Catalysis and chemodivergence in the interrupted, formal homo-nazarov cyclization using allylsilanes

Article abstract of DOI:10.1021/ol503305r

A chemodivergent, Lewis acid catalyzed allylsilane interrupted formal homo-Nazarov cyclization is disclosed. With catalytic amounts of SnCl₄ and in the presence of allyltrimethylsilane, a formal Hosomi-Sakurai-type allylation of the oxyallyl cation intermediate is observed. A variety of functionalized donor-acceptor cyclopropanes and allylsilanes were shown to be amenable to the reaction transformation and the allyl products were formed in up to 92% yield. Under dilute reaction conditions with stoichiometric SnCl₄ and at reduced temperatures, an unusual formal [3 + 2]-cycloaddition between the allylsilane and the oxyallyl cation occurred to give hexahydrobenzofuran products in up to 69% yield.

Full text of DOI:10.1021/ol503305r

Letter
pubs.acs.org/OrgLett
Catalysis and Chemodivergence in the Interrupted, Formal Homo-
Nazarov Cyclization Using Allylsilanes
Raynold Shenje,† Corey W. Williams,† Katherine M. Francois,† and Stefan France*,†,‡
†School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
‡Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
S
* Supporting Information
ABSTRACT: A chemodivergent, Lewis acid catalyzed allylsilane
interrupted formal homo-Nazarov cyclization is disclosed. With
catalytic amounts of SnCl4 and in the presence of allyltrime-
thylsilane, a formal Hosomi−Sakurai-type allylation of the
oxyallyl cation intermediate is observed. A variety of function-
alized donor−acceptor cyclopropanes and allylsilanes were
shown to be amenable to the reaction transformation and the
allyl products were formed in up to 92% yield. Under dilute
reaction conditions with stoichiometric SnCl4 and at reduced temperatures, an unusual formal [3 + 2]-cycloaddition between the
allylsilane and the oxyallyl cation occurred to give hexahydrobenzofuran products in up to 69% yield.
xyallyl cations represent a versatile class of electrophilic
reactive intermediates in organic synthesis.1 Their utility
Over the past several years, we have published various reports
on the eliminative formal homo-Nazarov reaction using donor−
acceptor−acceptor (D−A−A) cyclopropane substrates.11
Through the use of the secondary acceptor group on the D−A
cyclopropane, we were able to achieve catalysis using Lewis acids.
We envisaged extending our work through developing a
generalized, catalytic protocol for an interrupted formal homo-
Nazarov cyclization. Given the limitations of the Yadav et al.
study,10 we sought to examine the reaction of D−A−A
cyclopropanes with allylsilanes. Along that line, we disclose a
chemodivergent protocol for the interrupted formal homo-
Nazarov cyclization with allylsilanes, that selectively affords
formal allyl trapping products under catalytic conditions while
yielding unusual formal [3 + 2]-cycloaddition products under
stoichiometric conditions (Scheme 2).
