Access to Highly Functionalized Indanes from Arynes and α,γ-Diketo Esters

Article abstract of DOI:10.1021/acs.orglett.8b03919

An unprecedented method for the synthesis of highly functionalized indanes from arynes and α,γ-diketo esters is described. Importantly, mild and nearly pH-neutral conditions ensure excellent functional group tolerance. Theoretical studies indicated that t

Full text of DOI:10.1021/acs.orglett.8b03919

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Access to Highly Functionalized Indanes from Arynes and α,γ-Diketo
Esters
Wanyao Hu,†,§ Cong Zhang,†,§ Jie Huang,*,‡ Yingying Guo,† Zhenqian Fu,*,† and Wei Huang*,†
‡
†Key Laboratory of Flexible Electronics & Institute of Advanced Materials and Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech
University, 30 South Puzhu Road, Nanjing, 211816, China
S
* Supporting Information
ABSTRACT: An unprecedented method for the synthesis of
highly functionalized indanes from arynes and α,γ-diketo
esters is described. Importantly, mild and nearly pH-neutral
conditions ensure excellent functional group tolerance.
Theoretical studies indicated that the reaction proceeds
through a benzocyclobutane intermediate.
ndanes (benzocyclopentanes) are often presented as the core
structural scaffolds in numerous natural products and
Scheme 1. Synthetic Strategies for Indanes
I
pharmaceuticals with a wide range of promising biological
properties (Figure 1).1 Specifically, Indinavir,2 one of World
Figure 1. Selected indane-containing bioactive compounds, catalysts,
and ligands.
Health Organization’s List of Essential Medicines, is used for
treating HIV/AIDS. Fredericamycin A3 displays potent
antitumor activity against a variety of in vivo tumor models,
involving P388 leukemia, B16 melanoma, and CD8F mammary.
SB 2096704 exhibits a highly potent antagonist selective for the
endothelin receptors. Moreover, indanes are also found as the
core motifs for organocatalysts5 and ligands.6 Consequently,
considerable effort has been devoted to this field. Many elegant
approaches have been successfully developed,7 mainly including
intramolecular cyclization,8 intermolecular [4 + 1],9 and [3 +
2]10 annulation (Scheme 1). Notably, the above-mentioned
methods often require the use of acids, bases, or transition-metal
catalysts, hindering tolerance of functional groups. The
development of a conceptually new synthetic methodology for
highly functionalized indanes still remains a considerable
challenge and is in high demand.
Direct difunctionalization of arenes can directly and efficiently
increase the complexity of arenes. Representative methods
Received: December 8, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03919
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include transition metal-catalyzed direct difunctionalization of
aryl halides11 and transition metal-free direct difunctionalization
of arynes.12,13 Owing to arynes possessing several advantages,
such as ease of availability, high reactivity, transition metal-free,
and mild reaction conditions, the use of arynes for the direct
difunctionalization of arenes has received considerable
attention. As part of our ongoing interest in the synthesis of
carbo- and heterocycles,14 we envisaged that a new strategy for
the synthesis of highly functionalized indanes might be achieved
from the reaction of arynes and α,γ-diketo esters under mild
conditions. Actually, there are two possible reaction pathways
when α,γ-diketo esters were employed in aryne chemistry. One
involves a formal [3 + 2] annulation of arynes with α,γ-diketo
esters to give indanes 3′. The other involves the formation of
benzocyclobutane15 followed by ring-opening and intramolec-
ular cyclization, finally to generate indanes 3. We presumed that
five-membered ring formation would be dominant over four-
membered ring formation due to the ring stain. Consequently,
indanes 3′ should be the expected products. Surprisingly, the
unexpected products 3 were indeed obtained. Herein, we
describe an unprecedented approach for the direct synthesis of
highly functionalized indanes from arynes and α,γ-diketo esters
under mild and nearly pH-neutral conditions. Notably, in
contrast with phenyl moieties as three-, four-, or five-carbon
synthons in previous work, aryne precursors were used as two-
carbon synthons for the construction of indanes via an
unprecedented domino process. Importantly, mild and nearly
pH-neutral conditions ensure excellent tolerance of functional
groups.
was obtained in 70% yield with 2.4:1 dr (entry 1). Their
structures were confirmed by X-ray diffraction analysis.17 Other
common solvents screening, such as THF, DCM, 1,4-dioxane,
and the solvent mixture of CH3CN and THF, did not further
improve the product yield and diastereoselectivity. Switching F−
source to TBAF with CH3CN as solvent, the indane 3a was
obtained in 63% yield with 3.9:1 dr. Similarly, other common
solvents investigation did not give satisfactory outcomes.
