Access to Benzylic Quaternary Carbons from Aromatic Ketones

Article abstract of DOI:10.1021/acs.orglett.9b02204

The construction of benzylic all-carbon quaternary stereocenters, which are ubiquitous in biomolecules and drugs, is a task of high practical significance. Herein, we disclose a highly efficient one-pot method of constructing all-carbon quaternary structu

Full text of DOI:10.1021/acs.orglett.9b02204

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Access to Benzylic Quaternary Carbons from Aromatic Ketones
You Li,† Jingpeng Han,‡ Han Luo,‡ Qiaoyu An,‡ Xiao-Ping Cao,*,† and Baosheng Li*,†,‡
†State Key Laboratory of Applied Organic Chemistry (SKLAOC), College of Chemistry and Chemical Engineering, Lanzhou
University, 222 South Tianshui Road, Lanzhou, 730000, P. R. China
‡School of Chemistry and Chemical Engineering, Chongqing University, 174 Shazheng Street, Chongqing, 400030, P. R. China
S
* Supporting Information
ABSTRACT: The construction of benzylic all-carbon quaternary
stereocenters, which are ubiquitous in biomolecules and drugs, is a
task of high practical significance. Herein, we disclose a highly efficient
one-pot method of constructing all-carbon quaternary structural units
from aryl ketones, revealing that the entire process involves three
consecutive chemical events, namely nucleophilic addition, Meinwald
1,2-hydrogen migration, and alkylation. Interestingly, dimerization of
acetophenones results in formation of 2,4-diarylfurans under the
employed conditions rather than the quaternary carbon products.
ubstituent change is an effective way to increase the
from the traditional Chinese medicine Phlegmariurus carinatus,
is used to treat rheumatism, swelling, and pain,10 while
sporochnol, isolated from the Caribbean marine alga
Sporochnus bolleanus, is a herbivorous fish deterrent.11
1
Sbiological activity of drugs.
In particular, all-carbon
quaternary stereocenters, i.e., those featuring carbon bonded
to four carbon substituents, can address a myriad of structural
diversity and conformational constraint issues in medicinal
chemistry. However, such stereocenters are difficult to
synthesize in view of the spatial congestion around the central
carbon, which highlights the need for the development of new
synthetic strategies.2 As indicated in Figure 1a, many of the
recently developed strategies construct quaternary carbon
centers from sp2-hybridized carbon-containing substrates such
as substituted olefins,3 enolate equivalents,4 and carbenoids;5
however, the synthesis of these substrates is trivial and usually
involves multiple functional group interconversions. Thus, the
development of general methods for the rapid and direct
conversion of simple widespread groups into core structural
units is a task of high practical significance.
Inspired by the ubiquity of the keto group and the
pharmaceutical importance of benzylic all-carbon quaternary
stereocenters, we herein developed a highly efficient and
practical strategy of directly constructing benzylic quaternary
stereocenters from aryl ketones via three consecutive trans-
formations. The first of these transformations, namely the
reaction of aromatic ketones with CH2I2 and MeLi, affords
epoxides,12 LiI, and MeI (Figure 1c). Subsequently, epoxides
are converted into aldehydes via LiI-catalyzed Meinwald-type
1,2-H migration,13 and α-alkylation of these aldehydes affords
the desired quaternary carbon centers. The above three-steps
reaction can be conducted in a one-pot manner; however,
several side reactions and problems may occur, i.e., the
formation of tertiary alcohols via the nucleophilic attack of
carbonyl groups by MeLi; generation of carbonyl α-
methylation products in the presence of MeLi and CH3I;
and low alkylation yields due to the steric hindrance of α-
benzylic aldehydes.
To examine the feasibility of the hypotheses, the α-tetralone
(1a) served as a model substrate to commence our studies
(Table 1). Fortunately, α-tetralone (1a) was converted
successfully into the desired aldehyde (2a′) in the presence
of 1.2 equiv CH2I2 in THF when MeLi (1.2 equivlents) was
added at 0 °C and warmed up to room temperature stirred for
6 h. Considering the lability, the aldehyde (2a′) was isolated
by flash column chromatography and reduced to alcohols (2a)
(Table 1, entry 1). The yield of 2a could be improved by
adding MeLi at −78 °C (entry 2), and a further yield
improvement (to 75%) was achieved by increasing the amount
The development of a method allowing the construction of
all-carbon quaternary stereocenters from ketones would
obviate lengthy and laborious substrate syntheses; nonetheless,
the corresponding research remains rare. Trost and co-workers
pioneered the construction of quaternary carbons via the
condensation of ketones with diphenylsulfonium cyclopropy-
lides.6 However, this transformation is limited to the
preparation of α-quaternary carbon cyclobutanones and is
rarely used in other aspects. Recently, Pace and co-workers
have accessed allylic all-carbon quaternary stereocenters
utilizing an impressive and highly efficient cascade reaction
limited to α,β-unsaturated ketones as substrates.7 Thus,
strategies using the carbonyl group for the construction of
quaternary stereocenters need to be further developed.