O
has been demonstrated in Favorskii reactions,2 Nazarov
cyclizations,3 [4 + 3]-cycloadditions,4 [3 + 2]-cycloadditions,5
and nucleophilic substitutions.6 In the classic Nazarov
cyclization, in particular, a cyclic five-membered oxyallyl cation
intermediate is formed which can undergo elimination and
tautomerization to afford cyclopentenones. As pioneered by
West3e,7 and Tius,3b,d,g,8 the utility of the Nazarov reaction has
been extended through both inter- and intramolecular
nucleophilic trapping of the cyclic oxyallyl cation leading to a
wide array of functionalized cyclopentanones across a range of
applications. In the related but relatively underexplored formal
homo-Nazarov cyclization,9 a six-membered oxyallyl cation is
generated (Scheme 1). In the eliminative pathway, cyclo-
Scheme 1. Formal Homo-Nazarov Cyclization
Scheme 2. Chemodivergent Allylsilane-Interrupted Formal
Homo-Nazarov Cyclization with D−A−A cyclopropanes
The study began with alkenyl cyclopropyl ketone 1a as the
model substrate and In(OTf)3 as the Lewis acid catalyst to
initiate the reaction optimization (Table 1). The reaction of 1a,
allyl TMS 2a (10 equiv),12 and In(OTf)3 (20 mol %) at room
temperature in CH2Cl2 (0.1 M) afforded allyl-interrupted homo-
Nazarov product 3a (as a enol/keto mixture), resulting from a
Hosomi−Sakurai-type allylation,13 in 41% yield as a 1.7:1
hexenones are obtained. No examples of an interrupted formal
homo-Nazarov cyclization had been published until earlier this
year when Yadav and co-workers demonstrated trapping of the
six-membered cyclic oxyallyl cation intermediate using allylsi-
lanes in a formal [3 + 2]-cycloaddition to yield bicyclo[3.2.1]-
octan-8-ones.10 This transformation, while it remains the first
and only literature example of an interrupted formal homo-
Nazarov reaction, was only effective with stoichiometric amounts
of SnCl4 and demonstrated limited scope.
Received: November 13, 2014
© XXXX American Chemical Society
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a
Table 1. Reaction Optimization
a
Reactions run with x mol % of Lewis acid, 10 equiv of
allyltrimethylsilane 2a, and 1 equiv of cyclopropane 1a in CH2Cl2
b
(0.1 M) at 25 °C. Isolated yield mixture of keto/enol isomers after
column chromatography. Product ratios determined by H NMR of
the crude reaction mixture.
c
1
mixture with the untrapped homo-Nazarov product 6a. At
reduced loading (5 mol %), increased yield and chemoselectivity
were observed (63% yield, 3a/6a = 5.6:1) (Table 1, entry 2).
With Sc(OTf)3, the allyl product was formed in 43% yield with
4.2:1 selectivity (Table 1, entry 3). In contrast to In(OTf)3,
attempts to improve the reaction with Sc(OTf)3 failed. Yb(OTf)3
and Al(OTf)3 each gave extremely long reaction times (>70 h)
and were not revisited (Table 1, entries 4 and 5). Gratifyingly,
SnCl4 generated product 3a in 75% yield (as a mixture of enol
and keto forms) with a 17:1 selectivity toward the interrupted
product (Table 1, entry 6). Converting the complex enol/keto
mixture to the corresponding TMS enol silane significantly
simplified its NMR, revealing a 2:1 diastereomeric ratio (dr). As
anticipated, the major diastereomer was found to have the allyl
and phenyl groups in a trans relationship.14 Attempts to lower the
loading of SnCl4, alter solvent and reaction concentration, or
employ other Lewis acids all led to reduced chemoselectivities
and/or yields (see the Supporting Information). Therefore, we
proceeded with 20 mol % of SnCl4 and 10 equiv of allylsilane in
CH2Cl2 (0.1 M) at room temperature as the optimized
conditions.
In order to explore reaction scope, other D−A−A cyclo-
propanes were prepared and subjected to the optimized
conditions (Figure 1). (4-Methoxyphenyl)cyclopropane 1b
smoothly afforded the expected allyl product 3b in 92% yield
and a dr = 4.2:1. The 4-fluorophenyl substrate 1c gave a reduced
yield of 54% with a dr = 6.8:1. The phenylcyclopropane 1d gave
the desired product 3d as an intractable mixture. However, when
1d was treated with 5 mol % In(OTf)3, allyl trapping was
observed and 3d was obtained in 38% yield and a dr = 2.4:1.15 No
products were detected under either set of conditions for
cyclopropane 1e containing the highly electron-deficient 4-
(trifluoromethyl)phenyl donor group. In contrast, (2-
methoxyphenyl)cyclopropane 1f provided its trapped product
3f in 71% yield with a dr = 13.6:1. Similarly, both the naphthyl
and furyl cyclopropanes 1g and 1h were effective in the
interrupted reactions affording products 3g and 3h in 78% yield
(dr = 7.3:1) and 65% yield (dr = 2.0:1), respectively.
