Synthesis of Ynolates via Double Deprotonation of Nonbrominated Esters

Article abstract of DOI:10.1021/acs.orglett.9b02069

Herein, we report a double deprotonation method used for the preparation of ynolates starting from nonbrominated 2,6-di-tert-butylphenyl esters. The current method is superior to the previously described double lithium/halogen exchange approach because easily accessible starting materials are used. This method will be especially useful for preparation of ynolates bearing functional groups in organic synthesis.

Full text of DOI:10.1021/acs.orglett.9b02069

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Ynolates via Double Deprotonation of Nonbrominated
Esters
Jun Sun,† Toshiya Yoshiiwa,† Takayuki Iwata,‡ and Mitsuru Shindo*,‡
†Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, Kasuga-koen, Kasuga 816-8580, Japan
‡Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga-koen, Kasuga 816-8580, Japan
S
* Supporting Information
ABSTRACT: Herein, we report a double deprotonation method used for
the preparation of ynolates starting from nonbrominated 2,6-di-tert-
butylphenyl esters. The current method is superior to the previously
described double lithium/halogen exchange approach because easily
accessible starting materials are used. This method will be especially useful
for preparation of ynolates bearing functional groups in organic synthesis.
α,α-dibromoesters.4 Utilizing this method, we reported various
new synthetic reactions starting from ynolates, which were
ighly reactive, stable, energy-rich reagents or species are
Hvery useful and attractive for synthetic organic chemists
because they are potential key players for sequential reactions
and unprecedented bond formations. Ynolates, which contain
an electron-rich triple bond, are highly reactive, long-lived, less-
basic, and compact nucleophiles.1 Among several preparation
methods reported so far, Kowalski’s homologation2 and Julia’s
oxidation3 have been used (Scheme 1). These methods have
some limitations. The former one needs excess amounts of
strong bases and several operations, and the latter one requires
hazardous anhydrous tert-butylhydroperoxide in spite of simple
operation. We have developed a convenient and efficient
preparation method via cleavage of ester dianions derived from
used as dianion equivalents.5 This is a convenient method
starting from α,α-dibromoesters, which can be prepared via a
double Hell−Volhard−Zelinsky reaction of carboxylic acids or
double α-bromination of esters (Scheme 1).6 However, these
methods used to prepare α,α-dibromoesters have some
drawbacks, especially on a large scale. The former method is
limited to the preparation of only a few substrates, such as
methyl or tert-butyl substituted ynolates, and require long
reaction times under harsh conditions. The latter, which is
more general, requires two steps from the nonbrominated ester
precursor. Therefore, one may hesitate to prepare function-
alized ynolates due to these preparative drawbacks. If more
readily available starting materials can be directly converted
into ynolates, this carbanion species will be more widely used
in organic synthesis.
Scheme 1. Formation of Ynolates
A double elimination reaction is commonly used for the
formation of a triple bond. Therefore, double deprotonation of
nonbrominated esters to induce a double elimination step is a
promising protocol for the generation of ynolates rather than a
double lithium−halogen exchange approach. Herein, we report
the preparation of ynolates via the double deprotonation of
nonhalogenated esters.
In the first deprotonation step, to give an ester enolate, a
sterically hindered non-nucleophilic lithium amide base, such
as LDA, is not preferable because a secondary amine, such as
diisopropylamine, is generated. This amine will be reconverted
into the lithium amide base upon treatment with a strong base
in the second deprotonation step. To avoid the residual amine
species, alkyllithium reagents are the preferred base in the first
step to form the ester enolate. However, alkyllithium reagents
are also strong nucleophiles and thus undergo an addition
reaction to the carbonyl group instead of deprotonation. To
Received: June 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02069
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
suppress the addition reaction, the ester carbonyl should be
sterically blocked.
Table 1. Optimization of the Ynolate Generation Step
Therefore, we selected 2,6-disubstituted phenol esters as
promising precursors. This class of phenol ester, where BHT
esters7,8 are representative examples, has been known to
efficiently block the carbonyl group. The second deprotonation
step of the resulting ester enolate requires a stronger base to
generate the ynolate via the elimination of lithium phenoxide.
