodoarene, the ortho-diiodinated biaryl structure
should be essential for developing the transformations with good
performance. The minor manipulations of the substituents in the
bis(iodoarene)s would contribute to not only the ipso-cyclization
and the formation of the spirocyclized iodonium salts, but also
to the final substitution event by the nucleophiles at the alkenyl
moieties (see Scheme 1). Although the details of the explanation
are still under consideration, the use of 3h is important to suppress
contamination of the iodinated spirocycles that would be formed
by cleavage of the reagent Caryl–I(III) bonds in the last step. For
example, such a chemoselective issue16 might be associated with
In clear contrast to the mono-iodoarenes 3a–g, some
bis(iodoarene)s having the ortho-iodinated biaryl structures
showed very promising behavior for the ipso-cyclization and
iodonium salt-mediated strategy. We could confirm the formal
azidative spirocyclization of either 1a or 1b4b–d leading to the
spirocyclic compounds 2a and 2b in excellent yields when using
the bis(iodoarene) 3h (entries 8 and 9). The use of 0.55 equiv. of
3h was possible as both the iodine atoms can participate in the
alkyne transformations. The ortho-substituents R2 of the bis 3i–
k,8,9 which should limit the conformation of the biaryl structures,
decreased the reaction efficiency (entries 10–12). Among the
screened bis(iodoarene)s 3h–l, the best result of over 99% product
yield was obtained using the bis 3h for the aryl alkyne 2b
(entry 9).10 As the generation and formation of the iodonium
species and intermediate salts would be facilitated by the aid
of fluoroalcohols,11 the reactions were typically carried out by
adding 1b over 15 min to a pre-mixed trifluoroethanol (TFE)
solution including the bis(iodoarene) 3h, wet mCPBA (ca. 69%
purity, 1.1 equiv.), and p-TsOH monohydrate (2 equiv.). After
3 h, Bu4N+N3 (1.1 equiv.) in chloroform was added dropwise.
-
The ideal conditions for the azidative spirocyclization were thus
determined regarding the reagent combination and solvents,
though the optimized bis(iodoarene) 3h could provide flexibility
for the possible azide sources (Bu4N+N3 , NaN3, and TMSN3),
-
acids (methanesulfonic acid, triflic acid, etc.), and solvents (hex-
afluoroisopropanol, acetonitrile, etc.) to give similar results.
6900 | Org. Biomol. Chem., 2011, 9, 6899–6902
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Table 2 Scope of the substrates 1 in the azidative spirocyclization using
the bis(iodoarene) 3ha
Table 2 (Contd.)
Entry
9
Aryl alkyne (1)
Spiro product (2/N3)
Yieldb
99%
Entry Aryl alkyne (1)
Spiro product (2/N3)
Yieldb
a Performed using the reagent 3h and according to the conditions optimized
in Table 1. b Isolated yield based on the aryl alkyne 1 used.
1
2
3
4
R(1) = OMe, R(2) = H,
R(1) = OMe, R(2) = H,
2c/N3
86%
97%
88%
99%
1c
R(1) = H, R(2) = Cl,
R(1) = H, R(2) = Cl,
2d/N3
1d
R(1) = H, R(2) = tBu,
R(1) = H, R(2) = tBu,
2e/N3
1e
5
74%
Scheme 2 Introduction of other types of nucleophiles.
In summary, we have established a new and reliable one-pot
procedure for synthesizing the spirocyclic compounds 2 having
varied functionalities from the aryl alkynes 1 by utilizing the
results of hypervalent iodine chemistry. The fine tuning of the
bis(iodoarene) 3h in this strategy could permit significant increases
of the product yield. Thus, this new strategy could provide easy
access to a variety of functionalized spirocyclic motifs, which were
hardly obtainable by other spirocyclization methods, and might
serve as a platform for some functionalized natural products and
other useful molecules. The catalytic versions of the new synthetic
transformations by the bis(iodoarene) will be described in due
course.17
6
60%
7
99%
Acknowledgements
This work was partially supported by Grant-in-Aid for Scientific
Research (A) from the Japan Society for the Promotion of
Science (JSPS) and Ritsumeikan Global Innovation Research
Organization (R-GIRO) project. T.D. also acknowledges financial
support from the Industrial Technology Research Grant Program
from the New Energy and Industrial Technology Development
Organization (NEDO) of Japan and The Sumitomo Foundation.
