Regio- and Stereoselective Alkenylation of Allenoates with gem-Difluoroalkenes: Facile Access to Fluorinated 1,4-Enynes Bearing an All-Carbon Quaternary Center

Article abstract of DOI:10.1021/acs.orglett.9b00775

A regio- and stereoselective synthesis of fluorinated 1,4-enynes bearing an all-carbon quaternary center at the propargylic position is developed. The synthesis starts from readily available allenoates and gem-difluoroalkenes and proceeds via a key alkyny

Full text of DOI:10.1021/acs.orglett.9b00775

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regio- and Stereoselective Alkenylation of Allenoates with gem-
Difluoroalkenes: Facile Access to Fluorinated 1,4-Enynes Bearing an
All-Carbon Quaternary Center
Qi-Qi Zhang,† Shi-Yong Chen,† E Lin,† Honggen Wang,† and Qingjiang Li*,†,‡
†School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
‡State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
S
* Supporting Information
ABSTRACT: A regio- and stereoselective synthesis of fluorinated 1,4-enynes bearing an all-carbon quaternary center at the
propargylic position is developed. The synthesis starts from readily available allenoates and gem-difluoroalkenes and proceeds
via a key alkynylenolate intermediate following a nucleophilic addition/β-F elimination. This reaction occurs under mild
reaction conditions with good tolerance to a variety of functional groups. Synthetic utility is demonstrated by further
transformations of the products. Furthermore, the reaction can also be applied for the synthesis of α-alkenyl allenoates by using
3,3-disubstituted allenoates.
Scheme 1. α-Selective Functionalization of Allenoates
lkenes and alkynes are of pivotal importance in organic
Achemistry due to their versatility as synthons in synthetic
transformations.1 1,n-Enynes, with an alkenyl moiety attached
to an alkyne, show unique reactivities as examplied by their
involvement in intriguing cyclization reaction by metal-
catalyzed cyclization (or cycloisomerization) processes2 and
radical cascade transformations.3 In this regard, 1,4-enynes are
of particular value in organic synthesis and therefore gain much
endeavor toward their construction.4 Nevertheless, the 1,4-
enynes deconjugated by an all-carbon quaternary center5
represent a type of challenging target, and only a handful of
methods exist for their preparation.
Allenoates are readily available6 and have been widely
explored as intriguing synthons in organic transformations.
Specifically, upon base-promoted allenylic deprotonation, the
3-monosubstituted allenoates can be converted to the
alkynylenolate intermediates (Scheme 1), which can react
with diverse electrophiles to provide the α-functionalized
products bearing an all-carbon quaternary center under kinetic
control. Examples such as SN2-type alkylation,7 Michael
addition,8 SNAr arylation,9 and aldol condensation,10 among
others,11 were known (Scheme 1a−d). On the one hand, by
proper choosing of coupling partners, the thermodynamically
favored γ-functionalization of 3-monosubstituted allenoates is
also feasible.12 On the other hand, gem-difluoroalkenes13 are
electron-deficient fluorinated unsaturated system, which have
been employed in diverse organofluorine syntheses. The
notable inductive effect of the fluorine atoms along with the
electron repulsion between the double bond and the fluorine
atoms render the α carbon in gem-difluoroalkenes highly
electrophilic and susceptible for nucleophilic attack.14 Thus, a
Received: March 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00775
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
number of oxygen, nitrogen, sulfur, or even carbon-centered
nucleophiles were known to undergo addition−elimination
reactions to provide diversely substituted monofluoroalkenes
with or without a stereoselective manner.15 Alternatively,
instead of β-F elimination, a nucleophilic hydrofunctionaliza-
tion reaction of difluoroalkene would possibly deliver a gem-
difluorinated product.16 In continuation with our interest in
gem-difluoroalkene chemistry,17 we envisioned this electro-
philic species might serve as an intriguing coupling partner
when reacting with allenoates to deliver fluorinated 1,4-enynes.