On the basis of this concept, we screened several 2,6-
disubstituted phenol ester derivatives of propionic acid (1)
(Figure 1). The yields of the corresponding ynolates were
t-BuLi
benzophenone
(equiv)
a
entry
(equiv)
T (°C) t (h)
yield (%)
1
2
3
4
5
6
2.0
2.5
3.0
3.0
3.0
3.0
3.0
3.0
3.5
−78
−78
−78
−20
−50
−60
−78
−78
−78
1
1
1
1
1
1
2
2
2
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
24
31
44
30
44
43
5
b
7
c
8
25
40
9
a
b
c
NMR yield based on 1ea. In ether. In toluene−TMEDA (1:2).
We then tried to determine the actual amount of ester (1)
required for benzophenone (Table 2). As shown entries 1−3,
Table 2. Optimization of the Ynolate Generation Step
1ea
t-BuLi
T
1,2-dibromoethane
(equiv)
a
entry (equiv)
(equiv)
(°C)
yield (%)
68
90 (84)
58
99
>99 (95)
>99
Figure 1. Screening of sterically hindered esters used as an ynolate
precursor.
1
2
3
4
5
6
7
8
2.0
2.5
3.0
2.5
2.5
2.5
2.2
2.2
2.2
2.2
6.0
7.5
9.0
7.5
7.5
7.5
6.6
5.5
6.6
6.6
−78
−78
−78
−78
−78
−78
−78
−78
−50
−30
none
none
none
0.5
1.0
2.0
1.0
1.0
1.0
1.0
b
b
b
evaluated by those of the olefination product 2a formed upon
reaction with benzophenone, which itself is a high yielding
reaction.9 The initial screening reactions were performed at
−78 °C upon treatment with an excess amount (7.5 equiv) of
tert-butyllithium, allowing the reaction mixture to warm up to
0 °C and the addition of benzophenone. As shown in Figure 1,
2,6-di-tert-butylphenol ester 1ea provided a relatively good
yield of the desired olefin product (2a), which confirmed the
generation of the ynolate using this protocol. Less sterically
hindered esters (1aa−1da) gave lower yields, along with the
adducts formed upon the addition reaction between the
alkyllithium reagent and ester moiety. The reaction of 1fa
afforded some side products, which were attributed to the
generation of the benzyl anion. In the case of 1ha, the modest
yield was attributed to the poor leaving group. Other
commercially available alkyllithiums were less efficient than t-
BuLi (not shown).
Subsequently, we optimized the reaction conditions using
1ea as the ynolate precursor. To confirm the efficiency of the
ynolate generation, an excess amount (3.0 equiv) of the
trapping reagent (benzophenone) was reacted with the
ynolates generated in the reaction (Table 1). The use of 3
equiv of tert-butyllithium, which is 1.5 times the required
amount of base, provided the best yield (44%) among entries
1−3 and 9, suggesting that the efficiency of ynolate generation
was approximately 40−50%. The use of lower temperatures (T
= −20 to −60 °C) in the second step did not lead to an
improvement in the reaction yield (entries 4−6). Ether or
toluene−TMEDA, which are expected to be more stable in the
presence of alkyllithium reagents,10 were not effective (entries
7 and 8).
>99 (97)
85
9
10
>99
58
a
b
NMR yield based on benzophenone. Isolated yield.
when 2.5 equiv of ester were used, the best yield (84%) was
obtained. As the side products included the tert-butyl adduct of
benzophenone, an excess of t-BuLi was found to be present in
the solution of the prepared ynolate, although t-BuLi should be
decomposed by THF at room temperature. Therefore, we
decided to add 1,2-dibromoethane to the reaction mixture after
generating the ynolate in order to deactivate the excess
alkyllithium reagent. As a result, the yield of the product
significantly improved (up to >99%) (entries 4−6) upon the
addition of 0.5−2.0 equiv of 1,2-dibromoethane. Furthermore,
the amount of ester and t-BuLi can be reduced to 2.2 and 6.6
equiv, respectively (entry 7). Conducting the deprotonation
step at temperatures lower than −50 °C worked well, but
higher temperatures did not give better results (entries 9 and
10).