8
94%
Notes and references
1 For utilities and naturally occuring spirocyclic compounds, see the
following reviews: (a) C. H. Heathcock, S. L. Graham, M. C. Pirrung,
F. Plavac and C. T. White, In The Total Synthesis of Natural Products,
J. Apsimon, ed., Wiley-Interscience, New York, 1983; vol. 5, pp 264-
313; (b) M. Hesse, Alkaloide, Verlag Helvetica Chimica Acta, Zu¨rich,
Switzerland, 2000; (c) H. Greger, Planta Med., 2006, 72, 99; (d) V. I.
the spirocyclizations especially in the case of the bis(iodoarene) 3j
having the electron-withdrawing group (see Table 1).
This journal is
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Org. Biomol. Chem., 2011, 9, 6899–6902 | 6901
©

Minkin, Chem. Rev., 2004, 104, 2751; (e) R. Pudzich, T. Fuhrmann-
Lieker and J. Salbeck, Adv. Polym. Sci., 2006, 199, 83; (f) T. P. I. Saragi,
T. Spehr, A. Siebert, T. Fuhrmann-Lieker and J. Salbeck, Chem. Rev.,
2007, 107, 1011; (g) K. Ding, Z. Han and Z. Wang, Chem.–Asian J.,
2009, 4, 32.
2 The updated synthetic reviews: (a) S. Kotha, A. C. Deb, K. Lahiri and
E. Manivannan, Synthesis, 2009, 165; (b) S. Rosenberg and R. Leino,
Synthesis, 2009, 2651; (c) S. Rodriguez and P. Wipf, Synthesis, 2004,
2767; (d) C. Cismas, A. Terec, S. Mager and I. Grosu, Curr. Org. Chem.,
2005, 9, 1287.
3 For the studies in our laboratory using hypervalent iodine reagents, see
the selected examples: (a) Y. Tamura, T. Yakura, J. Haruta and Y. Kita,
J. Org. Chem., 1987, 52, 3927; (b) Y. Kita, H. Tohma, M. Inagaki, K.
Hatanaka and T. Yakura, J. Am. Chem. Soc., 1992, 114, 2175; (c) Y.
Kita, T. Takada, M. Gyoten, H. Tohma, M. H. Zenk and J. Eichhorn,
J. Org. Chem., 1996, 61, 5857; (d) M. Arisawa, N. G. Ramesh, M.
Nakajima, H. Tohma and Y. Kita, J. Org. Chem., 2001, 66, 59; (e) H.
Tohma and Y. Kita, Top. Curr. Chem., 2003, 224, 209 and references
cited therein.
4 (a) T. R. Appel, N. A. M. Yehia, U. Baumeister, H. Hartung, R. Kluge,
D. Stro¨hl and E. Fangha¨nel, Eur. J. Org. Chem., 2003, 47; (b) X. Zhang
and R. C. Larock, J. Am. Chem. Soc., 2005, 127, 12230; (c) B.-X. Tang,
D.-J. Tang, S. Tang, Q.-F. Yu, Y.-H. Zhang, Y. Liang, P. Zhong and
J.-H. Li, Org. Lett., 2008, 10, 1063; (d) B. X. Tang, Q. Yin, R. Y. Tang
and J. H. Li, J. Org. Chem., 2008, 73, 9008 and references therein.
5 (a) T. Dohi, A. Maruyama, M. Yoshimura, K. Morimoto, H. Tohma
and Y. Kita, Angew. Chem., Int. Ed., 2005, 44, 6193; (b) M. Ochiai, Y.
Takeuchi, T. Katayama, T. Sueda and K. Miyamato, J. Am. Chem. Soc.,
2005, 127, 12244; (c) R. D. Richardson and T. Wirth, Angew. Chem.,
Int. Ed., 2006, 45, 4402; (d) E. A. Merritt, V. M. T. Carneiro, L. F. Jr.
Silva and B. Olofsson, J. Org. Chem., 2010, 75, 7416.
8 Very recently, we reported the isolation of new iodonium salts formed
by the spirocyclization, in which the possibility of a similar one-
pot synthesis was described for specific cases. The utilization and
optimization of the in situ generated hypervalent iodine species from
iodoarenes were not treated in that study. See: T. Dohi, D. Kato, R.
