Formation of five- and seven-membered rings enabled by the triisopropylsilyl auxiliary group

Article abstract of DOI:10.1021/ol203209b

A highly convenient synthetic pathway to 2-indanones from aldehydes was established. The introduction of a triisopropylsilyl group greatly facilitated Meinwald rearrangement of the intermediate epoxides and alleviated the necessity of polysubstitution for the clean formation of indenes and cyclopentadienes via cyclodehydration of allylic alcohols; unprecedented freedom with respect to the product structure was thus achieved. The developed methodology could also be applicable to the formation of seven-membered rings leading to dibenzo[7]annulenes and dibenzosuberones.

Full text of DOI:10.1021/ol203209b

ORGANIC
LETTERS
2012
Vol. 14, No. 1
414–417
Formation of Five- and Seven-Membered
Rings Enabled by the Triisopropylsilyl
Auxiliary Group
Dmitry L. Usanov and Hisashi Yamamoto*
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago,
Illinois 60637, United States
*yamamoto@uchicago.edu
Received December 1, 2011
ABSTRACT
A highly convenient synthetic pathway to 2-indanones from aldehydes was established. The introduction of a triisopropylsilyl group greatly
facilitated Meinwald rearrangement of the intermediate epoxides and alleviated the necessity of polysubstitution for the clean formation of
indenes and cyclopentadienes via cyclodehydration of allylic alcohols; unprecedented freedom with respect to the product structure was thus
achieved. The developed methodology could also be applicable to the formation of seven-membered rings leading to dibenzo[7]annulenes and
dibenzosuberones.
Cyclodehydration of aryl-substituted allylic alcohols
represents an established route toward construction of
the indene scaffold. However, the existing protocols
require multiple aryl/alkyl stabilizing groups in the
substrates,1 which results in a substantially narrowed
scope of the available annulation products. Indeed, when
we subjected R-vinylbenzyl alcohol (1a) to 10 mol % of
boron trifluoride etherate in CH2Cl2, only a complex
mixture of products could be detected (Scheme 1). We
considered suppression of the numerous side pathways
by the introduction of the sole silyl group adjacent to
the alcohol moiety (Scheme 1). The reactivity of the
Scheme 1. AuI-Mediated Cyclization/Epoxidation/Meinwald
Rearrangement Sequence for Allylic Alcohols
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(c) Parham, W. E.; Egberg, D. C. J. Org. Chem. 1972, 37, 1545. (d)
Miller, W.; Pittman, C. J. Org. Chem. 1974, 39, 1955. (e) Singh, G.; Ila,
H.; Junjappa, H. Synthesis 1986, 744. (f) Pittman, C.; Miller, W. G.
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intermediate cationic species was expected to be con-
trolled by both steric and electronic factors (β-silicon
effect),2 thereby enabling aromatic electrophilic substi-
tution to proceed in a clean fashion; this concept was thus
supposed to allow the use of unsubstituted substrates.
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r
10.1021/ol203209b
Published on Web 12/16/2011
2011 American Chemical Society

