Facile Synthesis of 2,2-Diacyl Spirocyclohexanones via an N-Heterocyclic Carbene-Catalyzed Formal [3C + 3C] Annulation

Article abstract of DOI:10.1021/acs.orglett.8b03892

A novel strategy for the construction of 2,2-diacyl spirocyclohexanones 3 has been demonstrated on the basis of an NHC-catalyzed [3C + 3C] annulation of potassium 2-oxo-3-enoates with 2-ethylidene 1,3-indandiones. Furthermore, enantioenriched 3 was obtained in good to excellent yields with good enantioselectivities when chiral N-heterocyclic carbene (NHC) was employed. Notably, ring opening of the resulting 2,2-diacyl spirocyclohexanones 3 with hydrazine led to the formation of phthalazinones in good to excellent yields.

Full text of DOI:10.1021/acs.orglett.8b03892

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Facile Synthesis of 2,2-Diacyl Spirocyclohexanones via an
N‑Heterocyclic Carbene-Catalyzed Formal [3C + 3C] Annulation
Yaru Gao,†,‡ Dehai Liu,‡ Zhenqian Fu,*,†,‡ and Wei Huang*,†,‡
†Shaanxi Institute of Flexible Electronics (SIFE), Northwestern Polytechnical University (NPU), 127 West Youyi Road, Xi’an
710072, China
‡Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation
Center for Advanced Materials (SICAM), Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, China
S
* Supporting Information
ABSTRACT: A novel strategy for the construction of 2,2-
diacyl spirocyclohexanones 3 has been demonstrated on the
basis of an NHC-catalyzed [3C + 3C] annulation of
potassium 2-oxo-3-enoates with 2-ethylidene 1,3-indandiones.
Furthermore, enantioenriched 3 was obtained in good to
excellent yields with good enantioselectivities when chiral N-
heterocyclic carbene (NHC) was employed. Notably, ring opening of the resulting 2,2-diacyl spirocyclohexanones 3 with
hydrazine led to the formation of phthalazinones in good to excellent yields.
Scheme 1. Examples of NHC-Catalyzed [3C + 3C]
Annulation Reactions
ver the past decade, N-heterocyclic carbenes (NHCs)
Ohave been proven to be privileged organocatalysts and
enabled the construction of a series of structurally diverse
carbo- and heterocycles.1 In contrast to the well-studied NHC-
catalyzed [3 + 3] annulation for the synthesis of six-membered
heterocycles,2−4 the NHC-catalyzed [3C + 3C] annulation for
the synthesis of six-membered carbocycles is far less studied.5
In 2014, the Chi group5a reported a pioneering work on an
NHC-catalyzed oxidative formal [3C + 3C] cycloaddtion of β-
methyl enals (or esters)5b with enones for the construction of
benzene units (Scheme 1a). Subsequently, the group of Biju5c
described an NHC-catalyzed formal [3C + 3C] annulation of
α-arylidene pyrazolinones with enals for enantioselective
synthesis of pyrazolone-fused spirocyclohexadienones (Scheme
1b). Despite this progress, further development of a novel
NHC-catalyzed [3C + 3C] annulation reaction access to useful
molecules is still highly desirable. Moreover, due to chiral
spirocyclic scaffolds that are widespread in a large number of
natural products,6 bioactive compounds,7 and organic
optoelectronic materials,8 the synthesis of this class of
privileged structures has received considerable attention.9
Especially, an NHC-catalyzed construction of these chiral
spirocyclic compounds was identified as one of the most
attractive strategies.10 As part of our ongoing interest in the
NHC catalysis,11 we herein present a novel NHC-catalyzed
[3C + 3C] annulation of potassium 2-oxo-3-enoates 1 with 2-
ethylidene 1,3-indandione 212 for the synthesis of 2,2-diacyl
spirocyclohexanones (Scheme 1c), which are often presented
as core structural scaffolds in numerous polycyclic polypreny-
lated acylphloroglucinol natural products.13 Notably, com-
pared to well-studied β-methyl enones as 4C synthons,14 2-
ethylidene 1,3-indandiones 2 are found as 3C synthons in this
NHC-catalyzed reaction.