Figure 1. Catalytic, allylsilane-interrupted, formal homo-Nazarov
cyclizations.
a
Table 2. Optimizing Chemodivergence
a
Reactions run with x mol % of Lewis acid, 10 equiv of allylsilane 2,
and 1 equiv of cyclopropane 1b in CH2Cl2 at the indicated
b
1
temperature. Product ratios determined by H NMR of the crude
c
reaction mixture. Isolated yield after column chromatography.
Reaction did not reach completion, and unreacted 1b was recovered.
d
mixture. On the other hand, when cyclopropane 1j, bearing an
acyclic vinyl ether, was employed, the desired allyl product 3j was
obtained in 49% as a single diastereomer. Similarly, a single
diastereomer of 3k was observed in 66% yield when the
dihydropyranyl cyclopropane substrate 1k was employed. The
high diastereoselectivity observed in 3j and 3k can be rationalized
through product development control16 following allylsilane
attack, in which the conformation minimizing unfavorable
torsional strain determines the product outcome.
The effect of substituents on the allylsilane was also explored.
Again, cyclopropane 1b was chosen as the base system given the
efficiency of the trapping reaction with allyl TMS (92% yield).
No trapping product 3l was observed with for trimethyl(3-
methylbut-2-en-1-yl)silane, most likely due to steric conflicts
during silane approach. Conversely, trimethyl(2-methylallyl)-
silane gave product 3m as a single diastereomer in 68% yield. A
35% yield was obtained for 3n when cinnamyltrimethylsilane was
similarly employed in the reaction.17
Next, changes to the substituent on the alkenyl moiety were
probed for tolerance. The 4-methoxyphenyl substituent was
chosen as the donor group due to the observed excellent reaction
efficiency of cyclopropane 1b. Cyclopropane 1i, bearing an allyl
silane as the nucleophilic π-entity, failed to generate any desired
trapping products. Instead, the homo-Nazarov elimination
product 6b (see Table 2) was obtained as part of an intractable
Up to this point, all experiments were performed using
allyltrimethylsilanes. To determine the impact of changing the
B
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silyl group on the reaction (Table 2), the corresponding TBDPS
(2b), TIPS (2c) and TBS (2d) allyl silanes were prepared. Upon
treatment of cyclopropane 1b with allyl TBDPS 2b (10 equiv)
and SnCl4 (20 mol %) in dichloromethane (0.1 M) at −78 °C,18
an unanticipated product, hexahydrobenzofuran 4bb, resulting
from a formal [3 + 2]-cycloaddition of the allyl TBDPS across the
six-membered oxyallyl cation, was obtained in 20% yield along
with some unreacted starting material (Table 2, entry 1).
Lowering the reaction concentration to 0.01 M improved the
yield of 4bb (41%) but did not improve the conversion (Table 2,
entry 2). Full conversion of starting material 1b was only
observed with stoichiometric amounts of SnCl4 (Table 2, entries
3 and 4). Interestingly, reaction conditions as described by Yadav
et al.10 (120 mol % SnCl4, 10 equiv of TBDPS allylsilane, −78
°C) proved optimal and cleanly afforded the desired
hexahydrobenzofuran 4bb in 69% yield as a 3.9:3.8:1.1:1 mixture
of diastereomers (Table 2, entry 5). In comparison to allyl
TBDPS, allyl TIPS 2c and allyl TBS 2d afforded their respective
hexahydrobenzofurans, 4bc and 4bd, in 88% and 66% yield
(Table 2, entries 6 and 7). Under the reaction conditions of
Yadav et al., allyl TMS proved nonselective and gave a ∼1:1
mixture of 3b and 4ba (Table 2, entry 8).