superiority of the system consisting of chloro(triphenyl-
phosphine) gold(I)3 and silverhexafluoroantimonate(V) in
dichloromethane: toour delight, the product yield could be
increased to 92% yield.4
Table 1. Substrate Screening for AuI-Mediated Indene Synthe-
sis
With these results in hand, we considered the possibility
of indanone synthesis via Meinwald rearrangement of
epoxides5 (Scheme 1). The use of m-CPBA with indene
2d allowed clean formation of the corresponding epox-
ide along with the product 3d; as low as 0.1 mol % of tri-
flimide appeared to be sufficient for the clean and regiose-
lective conversion to 3d with 94% overall yield.
We then tested the Ph3PAuCl/AgSbF6 catalytic sys-
tem (10 mol %) on a range of TIPS-substituted allylic
alcohols 1dÀq (Table 1), which can easily be synthesized
via organolithium species formed from (1-bromovinyl)
triisopropylsilane, which in turn can be conveniently
prepared on a large scale in 3 steps from inexpensive
(3) For selected reviews on gold-catalyzed reactions, see: (a) Arcadi,
A.; Giuseppe, S. D. Curr. Org. Chem. 2004, 8, 795. (b) Zhang, L.; Sun, J.;
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(4) The use of Ph3PAuCl/AgSbF6 demonstrated the same trend as
BF3: increasing the size of the silyl group led to improved yields. For
substrates 1aÀd the corresponding indenes were obtained in <1%, 5%,
56%, and 92% yields respectively.
(5) Contrary to our approach, the overwhelming majority of meth-
ods on Meinwald rearrangement are based on the use of Lewis acids:
Rickborn, B. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 3; Chapter 3.3, p 733 and references
therein. For more recent studies, see: (a) Maruoka, K.; Ooi, T.;
Yamamoto, H. Tetrahedron 1992, 48, 3303. (b) Maruoka, K.; Murase,
N.; Bureau, R.; Ooi, T.; Yamamoto, H. Tetrahedron 1994, 50, 3663.
(c) Ishihara, K.; Hanaki, N.; Yamamoto, H. Synlett 1995, 721.
(d) Kulasegaram, S.; Kulawiec, R. J. J. Org. Chem. 1997, 62, 6547. (e)
Ranu, B. C.; Jana, U. J. Org. Chem. 1998, 63, 8212. (f) Suda, K.; Baba,
K.; Nakajima, S.; Takanami, T. Tetrahedron Lett. 1999, 40, 7243. (g)
Anderson, A. M.; Blazek, J. M.; Garg, P.; Payne, B. J.; Mohan, R. S.
Tetrahedron Lett. 2000, 41, 1527. (h) Martınez, F.; del Campo, C.;
Llama, E. F. J. Chem. Soc., Perkin Trans. 1 2000, 1749. (i) Bhatia, K. A.;
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Lett. 2001, 42, 8129. (j) Kita, Y.; Futamura, J.; Ohba, Y.; Sawama, Y.;
a Isolated yields after column chromatography. b Prepared via trans-
metalation with 2LiCl•CeCl3. c Carried out at 0 °C.
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Suda, K.; Kikkawa, T.; Nakajima, S.; Takanami, T. J. Am. Chem. Soc.
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Synlett 2009, 59. (s) Suda, K.; Nakajima, S.; Satoh, Y.; Takanami, T.
Introduction of a TMS-substituent did render the reac-
tion cleaner; however, the isolated yield of indene 2b
appeared to be unacceptably low (Scheme 1). The Triethyl-
silyl group provided a considerable increase in yield of
the product 2c. A triisopropyl-substituted alcohol 1d fur-
nished the desired indene 2d with the highest yield in the
series (67%). Screening of other Brønsted and Lewis acids
as a catalyst for the synthesis of 2d demonstrated the
€
€ €
Chem. Commun. 2009, 1255. (t) Ertur, E.; Gollu, M.; Demir, A. S.
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Org. Lett., Vol. 14, No. 1, 2012
415

