Phosphorus(III)-Mediated Stereoconvergent Formal [4+1]-Cycloannulation of 1,2-Dicarbonyls and o-Quinone Methides: A Multicomponent Assembly of 2,3-Dihydrobenzofurans

Article abstract of DOI:10.1021/acs.orglett.6b02122

A phosphorus(III)-mediated formal [4+1]-cycloaddition of 1,2-dicarbonyls and o-quinone methides to provide 2,3-dihydrobenzofurans is described. By exploiting the carbene-like nature of dioxyphospholenes, dihydrobenzofurans bearing a quaternary center at C2 are obtained in 30-92% yield with diastereoselectivities up to ≥20:1. This study highlights the subtle steric interactions involved in the [4+1]-cycloannulation and the impact they have on yield and stereoselectivity in dihydrobenzofuran formation.

Full text of DOI:10.1021/acs.orglett.6b02122

Letter
pubs.acs.org/OrgLett
Phosphorus(III)-Mediated Stereoconvergent Formal [4+1]-
Cycloannulation of 1,2-Dicarbonyls and o‑Quinone Methides: A
Multicomponent Assembly of 2,3-Dihydrobenzofurans
Kevin X. Rodriguez, Justin D. Vail, and Brandon L. Ashfeld*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
S
* Supporting Information
ABSTRACT: A phosphorus(III)-mediated formal [4+1]-cycloaddition
of 1,2-dicarbonyls and o-quinone methides to provide 2,3-dihydroben-
zofurans is described. By exploiting the carbene-like nature of
dioxyphospholenes, dihydrobenzofurans bearing a quaternary center at
C2 are obtained in 30−92% yield with diastereoselectivities up to ≥20:1.
This study highlights the subtle steric interactions involved in the [4+1]-
cycloannulation and the impact they have on yield and stereoselectivity
in dihydrobenzofuran formation.
nlike sequential fragment coupling/cyclization ap-
proaches, pericyclic and transition-metal-catalyzed cyclo-
U
additions1 offer convergent entry into functionalized hetero-
cycles. Despite impressive advances in intramolecular C−H
activations,2 [3+2]-cycloadditions are still widely used for 5-
membered heterocycle construction.3 In contrast, [4+1]-cyclo-
additions and chelotropic processes are significantly underutil-
ized in this context (Scheme 1).4 Frequently, high activation
energies and competing cyclopropane/aziridine formation from
carbenoids/nitrenoids limit the versatility of these strategies.5
Albeit nontrivial, addressing these challenges would enable site-
specific heterocycle functionalization through the geminal
substitution of a single carbon unit, such as 2,3-dihydrobenzofur-
ans bearing a C2 quaternary center. The 2,3-dihydrobenzofuran
ring system is an important motif present in a number of natural
products and pharmaceuticals for use in the treatment of an array
of maladies (Figure 1).6As a result, the development of new
methods toward this subunit has attracted the attention of
synthetic chemists for decades.7
Figure 1. Biologically active dihydrobenzofuran natural products.
of accessing carbenoid reactivity,10 this approach is often
hampered by the light and heat sensitivity of diazo compounds
and would likely suffer from competitive C−H arylations and
cyclopropanations en route to the desired dihydrobenzofurans.11
Inspired by recent independent studies conducted by Radosevich
and He, we chose to employ a Kukhtin−Ramirez-like
condensation in which the addition of a phosphine to ketone 5
bearing an α-electron-withdrawing group generates an oxy-
phosphonium enolate 7 that exhibits carbene-like reactivity
(Scheme 2).12 Generation of o-QM 6 from silyl ether 49c,13
followed by 1,4-addition of 7 sets the stage for an O-alkylation
Scheme 1. [4+1]-Approach toward Heterocycle Construction
Scheme 2. Proposed 2,3-Dihydrobenzofuran Synthesis
Despite their utility, few existing methods provide direct access
to 2,3-substituted dihydrobenzofurans in a stereoselective
fashion.7a,8 Speculating that a formal [4+1]-cycloaddition
approach would rapidly install quaternary substitution at C2
while maintaining structural flexibility at C3, we sought to apply
the retrosynthetic disconnect outlined in Scheme 1 by the
addition of a carbenoid derivative into an o-quinone methide (o-
QM).9 While decomposition of α-diazo carbonyls using
transition-metal catalysts is perhaps the most common means
Received: July 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02122
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Letter
a
event, in which PO bond formation acts as a thermodynamic
driving force, to provide 2,3-dihydrobenzofuran 8.14
Scheme 4. Fluoride-Mediated o-QM Generation
At the outset of this study, we were acutely aware of the
synthetic challenges this strategy carried with it, including the
potential for competitive C-alkylation of the initial conjugate
addition adduct to yield cyclopropane 9.9e,15 Additionally, we
were concerned that the low temperature conditions required for
o-QM generation may be incompatible with oxyphospholene
formation9c,13 and competitive self-condensation of ketone 5
would hinder dihydrobenzofuran formation.12b Herein, we
describe the successful implementation of this [4+1]-cyclo-
addition strategy toward 2,3-dihydrobenzofuran construction
and the development of a three-component assembly to access
vicinal 2,3-substitution with a high degree of diastereoselectivity.