To check that the enolate was formed as an intermediate,
the enolates derived from esters 1ea and 1ei were trapped with
benzaldehyde to provide aldol adducts 3a and 3i (Scheme 2).
The relative stereochemistry of the major adduct was
confirmed to be anti upon conversion into diols 4a11 and
4i12 via LiAlH4 reduction. This suggests the quantitative
formation of the (Z)-enolate based on the Zimmerman−
Traxler six-membered transition model.13 The (Z)-enolate will
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DOI: 10.1021/acs.orglett.9b02069
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
noteworthy that the ynolate precursors were easily prepared via
reacting the acid chloride with lithium 2,6-di-tert-butylphen-
oxide, and 2,6-di-tert-butylphenol was recovered quantitatively
after the reaction.
Scheme 2. Aldol Reaction of the Enolates Derived from 2,6-
di-tert-Butylphenylesters 1ea and 1ei
As synthetic applications, a tandem [2 + 2] cycloaddition-
Dieckmann condensation initiated by the as-prepared
ynolates5a was performed to give the desired cyclohex-2-
enone products 5a and 5m in good yield (Scheme 3).
Scheme 3. Synthetic Applications of Ynolates
easily undergo an anti-elimination reaction upon treatment
with base.
To show the generality of this method for the preparation of
ynolates, various kinds of ynolates were prepared from 1ea−
1eq as shown in Table 3. Ynolates containing a primary alkyl
Table 3. Synthesis of Various Ynolates
Torquoselective olefination using acylsilane5c also provided
vinyl silanes 6a and 6m in good yield. Furthermore, 1,3-dipolar
cycloaddition of the ynolates5b with nitrone afforded trans-
isoxazolidinones 7a and 7m in satisfactory yield.
When compared with the dibromoester method, this
protocol afforded several kinds of side products, which were
found to be tert-butyl ketones formed in 5−10% yield based on
the starting ester (Scheme 4). Lithium ester enolates are
Scheme 4. β-Elimination vs Ketene Formation (Side
Reaction)
a
b
Not examined. Condition A: Ester 1 (2.5 equiv), and t-BuLi (7.5
c
equiv) were used. Condition B: Ester 1 (2.2 equiv), t-BuLi (6.6
equiv), and 1,2-dibromoethane (1.0 equiv) were used.
known to decompose via the elimination of alkoxide at higher
temperatures (>−20 °C) to give a ketene intermediate,7 which
immediately reacts with a nucleophile. In this protocol, these
pathways will be a critical issue to be overcome in future
studies.
In conclusion, we have developed a double deprotonation
method used for preparation of ynolates starting from simple
and readily available nonbrominated esters. The current
method is superior to the previously reported double
group (R) were generated in good yield, but secondary and
tertiary alkyl groups gave poor yields (2c and 2d), which may
be attributed to steric hindrance inhibiting the second
deprotonation step. Ynolates bearing phenylethyl (2j) and
phenylpropyl (2k) groups can be prepared. We successfully
synthesized a variety of functionalized ynolates bearing alkene
(2l and 2m), alkyne (2n), and siloxy (2o) groups. It is
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DOI: 10.1021/acs.orglett.9b02069
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
(d) Umezu, S.; dos Passos Gomes, G.; Yoshinaga, T.; Sakae, M.;
Matsumoto, K.; Iwata, T.; Alabugin, I.; Shindo, M. Regioselective
One-Pot Synthesis of Triptycenes via Triple-Cycloadditions of Arynes
to Ynolates. Angew. Chem., Int. Ed. 2017, 56, 1298−1302. Recent
application using ynolates: (e) Winterton, S. E.; Ready, J. M. [3 + 2]-
Cycloadditions of Azomethine Imines and Ynolates. Org. Lett. 2016,
18, 2608−2611. (f) Wu, J.-L.; Lu, Y.-S.; Tang, B.; Peng, X.-S. Total
Syntheses of Shizukaols A and E. Nat. Commun. 2018, 9, 4040.