starting materials (82% overall, only one purification
step required). The acetophenone-derived substrate
1n could be prepared via transmetalation with the
2LiCl•CeCl3 complex to suppress undesired enolization.
Notably, a catalystloading lower than10mol % couldalso
be used for efficient cyclodehydration as was exemplified
for substrate 1e: the use of 5 mol % of the Ph3PAuCl/
AgSbF6 system still furnished the indene product with an
excellent outcome (99% yield); a further decrease of the
gold content to 1 mol % was also possible, although a
lower yield was detected (82%). The use of 10 mol % of the
gold(I) catalyst was chosen for the substrate screening
experiments since it generally provided somewhat higher
yields compared to the lower catalyst loadings.6
Scheme 2. 2-Indanones 3 Obtained from Indenes 2 and Deri-
vatives thereof (4À7)7
Excellent results were obtained for the AuI-mediated
cyclodehydration of the substrates derived from benzalde-
hyde (1d), 1-naphthaldehyde (1e), 2-naphthaldehyde (1f,
the angular tricyclic product 2f was formed exclusively),
and o- as well as p-tolualdehydes (1g/1j). The m-tolualde-
hyde derivative 1h furnished a mixture of isomers in a 1.7:1
ratio with the less sterically congested 5-substituted prod-
uct being predominant. The isomer ratio could be in-
creased to 3.3:1 for a bromo-analogue 1i, which is pre-
sumably due to the combination of steric and inductive
effects. A thiophene-2-carboxaldehyde-derived substrate
appeared to be too reactive for a clean catalysis outcome;
however, the reactivity could be successfully tuned via
introduction of benzannulation allowing clean formation
of tricyclic product 2k. An indole analogue 1l could be
subjected to cyclodehydration, although reactivity tuning
was also necessary (N-tosyl moiety). Ketone derivatives
1mÀp were successfully employed; notably, for substrates
1m and 1p a substantial loss of the silyl moiety was detected
when the reactions were run at room temperature; this
could be easily avoided by carrying out the catalysis at
0 °C. Indeed, a complete regioselectivity of annulation was
observed in the benzophenone-derived substrate 1o with
one of the aryl moieties being deactivated. Functionaliza-
tion of position 1 in the indene product was possible by the
use of a terminally alkylated substrate 1q.
eitherstage, allowing clean preparation ofisomeric couples
5m/5q and 6m/6q.
We then considered expansion of the developed method-
ology on the silylated allylic alcohols derived from R,β-
unsaturated aldehydes. To our delight, cyclopentadiene
synthesis proceeded smoothly for substrates 1rÀu with
good to excellent yields (Table 2).
A number of silylated 2-indanones 3 were then prepared
from indenes 2 via the one-pot epoxidation/rearrangement
sequence with generally good to excellent yields (Scheme 2).8
The 1-methylated indene 2q furnished the corresponding
syn- and anti-indanones 3q in a 1:5 ratio. The versatile na-
ture of the auxiliary TIPS group was demonstrated in the
examples of desilylation, iodination,9a and a bromination9b/
Suzuki coupling sequence (products 4À7). The latter
transformation is notable for the isomeric indenes 2m and
2q: no scrambling of the double bond was observed on
The importance of the R-substituent in the parent
aldehyde was postulated: only a complex mixture of prod-
ucts was obtained when a (E)-cinnamaldehyde derivative
was used. However, the presence of an R-methyl group in
1r was already sufficient for the necessary level of inter-
mediate stabilization (provided theβ-substituent was aryl).
Increasing the size of the R-substitution was beneficial
for the reaction yield as exemplified by 8r and 8s; both
products were prepared as virtually single isomers shown
in Table 2. On the contrary, the isomers with all the
possible positions of the double bonds were present in
the reaction mixture involving R-aryl,β-alkyl derivatives 1t
(6) The indene synthesis could also be accomplished using 5À
10 mol % of AuCl3 in CH2Cl2 for 0.5À1 h. However, the yields obtained
were usually somewhat lower than those provided by the AuI system.
For the data on other gold catalysts see Supporting Information.
(7) Abbreviations: HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol; NIS =
N-iodosuccinimide; o-tol = ortho-tolyl.
(8) Silyl indanones 3 are generally robust; however, for storage over
extended periods of time fridge/freezer temperatures are recommended.
(9) (a) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. Org. Lett. 2008, 10,
1727. (b) Carried out using the procedure analogous to iodination.9a
(10) (a) Garner, C. M.; Prince, M. E. Tetrahedron Lett. 1994, 35,
2463. (b) Threlkel, R. S.; Bercaw, J. E.; Seidler, P. F.; Stryker, J. M.;
Bergman, R. G. Org. Synth. 1987, 65, 42. (c) Jutzi, P.; Dahlhaus, J.
Synthesis 1993, 684. (d) Gassman, P. G.; Mickelson, J. W.; Sowa, J. R.,
Jr. J. Am. Chem. Soc. 1992, 114, 6942. (e) Fang, H.; Song, Q.; Wang, Z.;
Xi, Z. Tetrahedron Lett. 2004, 45, 5159. (f) Christie, S. D. R.; Man,
K. W.; Whitby, R. J. Organometallics 1999, 18, 348. (g) Wang, Z.; Fang,
H.; Xi, Z. Tetrahedron 2006, 62, 6967.
416
Org. Lett., Vol. 14, No. 1, 2012