Easily prepared and purified potassium (E)-2-oxo-4-phenyl-
but-3-enoate (1a), which has been successfully applied in
NHC-catalyzed reactions as an effective and versatile surrogate
for α,β-unsaturated aldehyde,11b was initially selected in the
Received: December 6, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03892
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
reaction with 2-(1-phenylethylidene)-1H-indene-1,3(2H)-
dione 2a for optimizing conditions. The key results are
summarized in Table 1. Delightingly, when triazolium N-Mes
Scheme 2. Substrate Scope
a
Table 1. Screening of Reaction Conditions
e
entry
NHC
base
Et3N
Et3N
LiCl (equiv)
solvent
yield (%)
1
2
3
4
5
6
A
B
A
A
A
A
A
A
A
A
A
A
A
-
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
-
THF
THF
THF
THF
THF
THF
THF
DCM
dioxane
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
54
28
29
62
45
54
71
18
75
29
56
80
nd
nd
36
Cs2CO3
DIPEA
K2CO3
NaOAc
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
b
7
b
8
b
9
b
10
c
11
b
12
b
13
b
14
1.0
1.0
bd
,
15
A
a
Reaction conditions: NHC precursor (15 mol %), 1a (1.5 equiv), 2a
(0.1 mmol), base (1.5 equiv), LiCl (2.0 equiv), [O] (2.2 equiv),
b
dioxane (1.0 mL), and 4 Å MS (10 mg), rt, 24 h. DIPEA (2.0 equiv).
a
c
d
e
Reaction conditions as in Table 1, entry 12. Yields (after SiO2
DIPEA (2.5 equiv). Cinnamaldehyde was used instead of 1a Yields
chromatography purification) were based on 2.
(after SiO2 chromatography purification) were based on 2a. nd = not
detected.
precursor A was employed with LiCl15,16 as an additive in the
presence of Et3N in THF at room temperature, the desired [3
+ 3] annulation product 3a was formed in 54% yield (entry 1).
None of the [4 + 2] annulation product was found. The use of
triazolium N-Ph precursor B instead of A decreased the
product yield considerably. Several bases were next evaluated,
and DIPEA proved to be the most effective choice (entries 3−
6). Increasing the amount of base loading to 2.0 equiv
increased the yield of product 3a significantly (entry 7).
Further solvent screening showed that dioxane was a better
solvent (entries 7−10). Reducing the amount of additive LiCl
increased the product yield considerably (entry 12). Notably,
in the absence of the additive LiCl or the catalyst, none of
desired product was found (entries 13 and 14). Replacement
of 1a with cinnamaldehyde led to a considerable decrease in
the product yield (entry 15).
With optimized conditions in hand (Table 1, entry 12), we
next evaluated the scope of the reaction for potassium 2-oxo-3-
enoates 1 by using 2a as a model substrate (Scheme 2). For
salts 1 bearing both electron-rich and electron-deficient
substituents on the γ-phenyl ring, the reactions proceeded
smoothly to generate the corresponding products (3a−g) in
good yields. γ-Styryl substituent 1h was also a suitable
substrate for this transformation, delivering the product 3h
in 70% yield. Delightingly, salts 1 bearing γ-heteroaryl
substituents (such as thiophen-2-yl, thiophen-3-yl, and
pyridin-3-yl) reacted well to give the desired products 3i−3k
in acceptable to excellent yields. Then, variation of the R2
group of 2-ethylidene 1,3-indandione 2 also showed a broad
scope and led to similar results as for the salts 1. Notably,
replacement of the aryl with a methyl group for R can provide
the desired product 3r, albeit with a lower yield. Notably, in
contrast to NHC-catalyzed α,β-unsaturated aldehyde reactions,
clear TLC ensures easy separation of product for reactions
involving salts 1.