(g) Nader, M. W.; Oberdorfer, F. [11C]Lithium Trimethylsilyl
Ynolate: A New [11C] Precursor and Its Application in Heterocyclic
Synthesis. Tetrahedron Lett. 2011, 52, 2309−2311.
lithium−halogen exchange strategy because readily accessible
starting materials bearing functional groups are used. It is
noteworthy that no lithium alkoxide coexists in the reaction
because the leaving group is the less basic lithium 2,6-di-tert-
butylphenoxide. This method will be especially useful for the
preparation of functionalized ynolates in organic synthesis.
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.9b02069.
(6) (a) Shindo, M.; Sato, Y.; Koretsune, R.; Yoshikawa, T.;
Matsumoto, K.; Itoh, K.; Shishido, K. Synthesis of α,α-Dibromo
Esters as Precursors of Ynolates. Chem. Pharm. Bull. 2003, 51, 477−
478. (b) Shindo, M.; Matsumoto, K.; Shishido, K. Generation of
Ynolate and Z-Selective Olefination of Acylsilanes: (Z)-2-Methyl-3-
Trimethylsilyl-2-Butenoic Acid. Org. Synth. 2007, 84, 11−21.
Experimental details, and 1H NMR and 13C NMR
spectra (PDF)
̈
(7) Haner, R.; Laube, T.; Seebach, D. Regio- and Diastereoselective
AUTHOR INFORMATION
Preparation of Aldols from α-Branched Ketone Enolates Generated
from BHT Ester Enolates and Organolithium ReagentsIn Situ
Generation and Trapping of Ketenes from Ester Enolates. J. Am.
Chem. Soc. 1985, 107, 5396−5403.
■
Corresponding Author
*E-mail: shindo@cm.kyushu-u.ac.jp
ORCID
(8) Heathcock, C. H.; Pirrung, M. C.; Montgomery, S. H.; Lampe, J.
Acyclic Stereoselection-13. Aryl Esters: Reagents for Threo-
Aldolization. Tetrahedron 1981, 37, 4087−4095.
(9) Shindo, M.; Sato, Y.; Yoshikawa, T.; Koretsune, R.; Shishido, K.
Stereoselective Olefination of Unfunctionalized Ketones via Ynolates.
J. Org. Chem. 2004, 69, 3912−3916.
Mitsuru Shindo: 0000-0002-0588-8075
Notes
The authors declare no competing financial interest.
(10) (a) Bates, T. F.; Clarke, M. T.; Thomas, R. D. Unusual Stability
of an Alkyllithium Dimer. Preparation, Properties, and Decomposition
Mechanism of tert-Butyllithium Dietherate Dimer. J. Am. Chem. Soc.
1988, 110, 5109−5112. (b) Stanetty, P.; Mihovilovic, M. D. Half-
Lives of Organolithium Reagents in Common Ethereal Solvents. J.
Org. Chem. 1997, 62, 1514−1515.
ACKNOWLEDGMENTS
■
This work was partially supported by JSPS KAKENHI (nos.
JP22390002, JP24106731, JP16H01157, JP26293004,
JP17K14449, JP18H04418, JP18H04624, and JP18H02557),
the Asahi Glass Foundation (T.I.), and the MEXT Project of
“Integrated Research Consortium on Chemical Sciences”
(T.I.). This work was performed under the Cooperative
Research Program of “Network Joint Research Center for
Materials and Devices.”
̈
(11) Pietruszka, J.; Schone, N. New 1,3-Disubstituted Enantiomeri-
cally Pure Allylboronic Esters by Johnson Rearrangement of Boron-
Substituted Allyl Alcohols. Eur. J. Org. Chem. 2004, 2004, 5011−5019.
(12) Faunce, J. A.; Grisso, B. A.; Mackenzie, P. B. Enantioselective
Aldol Chemistry via Alkyl Enol Ethers. Scope of the Lewis Acid
Catalyzed Condensation of Optically Active Trimethylsilyl and
Methyl 2-[(E)-1-Alkenyloxy]Ethanoates with Acetals. J. Am. Chem.
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D
DOI: 10.1021/acs.orglett.9b02069
Org. Lett. XXXX, XXX, XXX−XXX