Interestingly, the α-alkenylation of 3-monosubstituted alle-
noates has not been reported thus far. Herein, we disclose our
realization of a base-promoted regio- and stereoselective
alkenylation of allenoates with gem-difluoroalkenes via a
nucleophilic addition/β-F elimination mechanism. The reac-
tion leads to the mild and facile synthesis of fluorinated 1,4-
enynes bearing an all-carbon quaternary center at the
propargylic position in good efficiency (Scheme 1e).
undec-7-ene (DBU), lithium diisopropylamide (LDA), or
lithium bis(trimethylsilyl)amide (LHMDS) did not promote
the desired alkenylation either (entries 2−4). To our delight,
tert-butanolate or trimethylsilanolate as base in acetonitrile
successfully delivered the desired product (entries 5−7), with
lithium tert-butanolate being the best (75%, entry 6). The Z
geometry of the introduced double bond was determined by its
3JH−F coupling constant in the 1H NMR spectrum (ca. 37.0 Hz
for the Z isomer). Of note, only a trace amount of other
undefined isomers were detected by gas chromatography−
mass spectrometry (GC-MS). The use of inorganic bases such
as K2CO3 or NaOH was proven to be unsuccessful (entries 8
and 9). The solvent effect was also examined. While dimethyl
sulfoxide (DMSO) and dimethylformamide (DMF) (polar
aprotic solvent) exhibited comparable efficiency (entries 10
and 11), other solvents, such as dichloromethane (DCM),
Et2O, and 1,4-dioxane gave trace or no desired product
(entries 12−14). Inferior results were obtained when
increasing the reaction temperature to 50 °C (entry 15).
With the optimized conditions in hand (Table 1, entry 6),
the scope of the regio- and stereoselective alkenylation reaction
with respect to allenoates was then investigated, and the results
were summarized in Scheme 2. The effect of the R1 group at γ
We initiated our studies by examining the influence of
different bases and solvents in the reaction of α-methyl-γ-
phenyl-allenoate 1a with gem-difluoroalkene 2a at room
temperature (rt). The representative results are summarized
in Table 1. When tetra-n-butylammonium fluoride (TBAF), a
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope of Allenoates 1
b
entry
base
TBAF
DBU
solvent
MeCN
MeCN
THF
yield (%)
c
1
trace
0
2
d
3
d
LDA
0
0
4
Li[N(TMS)2]
t-BuOK
t-BuOLi
Me3SiOK
K2CO3
THF
5
6
7
8
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
DCM
Et2O
1,4-dioxane
MeCN
63
75
60
trace
trace
70
72
trace
0
9
NaOH
10
11
12
13
14
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
0
e
15
48
a
General reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.3
b
mmol, 1.5 equiv), base (2.0 equiv), solvent (2.0 mL), rt, 1 h. Isolated
yield. 1.0 M solution in tetrahydrofuran (THF). Conducted at −45
°C to rt. Conducted at 50 °C.
c
d
e
frequently used organic base in alkynylenolate chemis-
try,7c,8b,9,12b was employed, only trace amount of desired
alkenylation product was detected (entry 1). Instead, a
nucleophilic addition reaction of F− to gem-difluoroalkene 2a
occurred, predominantly giving a hydrofluorination product 4
(eq 1).16b Other organic bases such as 1,8-diazabicyclo[5.4.0]-
a
General reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2a (0.3 mmol,
1.5 equiv), t-BuOLi (2.0 equiv), CH3CN (2.0 mL), rt, 1 h under N2,
b
isolated yield. Yield in parentheses based on the recovered starting
c
material. The ratio to other isomers was determined by 19F NMR.
position was first examined. The reaction proceeded smoothly
for both aromatic (3aa, 3ba) and aliphatic (3ca-3ha)
substrates, furnishing the corresponding 1,4-enyne products
in generally moderate to good yields. A lower yield of 38% was
observed when t-butyl-substituted allenoate (3fa) was
employed, probably for steric reasons. The synthesis of
terminal alkynes is an important but challenging topic in
B
DOI: 10.1021/acs.orglett.9b00775
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Organic Letters
Letter
organic chemistry. To our great surprise, by reacting 1,1-
disubstituted allenoate 1i with 2a, the desired terminal alkyne
3ia was obtained in good yield (68%). Next, the scope on R2
and the ester group were also explored. Valuable functional
groups such as benzyl (3ka), allyl (3la, 3ma), and propargyl
(3na, 3pa) were well-tolerated, and the corresponding highly
unsaturated products were obtained in moderate yields. The
use of methyl ester did not affect the reactivity (3pa), whereas
the sterically demanding t-butyl ester gave a relatively lower
yield (3qa). It was noted that the ratio of the desired Z-1,4-
enyne product to other isomers was more than 20:1 in most
cases.