After successful establishment of this efficient strategy, a
chiral NHC-catalyzed enantioselective [3C + 3C] annulation
for the synthesis of chiral spirocyclic cyclohexanones was then
investigated. In fact, it is very challenging to realize the
asymmetric [3C + 3C] annulation due to the R group far away
from the reaction site. Gratifyingly, the desired chiral product
3s was obtained in 90% yield with good enantioselectivity
(81:19 er) when aminoindanol-derived triazolium precatalyst
E was used (for details, see Supporting Information).
Replacement of the methyl group with the ethyl or benzyl
group did not improve enantioselectivity (Scheme 3). Absolute
configuration of the asymmetric products 3 was confirmed via
X-ray diffraction analysis of 3w.
B
DOI: 10.1021/acs.orglett.8b03892
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
the free carbene and form intermediate VII, which undergoes
further oxidation finally to generate the product 3a.
Scheme 3. Substrate Scope
Subsequently, further synthetic utility of 2,2-diacyl cyclo-
hexanones was performed as shown in Scheme 5. Ring opening
Scheme 5. Synthetic Transformations
a
Reaction conditions as in Table S1, entry 10. Yields (after SiO2
chromatography purification) were based on 2.
The proposed pathway for NHC-catalyzed formal [3 + 3]
annulation to assemble 2,2-diacyl spirocyclohexanones is
illustrated in Scheme 4. The salt 1a was activated by LiCl
a
Reaction conditions: 3 (0.2 mmol), hydrazine hydrate (1.0 equiv),
NaOAc (0.5 equiv), and DMF (2.0 mL), 100 °C, 8 h.
Scheme 4. Proposed Mechanism
of the resulting products 3 could be readily realized by
treatment with hydrazine hydrate in DMF under basic
conditions at 100 °C, leading to the formation of
phthalazinones 4a−f in good to excellent yields. Notably,
phthalazinones were found to possess a range of promising
biological activities, such as antimicrobial activity, antitumor
activity, and anticancer activity.17 They were used as PARP
inhibitors and androgen receptor antagonists as well.18
In summary, an NHC-catalyzed [3C + 3C] annulation of
potassium 2-oxo-3-enoates with 2-ethylidene 1,3-indandione
has been demonstrated. A diverse set of 2,2-diacyl
spirocyclohexanones 3 was generated in good to excellent
yields. Furthermore, enantioenriched 3 was obtained in good
to excellent yields with good enantioselectivities when chiral
NHC was employed. Ring opening of the generated products 3
with hydrazine led to the formation of important bioactive
phthalazinones in good to excellent yields. Other reaction
models for salts 1 are currently under investigation in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03892.
via coordination to give more reactive intermediate I, which
reacts with NHC to form homoenolate intermediate II after
liberation of CO2. Subsequently, oxidation of homoenolate
intermediate I results in the formation of α,β-unsaturated acyl
triazolium intermediate III.1k Then, Michael addition of
intermediate IV obtained from 2a via deprotonation, to α,β-
unsaturated acyl triazolium intermediate III, furnishes
intermediate V. Intermediate V further undergoes proton
transfer followed by intramolecular cyclization to regenerate
Experimental procedures and spectral data for all new
compounds (PDF)
Accession Codes
CCDC 1858928 contains the supplementary 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
C
DOI: 10.1021/acs.orglett.8b03892
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: iamzqfu@njtech.edu.cn.
*E-mail: iamwhuang@njtech.edu.cn.
ORCID
Zhenqian Fu: 0000-0002-3806-6684
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support by the National Natural
Science Foundation of China (21602105), National Key R&D
Program of China (2017YFA0204704), and Natural Science
Foundation of Jiangsu Province (BK20171460).
(4) Yi, L.; Chen, K.; Liang, Z.; Sun, D.; Ye, S. Adv. Synth. Catal.
2017, 359, 44.
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DOI: 10.1021/acs.orglett.8b03892
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