Benzylic all-carbon quaternary units are ubiquitous in many
natural products and pharmaceuticals (Figure 1b) and often
serve as versatile building blocks to access bioactive
molecules.8 For example, galanthamine is used for the early
treatment of Alzheimer’s disease,9 and carinatine A, isolated
Received: June 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02204
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Letter
complex mixture containing only trace amount of the desired
product (entry 7).
With the optimized conditions in hand, we investigated the
substrate scope of the above transformation (Table 2),
a
Table 2. Substrate Scope
Figure 1. (a) Access to all-carbon quaternary stereocenters from sp2
carbon atom, (b) representative natural products containing benzylic
quaternary centers, and (c) strategy of all-carbon quaternary center
construction used in the present study.
a
a
Table 1. Optimization of Reaction Condition
Unless otherwise noted, all reactions were performed with ketone
(0.20 mmol), CH2I2 (2.2 equiv) in THF (4 mL), MeLi (2.2 equiv)
was added at −78 °C and warmed up to rt stirred for 6 h under Ar.
The aldehyde was obtained by flash column chromatography. Then
the aldehyde was reduced with NaBH4 (1.0 equiv) in MeOH (2 mL)
b
at 0 °C for 10 min. Yields of the isolated product. No reduction
c
d
progress. ClCH2I was used instead of CH2I2. Allyl bromide (3.0
equiv) was added.
CH2I2/MeLi
(equiv)
time
(h)
yield
b
entry
temp (°C) solvent
(%)
1
2
3
4
5
1.2/1.2
1.2/1.2
2.2/2.2
2.2/2.2
2.2/2.2
2.2/2.2
2.2/2.2
0 to rt
THF
THF
THF
Et2O
toluene
THF
THF
6
6
6
6
6
6
6
20
31
75
56
40
trace
trace
−78 to rt
−78 to rt
−78 to rt
−78 to rt
−78 to rt
−78 to rt
revealing that the highest yield of the desired product (2b)
was obtained for 6-methoxytetralone (1b). For selectivity
investigation, α,β-unsaturated naphthalenone (1c) was reacted
under the standard reaction conditions to furnish an allylic
quaternary carbon center with excellent chemoselectivity and
in acceptable yield. Similarly, α-methyl tetralone (1d) afforded
the desired product with high diastereoselectivity (dr >20:1)
and in moderate yield. In addition, indanones were also
compatible with the standard conditions; e.g., species bearing
electron-donating (methyl group, 1e) and electron-with-
drawing (chloro group, 1f) substituents were converted into
the desired products in high yields. Intriguingly, non-
substituted indanone 1g yielded an aldol condensation product
2g, rather than desired aldehyde product. 2g was formed in situ
between aldehyde product 1g′ and substrate 1g. This
condensation reaction could not be suppressed by variation
of reaction conditions, in which case unidentified mixtures and
decreased yields were observed.
c
6
7
d
a
Unless otherwise noted, the reactions of ketone 1a (0.20 mmol) and
CH2I2 (2.2 equiv) were performed in 4 mL THF, MeLi (2.2 equiv)
was added at the indicated temperature and warmed up to rt stirred
for 6 h under Ar. The aldehyde 2a′ was obtained by flash column
chromatography. Then the aldehyde 2a′ was reduced with NaBH4
b
(1.0 equiv) in MeOH (2 mL) at 0 °C for 10 min. Isolated yields.
c
d
CeCl3 (1.0 equiv) was added. CH2Br2 instead of CH2I2.
of CH2I2/MeLi to 2.2 equiv (entry 3). Solvent screening
indicated that THF is the best solvent (entries 4 and 5), and
no further yield increase was achieved. Notably, aldehyde
formation was severely suppressed in the presence of CeCl3
(entry 6), and the use of CH2Br2 instead of CH2I2 afforded a
To increase the synthetic utility of the developed strategy,
we applied it to heteroaromatic ketones (1h−1l) with furan,
B
DOI: 10.1021/acs.orglett.9b02204
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Letter
thiophene, pyrrole, and indole moieties, obtaining the
corresponding quaternary carbon centers in satisfactory yields
(2h−2l).
