Triflimide-catalyzed allylsilane annulations of benzylic alcohols for the divergent synthesis of indanes and tetralins

Article abstract of DOI:10.1039/c6sc04762a

The development of a triflimide-catalyzed annulation of benzylic alcohols with allylsilanes for the synthesis of indane or tetralin structures is reported. In this fragment coupling reaction, complexity is built rapidly from readily available starting materials to yield diverse sets of products with up to three contiguous stereocenters. Indanes or tetralins can be generated from common precursors depending on the structure of the allylsilane reagent used. The concise synthesis of several lignan natural products highlights the utility of this newly devised methodology.

Full text of DOI:10.1039/c6sc04762a

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Triflimide-catalyzed allylsilane annulations of
benzylic alcohols for the divergent synthesis of
Cite this: DOI: 10.1039/c6sc04762a
indanes and tetralins†
*
Jordan C. T. Reddel,‡ Weiwei Wang,‡ Kalli Koukounas and Regan J. Thomson
The development of a triflimide-catalyzed annulation of benzylic alcohols with allylsilanes for the synthesis
of indane or tetralin structures is reported. In this fragment coupling reaction, complexity is built rapidly
from readily available starting materials to yield diverse sets of products with up to three contiguous
stereocenters. Indanes or tetralins can be generated from common precursors depending on the
structure of the allylsilane reagent used. The concise synthesis of several lignan natural products
highlights the utility of this newly devised methodology.
Received 26th October 2016
Accepted 5th December 2016
DOI: 10.1039/c6sc04762a
www.rsc.org/chemicalscience
a similar manner, allowing for a subsequent 6-endo-trig cycli-
zation/alkene isomerization en route to 10 and representing
Introduction
a convergent approach to tetralin lignans (i.e., 13).
Fragment coupling reactions that assemble complex products
convergently from two or more reaction partners are excep-
tionally useful in synthesis.1 This utility is amplied greatly
when new stereochemical elements and rings are formed as
a consequence of the reaction, allowing the synthesis practi-
tioner to transform simple starting materials into complex
cyclic or polycyclic products directly. Within this context, allyl-
silane reagents have received signicant attention due to their
capacity to participate in a wide range of complexity-generating
annulations leading to the development of efficient methods for
the concise synthesis of numerous chemical architectures,2
including heterocycles3 and carbocycles.3a–c,4
We saw an opportunity to contribute to this eld through the
development of a Brønsted acid-catalyzed allylsilane annulation
that transforms simple benzylic alcohols into a range of
indanes5,6 or tetralins5c,d,7 depending upon the choice of silane
reagent used (Scheme 1). For the case of simple allylsilanes of
type A (i.e., 2) we envisioned a scenario where formation of
a carbocation from alcohol 1 followed by allylsilane addition
would lead to intermediate 5. An ensuing Friedel–Cras alkyl-
ation would then deliver indane 8, whose structure maps onto
a variety of useful compounds such as 11. Under the same
reaction conditions, type B silanes (i.e., 3) would give rise to an
intermediate allylic alcohol 6, which would then undergo an
acid-catalyzed 5-exo-trig cyclization to afford indane 9, a struc-
ture reminiscent of essential oil component 12. Use of the
isomeric type C silane (i.e., 4) would yield intermediate 7 in
Department of Chemistry, Northwestern University, 2145 Sheridan Rd., Evanston, IL
60208, USA. E-mail: r-thomson@northwestern.edu
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data for all new compounds. See DOI: 10.1039/c6sc04762a
‡ These authors contributed equally.
Scheme 1 Divergent access to indanes or tetralin products by way of
a tandem allylation/ring-closure sequence catalyzed by triflimide.
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best catalyst, with nitromethane as the optimal solvent (see ESI
for more details†). Using 10 mol% of triimide, the reaction
proceeded over the course of two hours at room temperature
and proved tolerant to a range of benzylic alcohol precursors,
thus delivering a diverse set of indane products in good to
excellent yields (Table 1). In no cases did we observe products
derived from silyl migration. For the case of benzhydryl alcohols
where one aromatic ring was a simple phenyl group (8a–8g), the
reaction proceeded such that cyclization took place on the more
electron-rich ring. In some cases, such as 8b or 8c, yields were
improved by running reactions at a higher temperature (60 ꢀC)
to overcome the steric encumbrance of cyclization onto
aromatic rings with ortho-substituents. Only cyclization to the
more electron-rich 1-position, rather than the 3-position, is
observed for 8f. In product 8g, cyclization has occurred onto
a benzofuran ring system to yield a 5,5,6-fused ring system,
which while not technically an indane still represents a useful
chemotype.8
Results and discussion
We initiated our investigations (Table 1) using methallylsilane
(2a), a commercially available type A silane, and quickly iden-
tied bis(triuoromethanesulfonyl)imide (triimide) as the
Table 1 Substrate scope for [3 + 2] annulation reaction with benz-
hydryl and benzyl alcoholsa
Complete regioselectivity is observed for the cyclization
leading to indanes 8h–8o (Table 1), in line with the expectation
that the Friedel–Cras alkylation would take place para to the
most electron releasing substituent. For cases where both rings
are activated for cyclization, mixtures of regioisomeric products
were obtained with modest to good selectivity (Table 1, 8p–8s). A
number of benzyl alcohols with alkyl substituents were
employed using the same reaction conditions (Table 1, 8t–8y).
Indanes with two quaternary centers are formed in good yields