Scheme 3. Proposed Mechanism
product distributions. As expected, higher temperatures and
concentration promote desilylation due to increased molecular
collisions with Lewis basic sites on other species in the solution,
leading to allylated product 3. In addition, less bulky silyl groups
also facilitate the desilylation pathway due to silane lability. On
the other hand, increased steric bulk on the silane and lowered
temperatures and concentrations all result in the persistence23 of
intermediate III. This persistence presumably allows for the
occurrence of alternative pathways to quench the cation. One
such channel, pathway b, is observed and leads to hexahy-
drobenzofuran 4 while the other, pathway c, would yield
bicyclo[3.2.1]octanes 5. In stark contrast to Yadav et al.’s
report,10 the formation of bicyclic products 5 was not observed
during this study. We attribute this observation to the reaction
being under kinetic control with a preference for O-alkylation.24
Additionally, the nucleophilicity of the enolate carbon is
substantially reduced due to being part of a vinylogous system,
furthermore supporting the preference for O-alkylation.
Due to the utility of the TBDPS group in various
functionalization reactions,19 allyl TBDPS 2b was used to
probe the scope for hexahydrobenzofuran formation (Figure
2).20 The reactions of 2b with different cyclopropanes 1 were
The allyl products 3 from the trapping reactions can serve as
useful building blocks for further synthesis. As a demonstration
of this synthetic utility, 3b could also be allylated to form 9 which,
following ring-closing metathesis, afforded the functionalized
bicyclo[4.3.1]dec-3-ene 10, a framework found in caryolane-
based natural products (Scheme 4).25
Figure 2. Synthesis of 2,3,3a,4,5,6-hexahydrobenzofurans.
Scheme 4. Chemical Derivatization of 3b
examined under the optimized reaction. The gem-disubstituted
methyl phenyl cyclopropane 1a afforded its product 4ab in 47%
yield with a dr = 1.6:1.4:1.3:1, while the 4-fluorophenyl
cyclopropane 1c gave hexahydrobenzofuran 4cb in poor yield
(20%) but good relative diastereoselectivity (dr =
10.6:9.7:1.7:1). The 2-naphthyl- and 2-furylcyclopropanes (1g
and 1h) each gave their corresponding trapped products 4gb and
4hb in 49% yield. Finally, using (ethoxyvinyl)cyclopropane 1j,
the hexahydrobenzofuran 4jb was formed in 40% yield with high
diastereoselectivity (dr = 42.9:3.1:1:0).
Mechanistically, the reaction with D−A−A cyclopropane 1
involves formation of the cyclic oxyallyl cation II followed by
capture by the allylsilane to generate the silyl-stabilized
carbocation III (Scheme 3). Three chemodivergent pathways
are possible for III: (1) Hosomi−Sakurai-type desilylation13 to
form the allyl cyclohexenol 3 (pathway a);21 (2) enolate O-
alkylation to form hexahydrobenzofuran 4 (pathway b);22 and
(3) enolate C-alkylation to afford bicyclo[3.2.1]octanes 5
(pathway c). The Lewis acid loading, reaction concentration,
temperature and the choice of silyl group directly influence
In summary, we have developed a chemodivergent interrupted
formal homo-Nazarov cyclization using allylsilanes as nucleo-
philes for trapping the six-membered oxyallyl cation intermediate
derived from D−A−A cyclopropanes. Using catalytic SnCl4 and
allyl TMS, formal allylations of the intermediate oxyallyl cations
are observed. Allyl products are formed in up to 92% yield and a
dr’s up to >99:1. This transformation represents the first example
of effective catalysis for the interrupted formal homo-Nazarov
cyclization. When the reaction is operated with stoichiometric
SnCl4 at lowered concentrations and temperatures using bulkier
allylsilanes, hexahydrobenzofuran products are obtained in up to
88% yield. For both product pathways, modifications at the
donor groups and nucleophilic π-systems are well-tolerated. The
products formed can be readily derivatized to give other
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(11) (a) Patil, D. V.; Phun, L. H.; France, S. Org. Lett. 2010, 12, 5684.
(b) Patil, D. V.; Cavitt, M. A.; Grzybowski, P.; France, S. Chem. Commun.