Notably, when an ortho,ortho-dimethyl analogue 1y was
used, a 1,2-shift of the alkyl group was observed to furnish
rearranged product 2y (Scheme 3).
Table 2. AuI-Mediated Cyclopentadiene Synthesis
Scheme 3. Formation of 7-Membered Rings via AuI-Catalysis
a Isolated yields after column chromatography. b >90% of the
shown isomer. c A mixture of isomers was obtained.
and 1u; excellent overall yields were still obtained. The
presence of an aryl group, in either the R- or β-position of
the parent aldehyde, was crucial for efficient catalysis;
inferior results were obtained with dialkyl analogues. Only
a few examples on cyclodehydration of bis-allylic alcohols
have been published;10 indeed, polyalkyl/polyaryl substi-
tution in the substrates was required. In this context it is
notable that our method provides access to trisubstituted
cyclopentadienes, which were beyond the scope of pre-
vious cyclodehydration procedures.
We have also considered the possibility of building
seven-membered cycles employing the developed meth-
odology. Gratifyingly, terphenylcarbaldehyde-derived
alcohols 1vÀx could be easily converted to dibenzo[7]
annulenes 9vÀx with excellent yields (Scheme 3).11 The
constructed 6,7,6-tricyclic system is particularly interest-
ing in light of its presence in allocolchicinoids, the class of
compounds of great importance in cancer chemotherapy.12
In summary, we have discovered the crucial effect of the
TIPS moiety in aryl-substituted allylic alcohols in the
context of gold(I)-mediated annulation, which resulted in
the development of a mild, operationally simple and high-
yielding three-step conversion of aromatic aldehydes into
corresponding R-silyl-2-indanones. The methodology pro-
vided a route to a range of unsubstituted derivatives which
were previously unaccessible via the cyclodehydration
pathway. The concept could also be expanded to cyclo-
pentadiene synthesis. Finally, the first example of an
intramolecular electrophilic cyclization leading to a
dibenzo[7]annulene system was successfully accomplished.
Acknowledgment. This work was made possible by the
generous support of the NSF (CHE-1049551). D.L.U.
gratefully acknowledges the Martha Ann and Joseph A.
Chenicek Graduate Research Fund for a personal fellow-
ship. We also thank Dr. Marina Naodovic (The University
of Chicago13) for involvement in the preliminary stage of
this project and Dr. Antoni Jurkiewicz (Department of
Chemistry, The University of Chicago) for his assistance
with NMR experiments.
(11) On the evidence of the formation of dibenzo[7]annulene scaffold
see Supporting Information.
(12) The members of this family, e.g. allocolchicine, N-acetylcolchi-
cinol methyl ether, N-acetylcolchicinol, and ZD 6126, have received
much attention in the context of antitumor activity. For the most recent
synthetic works and further details, see the following publications and
references therein: (a) Boyer, F.-D.; Le Goff, X.; Hanna, I. J. Org. Chem.
2008, 73, 5163. (b) Boyer, F.-D.; Hanna, I. Eur. J. Org. Chem. 2008, 29,
Supporting Information Available. Complete experi-
mental procedures, characterization data of the prepared
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
€
4938. (c) Nicolaus, N.; Zapke, J.; Riesterer, P.; Neudorfl, J.-M.; Prokop,
A.; Oschkinat, H.; Schmalz, H.-G. ChemMedChem 2010, 5, 661. (d)
Boyer, F.-D.; Dubois, J.; Thoret, S.; Tran Huu Dau, M.-E.; Hanna, I.
Bioorg. Chem. 2010, 38, 149. (e) Djurdjevic, S.; Yang, F.; Green, J. R.
J. Org. Chem. 2010, 75, 8241. (f) Nicolaus, N.; Reball, J.; Sitnikov, N.;
Velder, J.; Termath, A.; Fedorov, A. Yu.; Schmalz, H.-G. Heterocycles
2011, 82, 1585.
(13) Current affiliation: University of Rochester.
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