To demonstrate the practical utility of the developed
method, a gram-scale reaction was performed, leading to the
formation of 2b with 61% yield (Scheme 1a). Also, it was
As the above cascade reaction was well suited for the
construction of methyl-substituted quaternary carbons, we
decided to examine the effects of additional electrophiles to
enhance product diversity and practicability. In particular, allyl
bromide was used as an electrophile to form multifunctional
quaternary carbon units. When 3.0 equiv of allyl bromide were
added to the reaction system, products 2m and 2n containing
allyl-substituted quaternary carbons were obtained in 66% and
60% yield, respectively, which indicated that allyl bromide
could be trapped by the enolate intermediate.
Scheme 1. Synthetic Transformation and Application
Finally, acyclic aromatic ketones were investigated to further
expand the substrate scope. Ketone 1o bearing a tethered
alkene substituent afforded an acyclic quaternary carbon-
containing product (2o) in 63% yield. However, when
acetophenone (3) was employed, 2,4-diphenylfuran (4a)14
was isolated in 41% yield instead of the expected quaternary
carbon product (Table 3). This unexpected result was ascribed
a b
,
Table 3. Syntheses of Furans from Acetophenones
applied to the synthesis of structurally interesting molecules
and bioactive natural products. Notably, 2b′ (obtained from
1b in 84% yield) was converted into symmetric ether 5 via
reduction with NaBH4 in CF3CO2H (Scheme 1b). Next, our
method was applied to the synthesis of ( )-sporochnol.12
Under standard conditions, aldehyde 2o′ was generated from
1o, CH2I2, and MeLi in 66% yield, and the following Wittig
methylation of 2o′ gave terminal alkene 6 in 80% yield, which
completed the formal synthesis of ( )-sporochnol (Scheme
1c).
In summary, the transformation of aromatic ketones into
benzylic all-carbon quaternary stereocenters has been achieved
via three consecutive chemical events in one pot, and this
strategy is of high practicability for the synthesis of natural
products and pharmaceuticals. In particular, the developed
method was employed in the formal synthesis of sporochnol
and the selective synthesis of furans from acetophenones.
Thus, we anticipate that our methods will be widely used in the
synthetic community. Further use of this strategy is in progress,
and the results will be reported in due course.
a
Reaction condition: 3 (0.20 mmol), MeLi (4.4 equiv), I2 (1.1 equiv)
b
in THF (4 mL), Ar, 0 °C, 4 h. Yields of isolated product.
to the formation of α-iodo-acetophenone (3′)15 in the
presence of I2 generated from LiI under oxidative conditions.
The aldol condensation of 3 and 3′ afforded chalcone
derivative 3′′, and subsequent annulation furnished the furan
product.14b
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.9b02204.
Syntheses of furans from simple ketones through a series of
chemical transformations especially condensation of aceto-
phone and haloacetophenone remain rare.14c Therefore, we
decided to increase the yield of furans obtained under our
conditions. After a brief optimization of reaction conditions
(4.4 equiv MeLi, 1.1 equiv I2, THF, 0 °C, 4 h), the yield of 4a
was increased to 77%. Substrates with aryl moieties bearing
both electron-donating and electron-withdrawing groups
readily participated in this transformation, affording the desired
products (4b−4g) in good yields with no significant
differences (Table 3). para-Methyl phenylacetone is also
suitable for this reaction, with a slightly decreased yield (55%).
This transformation was concluded to be an effective strategy
for the synthesis of 2,4-diaryl furans.
Experimental procedure, characterization data and
spectra of new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: caoxplzu@163.com.
*E-mail: libs@cqu.edu.cn.
ORCID
Xiao-Ping Cao: 0000-0001-8340-1122
Baosheng Li: 0000-0002-6953-687X
C
DOI: 10.1021/acs.orglett.9b02204
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the National
Natural Science Foundation of China (Grant Nos. 21772019
and 21572085); Young Elite Scientist Sponsorship Program by
CAST (Grant No. 2016QNRC001). The Fundamental
Research Funds for the Central Universities (Project No.
2019CDQYHG015); the Basic and Frontier Research Project
of Chongqing (cstc2018jcyjAX0716). We thank Analytical and
Testing Center of Chongqing University for assitance with
NMR spectrum analysis.
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