Hyodo, D. Yamashita, M. Shiro and Y. Kita, Angew. Chem., Int. Ed.,
2011, 50, 3784.
9 The bis(iodoarene)s also showed the high catalytic efficiencies in the
spirocyclization of the N-methoxy aryl amides. See: T. Dohi, N.
Takenaga, K.-I. Fukushima, T. Uchiyama, D. Kato, M. Shiro, H.
Fujioka and Y. Kita, Chem. Commun., 2010, 46, 7697.
10 Other regioisomeric bis(iodoarene)s of 3h were less effective than the
2,2¢-derivative in this transformation.
11 The fluoroalcohols can accelerate generation of hypervalent iodine(III)
species from iodoarenes and formation of the diaryliodonium salts.
See: (a) T. Dohi, A. Maruyama, Y. Minamitsuji, N. Takenaga and Y.
Kita, Chem. Commun., 2007, 1224; (b) T. Dohi, M. Ito, K. Morimoto,
Y. Minamitsuji, N. Takenaga and Y. Kita, Chem. Commun., 2007,
4152; (c) T. Dohi, N. Yamaoka and Y. Kita, Tetrahedron, 2010, 66,
5775.
12 The use of excess amounts of the nucleophiles (~5 equiv.) was possible in
order to avoid introduction of mCPBA to the final spirocyclic products,
though it was a very minor competitive path.
13 For selected examples of natural product syntheses containing the
related ortho-spirolactone structures, see: (a) K. Watanabe, Y. Iwata,
S. Adachi, T. Nishikawa, Y. Yoshida, S. Kameda, M. Ide, Y. Saikawa
and M. Nakata, J. Org. Chem., 2010, 75, 5573; (b) D. A. Henderson, P.
N. Collier, G. Pave, P. Rzepa, A. J. P. White, J. N. Burrows and A. G.
M. Barrett, J. Org. Chem., 2006, 71, 2434; (c) F. Konno, T. Ishikawa,
M. Kawahata and K. Yamaguchi, J. Org. Chem., 2006, 71, 9818; (d) C.
Cox and S. J. Danishefsky, Org. Lett., 2000, 2, 3493.
6 Formation of alkenylodonium salts by the oxygenations of alkynes:
(a) G. F. Koser, L. Rebrovic and R. H. Wettach, J. Org. Chem., 1981,
46, 4324; (b) L. Rebrovic and G. F. Koser, J. Org. Chem., 1984, 49, 4700;
(c) T. Kitamura, R. Furuki, H. Taniguchi and P. J. Stang, Tetrahedron
Lett., 1990, 31, 703. On the other hand, no general method using
hypervalent iodine reagent to furnish carbon–carbon bonds toward
alkynes was reported.
14 The pKa values of conjugated acids of the nucleophiles are typically
lower than 5.
15 Comparable reaction yields were obtained for the substrates 1 in Table
1 in these nucleophiles.
16 (a) M. Ochiai, K. Oshima and Y. Masaki, Chem. Lett., 1994, 871; (b) M.
Ochiai, T. Shu, T. Nagaoka and Y. Kitagawa, J. Org. Chem., 1997, 62,
2130.
7 Reactions of alkenyliodonium salts with nucleophiles: (a) M. Ochiai, K.
Sumi, Y. Takaoka, M. Kunishima, Y. Nagao, M. Shiro and E. Fujita,
Tetrahedron, 1988, 44, 4095; (b) J.-M. Chen and X. Huang, Synlett,
2004, 552; (c) J. Yan, H. Jin and Z. Chen, J. Chem. Res., 2007, 233.
17 For the related bis(iodoarene) catalysts developed by us, see: (a) T.
Dohi, A. Maruyama, N. Takenaga, K. Senami, Y. Minamitsuji, H.
Fujioka, S. Caemmerer and Y. Kita, Angew. Chem., Int. Ed., 2008, 47,
3787; (b) T. Dohi and Y. Kita, Chem. Commun., 2009, 2073.
6902 | Org. Biomol. Chem., 2011, 9, 6899–6902
This journal is
The Royal Society of Chemistry 2011
©