2011, 47, 10278. (c) Phun, L. H.; Patil, D. V.; Cavitt, M. A.; France, S.
Org. Lett. 2011, 13, 1952. (d) Cavitt, M. A.; Phun, L. H.; France, S. Chem.
synthetically useful precursors. Further work will focus on
capturing the oxyallyl cation using other nucleophiles (both
inter- and intramolecularly) to allow for access to a range of
functionalized cyclohexanones, bicyclics, and potentially other
scaffolds.
́
Soc. Rev. 2014, 43, 804. (e) Aponte-Guzman, J.; Taylor, J. E., Jr.; Tillman,
E.; France, S. Org. Lett. 2014, 16, 3788.
(12) Other loadings of allyl TMS were employed but proved to be less
effective. See the Supporting Information for details.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral and analytical data for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(13) Hosomi, A.; Sakurai, H. J. Am. Chem. Soc. 1977, 99, 1673.
(14) See the Supporting Information for detailed NMR correlations.
(15) For each of the other substrates explored, In(OTf)3 (5 mol %)
was employed, but it proved to be less effective than SnCl4.
(16) (a) Takaishi, N.; Inamoto, Y.; Aigami, K. Chem. Lett. 1979, 803.
(b) Wigfield, D. C.; Gowland, F. W. Tetrahedron Lett. 1979, 2209.
(17) A complex mixture of diastereomers was obtained.
(18) No desired product was obtained at room temperature.
(19) (a) Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2009, 131, 10844.
(b) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson, P. E.
J. J. Chem. Soc., Perkin Trans. 1 1995, 317.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: stefan.france@chemistry.gatech.edu.
Notes
(20) When allyl TIPS was employed to expand scope, the results were
inconsistent. Therefore, allyl TBDPS remained the clear choice.
(21) Formation of the desilylated product as the major product is
unique in that the desilylated products have only been obtained in low
yields (<15%) in both of West’s interrupted Nazarov cyclizations and
Yadav’s interrupted homo-Nazarov cyclizations with allylsilanes (ref
10): Giese, S.; Kastrup, L.; Stiens, D.; West, F. G. Angew. Chem., Int. Ed.
2000, 112, 2046.
(22) The formation of hexahydrobenzofuran 4 is reminiscent of
oxygen capture observed in West’s intramolecular interrupted Nazarov
cyclization with olefins: Bender, J. A.; Blize, A. E.; Browder, C. C.; Giese,
S.; West, F. G. J. Org. Chem. 1998, 63, 2430.
(23) (a) Lambert, J. B.; Zhao, Y. J. Am. Chem. Soc. 1996, 118, 7867.
(b) Hagen, G.; Mayr, H. J. Am. Chem. Soc. 1991, 113, 4954.
(24) Mayr, H.; Breugst, M.; Ofial, A. R. Angew. Chem., Int. Ed. 2011, 50,
6470.
(25) (a) Goldring, W. P. D.; Paden, W. T. Tetrahedron Lett. 2011, 52,
859. (b) He, X.-F.; He, Z.-W.; Jin, X.-J.; Pang, X.-Y.; Gao, J.-G.; Yao, X.-
J.; Zhu, Y. Phytochem. Lett. 2014, 10, 80. (c) Huang, H.; Gao, X. J.; Liu, J.;
Li, S.; Han, Y. F.; Zhou, B. C.; Xia, M. Nat. Prod. Res. 2013, 27, 350.
(d) Nisnevich, G. A.; Makal’skii, V. I.; Korchagina, D. V.; Gatilov, Y. V.;
Bagryanskaya, I. Y.; Barkhash, V. A. Zh. Org. Khim. 1994, 30, 161.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.F. gratefully acknowledges financial support from the National
Science Foundation (CAREER Award CHE-1056687) and
Georgia Tech for a Blanchard Assistant Professor Fellowship.
K.M.F. acknowledges Georgia Tech and the National Science
Foundation for a summer REU (NSF REU 1156657).
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