To evaluate our strategy outlined in Scheme 2, we examined
the addition of α-ketoester 5a to o-QM precursor 4a in the
presence of P(NMe2)3 and a fluoride source (Scheme 3). While
TBAF led to an intractable mixture of products, we discovered
that TBAT gave dihydrobenzofuran 8a in 43% yield.16 The yield
improved to 82% using CsF and 18-c-6, and time and
temperature proved critical toward minimizing o-QM dimer
formation and self-condensation of 5a.12b Allowing the reaction
to warm slowly from −78 °C to room temperature, following the
sequential addition of fluoride and P(NMe2)3, effectively
eliminated these side reactions. Likewise, treatment of isolable
o-QM 6a to 5a and P(NMe2)3 yielded syn-2,3-dihydrobenzofur-
an 8b as a single stereoisomer in 76% yield.17
a
Conditions: CsF (0.52 mmol) and 18-c-6 (0.52 mmol) were added to
4 (0.26 mmol) in CH2Cl2 (0.5 M) followed by 5 (0.34 mmol) and
P(NMe2)3 (0.34 mmol).
Scheme 3. Initial Findings
ing o-QM.9e,18 Whereas the addition of MeMgBr or MeLi/
MgBr2·OEt2 to salicylaldehyde 10a failed to provide dihydro-
benzofuran 8h, the addition of MeLi, followed by 5a and
P(NMe2)3, produced adduct 8h in 92% yield (Scheme 5).
Interestingly, the addition of HMPA (1 equiv) led to a decrease
in the yield of 8h, which would seem to highlight a delicate
balance in metal alkoxide charge separation for controlled o-QM
generation. This modification of Pettus’ method enabled ready
access to 2,3-disubstituted dihydrobenzofurans.
Excited by these initial results, we next evaluated the functional
group compatibility of this approach (Scheme 4). While both
electron-rich and electron-poor aryl-substituted α-ketoesters
were tolerated, the yield of dihydrobenzofuran 8 was higher with
electron-deficient arenes. This is consistent with a mechanism
involving an initial nucleophilic addition of P(NMe2)3 to the α-
ketoester as proposed by Ramirez and co-workers.12c Similarly,
chloride substitution on 4b gave cycloadduct 8g in 92% yield.
While benzylic substitution on 4c did not hinder formation of 8h,
the reaction proceeded with 1:1 diastereoselectivity. Symmetrical
and unsymmetical 1,2-diketones were effective as demonstrated
by the conversion of benzil 5f to 8i in 77% yield and
unsymmetrical diketone 5g to methyl ketone 8j in 48% as a
single regioisomer. Interestingly, employing α-ketoesters bearing
alkyl and vinyl β-substituents failed to provide the corresponding
benzofuran in appreciable yields.
Unfortunately, synthesis of the secondary benzylic bromides
proved low yielding and hampered the application of this method
toward 2,3-substituted cycloadducts. To address this issue we
were inspired by Pettus’ work on hetero-Diels−Alder cyclo-
additions in which he showed that addition of Grignard reagents
to Boc-protected salicylaldehyde derivatives initiates a 1,5-acyl
migration/β-elimination sequence to generate the correspond-
Scheme 5. Organometallic o-Quinone Methide Generation
In general, good to excellent yields of the cycloadducts were
obtained from various salicylaldehydes 10 and organolithium
reagents (Scheme 6). Substitution on 10 did not adversely affect
the formation of dihydrobenzofurans 8k−m, as exemplified by
the presence of two electron-donating groups in 8m. Using PhLi
enabled smooth o-QM formation to give adducts 8n−p.