difluoroalkene 2a under the standard reaction conditions
with slightly higher yield (50%, Scheme 4a). In addition,
Scheme 4. Gram-Scale Synthesis and Synthetic
Transformations of the Products
The scope of the reaction with respect to aryl gem-
difluoroalkenes 2 was also explored by changing the solvent
to DMSO (Scheme 3). Not unexpectedly, the reaction is quite
a
Scheme 3. Substrate Scope of Aryl gem-Difluoroalkenes 2
a
General reaction conditions: 1k (0.2 mmol, 1.0 equiv), 2 (0.3 mmol,
synthetic decoration of the formed products led to a series of
complex monofluoroalkenylated structures. For instance, upon
treatment with Pd/H2, the stereoselective hydrogenation of
C−C triple bond of 3ja gave 1,4-diene 7 in 50% yield (Scheme
4b, right). Starting from the same substrate, the functionalized
γ-lactone 8 was obtained in 65% yield via a mild and efficient
I2-mediated electrophilic cyclization reaction (Scheme 4b,
left). 1,3-Cyclohexadiene 9 could be readily obtained directly
from 1,5-enyne 3la by the use of a catalytic amount of a gold
complex activated by silver hexafluoroantimonate (Scheme
4c).19 Finally, the Cu-catalyzed [3 + 2] cycloaddition of
terminal alkyne 3ia with BnN3 10 gave the corresponding
triazole 11 (Scheme 4d, not optimized yield).20
In summary, we have developed a simple and efficient
method for the construction of 1,4-enynes bearing an all-
carbon quaternary center. The appended acetylene, mono-
fluoroalkene, and ester groups are useful functionalities for
further transformations. The approach, starting from readily
available allenoates and gem-difluoroalkenes, proceeds in a
regio- and stereoselective manner under mild reaction
conditions, with good tolerance to a variety of functional
groups and moderate to good yields being observed. The
synthetic utility of the reaction was demonstrated by a practical
gram-scale synthesis and further transformations of the
products to attractive structural motifs such as 1,4-diene, γ-
lactone, 1,3-cyclohexadiene, and triazole. In addition, the
reaction can also be applied for the synthesis of α-alkenyl
allenoates by using 3,3-disubstituted allenoates. In consid-
eration of the ready availability of the starting materials and the
importance of the 1,4-enynes and fluorine atom, we anticipate
this method will find applications in organic synthesis.
1.5 equiv), t-BuOLi (2.0 equiv), DMSO (2.0 mL), rt, 1 h under N2,
b
isolated yield. Yield in parentheses based on the recovered starting
c
1
material. The ratio to other isomers was determined by H NMR.
d
The ratio to other isomers was determined by 19F NMR.
sensitive to the electronic properties of the substituents on the
benzene ring. While the use of electron-donating substituents
led to low yields, electron-withdrawing substituents were
generally tolerated in the reaction. Thus, irrespective of the
substituted position, substituents such as ester (3kb),
trifluoromethyl (3kc), bromo (3kd, 3kg, 3kj), chloro (3kf,
3kh, 3ki), and fluoro (3kk) yielded the corresponding
products with good efficiency. The reaction of nitro-
substituted gem-difluoroalkene (3ke) gave a lower yield. Of
note, steric hindrance at the 2-position of benzene ring was
also tolerated well (3ke-3kj).
Since the α-proton of 3,3-disubstituted allenoates could also
be easily removed by a base, this sequentially prompted us to
explore the reactivity of 3,3-disubstituted allenoates with gem-
difluoroalkenes. As expected, the method can also be applied
for the synthesis of α-alkenyl allenoates18 by using 3,3-
disubstituted allenoates as substrates. Thus, γ-phenyl-γ-methyl
or γ-phenyl-γ-ethyl allenoates 5 successfully underwent an α-
selective alkenylation reaction under our standard conditions
to deliver the corresponding α-monofluoroalkenyl allenoates 6,
albeit lower yields were observed at present (eq 2). The low
yields rose from the large amounts of unreacted starting
materials.
A gram-scale synthesis was performed to demonstrate the
practicality of this reaction. Thus, 1.02 g of 1,4-enyne 3la was
obtained via the alkenylation of allenoate 1l with gem-
C
DOI: 10.1021/acs.orglett.9b00775
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
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* Supporting Information
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(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: liqingj3@mail.sysu.edu.cn
ORCID
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L.; Feng, X. ACS Catal. 2016, 6, 2482. (g) Selig, P.; Turockin, A.;
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Shi-Yong Chen: 0000-0003-1824-5404
Honggen Wang: 0000-0002-9648-6759
Qingjiang Li: 0000-0001-5535-6993
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the support of this work by the National
Natural Science Foundation of China (21502242 and
81402794) and the State Key Laboratory of Natural and
Biomimetic Drugs (K20150215).
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