Subsequently, we moved to using KF as a F− source and 18-
crown-6 as an additive in THF at room temperature, the product
3a was obtained in up to 74% yield with 5.1:1 dr. To our delight,
decreasing reaction temperature (0 °C) can further improve the
product yield to 78% with up to 6.0:1 dr. Notably, other
diastereomers of 3a were not detected, perhaps due to this
transformation through a sequential domino process.
With acceptable optimized conditions in hand (Table 1, entry
12), we then evaluated the scope of α,γ-diketo esters substrates
by using Kobayashi benzyne precursor 2a as a model substrate
(Scheme 2). Changing the R1 group from ethoxy group to
methoxy group, benzoxy, and even methyl group, the reactions
proceeded smoothly to give the corresponding products 3b−3d,
respectively. For R2, the methyl group can be replaced with an
ethyl or phenyl group, with the corresponding products 3d and
3e obtained with moderate yields and dr. The substrates with R3
bearing several substituted groups (Me, OMe, F, Cl, Br) on the
aromatic rings were used under standard conditions, affording
the corresponding products 3f−3l in acceptable yields and dr.
When R3 is the 2-naphthyl group, the indane 3m was obtained in
69% yield with 2.2:1 dr. Only ring-opening product 3n was
found probably due to unsuccessful deprotonation of ester
groups under reaction conditions. When α,δ-diketo ester 1o was
used, expected benzocyclohexane was not detected. Instead,
ring-opening product 3o was formed, albeit with a lower yield.
Notably, a 1-g reaction of 2a worked very well, affording 3a in
61% yield and 2.1:1 dr. Replacement of R2CO with methyl or
phenyl did not give the desired product.
The reaction of readily available ethyl 2-acetyl-4-oxo-4-
phenylbutanoate 1a and Kobayashi benzyne precursor16 2a
was selected as a model reaction for optimizing the conditions.
The key results are summarized in Table 1. When CsF was used
as the F− source in CH3CN at room temperature, the expected
indane 3a′ was not observed. Instead, the unexpected indane 3a
Then, we investigated the generality of aryne precursors 2,
and the results are summarized in Scheme 3. Arynes bearing
electron-donating groups, such as 4-methyl, 4,5-dimethoxy, and
3-methoxy groups on the aromatic rings, the reactions
proceeded smoothly to furnish the indanes 3p and 3r in 53−
69% yields with 2.2:1−5.7:1 dr. Both symmetric and
unsymmetric naphthyl aryne precursors were suitable substrates
for this transformation to give the products 3s and 3t,
respectively. To our delight, aryne precursor with a 4,5-difluoro
group was also a suitable substrate, leading to the formation of
product 3u in 42% yield with 3.9:1 dr.
Based on previous work, the current results, and theoretical
studies, a proposed reaction pathway for the formation of
indanes is illustrated in Scheme 4. Aryne intermediate I was in
situ generated from o-silyl aryl triflate 2a mediated by the F−
source under mild and nearly pH-neutral conditions. Inter-
mediate II, derived from 1a via deprotonation, attacks aryne
intermediate I to form intermediate III. Subsequently, there are
two possible pathways. One is directly to form indane 3a′
(pathway 4). The other is to form benzocyclobutane
intermediate IV followed by ring-opening to give intermediate
V. Then, intermediate V undergoes proton transfer followed by
intramolecular cyclization and protonation to form indane 3a.
In order to understand the mechanism, theoretical studies
were performed as shown in Figure 2a (technical details given in
Supporting Information). Theoretical studies indicate that the
energy barrier for the formation of the benzocyclobutane
a
Table 1. Screening Reaction Conditions
F−
yield
b
c
entry
source
additive
solvent
CH3CN
THF
(%)
dr
1
2
CsF
CsF
70
61
68
52
68
63
59
60
62
74
50
78
2.4:1
1.9:1
1.8:1
1.5:1
2.1:1
3.9:1
3.5:1
2.0:1
2.5:1
5.1:1
3.0:1
6.0:1
3
CsF
DCM
4
CsF
dioxane
CH3CN/THF = 1:1
CH3CN
THF
5
CsF
6
7
8
9
TBAF
TBAF
TBAF
TBAF
KF
DCM
dioxane
18-crown-6 THF
18-crown-6 CH3CN
18-crown-6 THF
10
11
KF
KF
d
12
a
Reaction conditions: 1a (0.2 mmol), 2a (1.2 equiv), F− source (3.0
equiv), 18-crown-6 (3.0 equiv) in solvent (2.0 mL) at room
temperature. Isolated yields after column chromatography. Diaster-
b
c
1
eomeric ratio of 3a, determined via H NMR analysis of unpurified
d
reaction mixtures. At 0 °C.