Consistent with our previous results, electron-poor aryl α-
ketoesters gave higher yields of 8 than their electron-rich
counterparts (i.e., 8o and 8p). Employing phenyl acetylide gave
8q bearing an alkyne at C3. It is also noteworthy that although
the C3-methyl-substituted dihydrobenzofuran 8r was obtained
in 73% yield, employing PhLi led to a diminished yield of 8s.
Over the course of these studies, we became acutely aware of
the discrepancy between the diastereoselectivities observed for
B
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Letter
a
a,b
Scheme 6. Dihydrobenzofuran Assembly
Scheme 8. Dihydronaphthylfuran Synthesis
a
Conditions: MeLi (0.28 mmol) was added to 11 (0.26 mmol) in
PhMe (0.2 M), followed by 5 (0.34 mmol) and P(NMe2)3 (0.34
b
1
mmol). Ratios determined by H NMR (500 MHz).
leading to formation of 12b and 12c in excellent yield and
consistently high diastereoselectivity. Employing α-keto esters
5b and 5c likewise gave the corresponding dihydronaphthylfur-
ans 12d and 12e exclusively in 75% and 45% respectively.
Strikingly, we observed a stereoconvergent dihydrobenzofuran
assembly to the syn-2,3 isomer, whether employing the
presumptive Z-alkylidene from 11 or E-alkylidene 6a.
On the basis of these results, a preliminary picture arises of the
stereochemical control elements in this formal [4+1]-cyclo-
annulation. Addition of P(NMe2)3 to 5a provides an equilibrium
of oxyphospholene 7a and zwitterion 7b (Scheme 9). Ramirez
a
Conditions: R2Li (0.29 mmol) was added to 10 (0.26 mmol) in
PhMe (0.2 M), followed by 5 (0.34 mmol) and P(NMe2)3 (0.34
mmol).
Scheme 9. Dioxyphospholene/Zwitterion Formation
dihydrobenzofurans in Schemes 4 and 6 and the high degree of
selectivity for 8b (Scheme 3). Given that the E-alkylidene 6a gave
exclusively the anti isomer of 8b, we speculated that o-QM
alkylidene integrity was critical to 2,3-diastereoselectivity.8d
Based on this assertion, it is plausible that an unselective in situ
generation of the o-QM or rapid E-to-Z isomerization mediated
by P(NMe2)3 is responsible for the low diastereoselectivities
observed with those substrates in Scheme 6.19 This is consistent
with the observation that treatment of 6a, which provided 8b as a
single stereoiosomer, with P(NMe2)3 in the absence of 5a failed
to provide the corresponding Z-isomer (Scheme 7). The sharp
contrast in diastereoselectivity between 8b and 8k−s suggests
that the selective generation of a geometrically stable o-QM
alkylidene is critical to achieving high C2−C3 diastereoselectiv-
ity.
has shown that this equilibrium favors the more nucleophilic
zwitterion 7b (L = NMe2).20 If we assume an electrostatic
attraction between the o-QM carbonyl oxygen and phosphonium
cation, transition states 13a and 13b arise from the addition of 7b
to o-QMs 6a and 11, respectively (Scheme 10). Minimizing
gauche interactions orients the larger aryl group away from the o-
QM benzenoid ring in 13a, resulting in phosphine oxide
displacement through anti-conformer 14a to give syn-8b.
Preference for syn-12 from the Z-naphthyl alkylidene is
potentially due to a combination of favorable π−π stacking
between the aryl group on 5 and the naphthyl ring and
Scheme 7. Alkylidene Geometric Stability
Scheme 10. Proposed Rationale for Diastereoselection
To test this hypothesis further, we examined 2-hydroxynaph-
thaldehyde derivatives 11 with a preference for Z-alkylidene
formation in the formation of dihydronaphthylfurans 12
(Scheme 8).8c Addition of MeLi to naphthaldehyde 11a followed
by 5a and P(NMe2)3 provided 12a in 80% yield and ≥20:1
stereoselectivity. Electron-withdrawing halogens at C6 of the
naphthyl ring were well tolerated in the cycloaddition event
C
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02122.
■
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Experimental procedures and spectroscopic data for all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bashfeld@nd.edu.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CAREER CHE-
1056242) and Walther Cancer Foundation Advancing Basic
Cancer Research Program for financial support of this research.
K.X.R. was supported by a Walther Cancer Foundation
ENSCCII Training Grant. We thank the Mike and Josie Harper
Cancer Research Institute for their support.
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Ashfeld, B. L. Angew. Chem., Int. Ed. 2013, 52, 11589.
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