(8w–8z). The efficient construction of spiroindane 8y is partic-
ularly notable since this tricyclic core is found in many bioactive
compounds and natural products.9
Use of alternative type A allylsilanes allowed access to a range
of stereochemically complex indanes (Table 1, 8aa–8ff). For
example, silane 2b allows for the introduction of two stereo-
centers within the indane products (8aa–8ee) with modest to
excellent diastereoselectivity. For the three alkyl substituted
products (8aa–8cc), the observed anti selectivity was modest as
a consequence of low stereoselectivity in the initial addition of
silane 2b into the unsymmetrical benzyl cation intermediate
derived from 1 (R1 ¼ Me, Bu or iPr, R2 ¼ H). Cyclization in these
cases does not generate a new stereocenter. On the other hand,
indane 8dd was generated in >20 : 1 dr due to preferential
cyclization on one of the two diastereotopic electron-rich
aromatic rings of the intermediate following initial silane
addition. This outcome is consistent with related observations
we had made during our previously reported synthesis of lignan
natural products.10 Use of silane 2c gave rise to compound 8ee
that contains three contiguous stereocenters in high yield, but
as a 2 : 1 mixture of diastereomers due to poor selectivity during
cyclization to form the new quaternary stereocenter. A similar
outcome was observed utilizing silane 2d to produce indane 8ff.
In this last example, it was necessary to reduce the number of
equivalents of allylsilane in order to suppress the competitive
formation of a 7-membered ring analog formed by double
addition of the silane (see ESI†).
a
Isolated yields aer column chromatography. b Reaction run at 60 ꢀC.
We next sought to explore the utility of type B and type C
silanes that would give rise to indanes or tetralins, respectively
(see Scheme 1). While the desired type C silanes (i.e., 4) have
c
d
Reaction run at 80 ꢀC. Mixture of cyclization regioisomers; major
product shown. Diastereomeric ratio determined by 1H NMR
e
spectroscopy. f 0.9 equiv. of silane 2d used.
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been reported in the literature,11 general protocols to access the
requisite type B silanes (i.e., 3) were less well developed.12 We
therefore developed an effective protocol for the synthesis of
silanes 3a–3c based on the regioselective addition of Grignard
reagent-derived vinylcuprates to trimethylsilylepoxide 14
(Scheme 2).13
Utilizing the symmetrical benzhydryl alcohol 15 as
a common precursor we next demonstrated the capacity of type
B and C allylsilanes to undergo the desired triimide-catalyzed
annulation processes (Scheme 3). The type B silanes 3a–3c gave
rise to three different vinyl substituted indane products (9a–9c)
in reasonable yield and with modest levels of diaster-
eoselectivity, as observed for the corresponding type A silanes.
Type C silane 4a was found to be superior to the corresponding
free alcohol derivative, undergoing the desired addition/6-endo-
trig cyclization/alkene isomerization to provide tetralin 10a in
46% yield. Type C silane 4b was more effective than silane 4a,
providing tetralin 13 in 78% yield and with >20 : 1 selectivity for
the anti stereochemistry. In this instance the product of the new
annulation process is the natural product cyclogalgravin (13),
thus establishing a highly efficient two-step total synthesis of
this lignan from simple starting materials.14
Scheme 2 Synthesis of allylsilane reagents from trimethylsilylepoxide
14.
Recognizing the power of this annulation process in
accessing cyclolignan natural products,15 we targeted the
synthesis of several other related natural products in order to
further demonstrate the usefulness of this methodology
(Scheme 4). For example, symmetrical benzhydryl species 16
underwent the triimide-catalyzed annulation with silane 4b to
deliver dihydronaphthalene 10b in 49% yield (Scheme 4A).
Selective removal of the two isopropyl ethers from 10b delivered
the natural product 40,5-O-didemethylcyclogalgravin (17)16 in
81% yield, while simple oxidation of 10b with DDQ allowed
access to cinnamophilin A (18)17 aer isopropyl group cleavage
(81%, 2 steps). Conducting the same reaction sequences on the
Scheme 3 Divergent synthesis of indane and tetralin compounds.
Scheme 4 A general approach for accessing tetralin lignan natural products utilizing a triflimide-catalyzed allylsilane annulation.
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´
more highly substituted benzhydryl starting material 19
provided access to the higher oxidation state analogs, saci-
dumlignan B (20) and A (21) with similar levels of efficiency
(Scheme 4B).18 The unsymmetrical benzhydryl 22 delivered the
annulated product 10d as a mixture of cis and trans stereoiso-
mers, along with some of the naphthalene product 23. Cycli-
zation only occurred on the more electron-rich aromatic ring,
and this mixture could be treated with DDQ without prior
purication to deliver pycnanthuligene C (23) in 73% yield over
two steps from 22.19
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In summary, we have developed a Brønsted acid-catalyzed
annulation for the divergent synthesis of substituted indanes
and tetralins from a set of common precursors. The strategic
ability to rapidly build complexity from commercially available
or easily prepared starting materials makes this methodology
amenable to the concise preparation of various chemotypes,
including bioactive natural products. Future work will focus on
the development of enantioselective variants of these reactions
using chiral strong Brønsted acids, which is an exciting pros-
pect given the recent advancements in that eld.20
Acknowledgements
We thank support in part from the NSF (CHE1361173) and
Northwestern University. We gratefully acknowledge the award
of a CLP Lambert Fellowship to KK.
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