B
DOI: 10.1021/acs.orglett.8b03919
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. Substrate Scope
Scheme 3. Substrate Scope
a
Reaction conditions as in Table 1, entry 12; yields (after SiO2
chromatography purification) were based on α,γ-diketo esters 1.
Scheme 4. Proposed Mechanism
a
Reaction conditions as in Table 1, entry 12; yields (after SiO2
chromatography purification) were based on α,γ-diketo esters 1. 5
mmol scale reaction.
sesses lower energy barrier and more energy stable than minor
isomers (for details, see Supporting Information). These led to
the products obtained with good diastereoselectivities.
Subsequently, further synthetic transformation of the highly
functionalized indanes was conducted as shown in Scheme 5.
Treatment of 3c with ammonium acetate efficiently furnished
trisubstituted pyrole 4 in 65% yield via a [4 + 1] cyclization and
retro-aldol process. Dehydration of indane 3c was readily
realized with P2O5 in toluene at reflux and led to the formation of
indene 5 in 88% yield. Interestingly, DIBAL-H can selectively
reduce the carbonyl group from acetyl moiety, rather than
benzoyl moiety, generating 6 containing two hydroxyl groups in
89% yield with good selectivity of the hydride reduction (10:1
dr).
intermediate IV is over 1.0 kcal/mol relative to its intermediate
III. Meanwhile, the energy barrier for the formation of a five-
membered ring is 9.5 kcal/mol for pathway 2. The energy
difference suggests that pathway 1 should be more energetically
favorable in kinetics. Additionally, the final product 3a for
pathway 1 is more stable than 3a′ by 7.8 kcal/mol. Therefore,
pathway 1 should be more energetically preferred than pathway
2. Moreover, both of the pathways are strongly exothermic,
rendering the reaction irreversible.
As shown in Figure 2b, major_int_1 and minor_int_1 were
generated from the rotation of acetyl group of intermediate VI.
Interaction between methyl group and on the same side of
benzoyl group reduces their distance and also stabilizes the
intermediate major_int_1. Furthermore, major isomer pos-
In summary, we have developed an unprecedented method
for the synthesis of highly functionalized indanes from arynes
and α,γ-diketo esters. A diverse set of indanes with highly
functionalized groups was efficiently obtained in acceptable to
C
DOI: 10.1021/acs.orglett.8b03919
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Organic Letters
Letter
Accession Codes
CCDC 1835638, 1893205, and 1893210 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: iamjhuang@njtech.edu.cn.
*E-mail: iamzqfu@njtech.edu.cn.
*E-mail: iamwhuang@njtech.edu.cn.
ORCID
Zhenqian Fu: 0000-0002-3806-6684
Author Contributions
§W.H. and C.Z. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Figure 2. (a) Free energy profile for the reaction obtained at the SMD-
M06-2X/6-311++G(2d,2p)//SMD-M06-2X/6-31G(d) level in THF
solution. (b) Geometries of major_int_1 and minor_int_1 obtained
with SMD-M06-2X/6-31G(d) method.
We acknowledge financial support by National Natural Science
Foundation of China (Grant 21602105), Natural Science
Foundation of Jiangsu Province (Grant BK20171460), National
Key R&D Program of China (Grant 2017YFA0204704), and
National Key Basic Research Program of China (973) (Grant
2015CB932200). We thank D. Liu in this group for reproducing
the reactions of 3a, 3f, and 3h. We greatly appreciate the High
Performance Computing Center of Nanjing Tech University for
providing computational resources.
Scheme 5. Synthetic Transformations
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03919.
Experimental procedures and spectral data for all new
compounds (PDF)
D
DOI: 10.1021/acs.orglett.8b03919
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DOI: 10.1021/acs.orglett.8b03919
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