Synthesis of γ-acetoxy β-keto esters through regioselective hydration of γ-acetoxy-α,β-alkynoates

Article abstract of DOI:10.1021/acs.joc.5b00400

The Au(I)-catalyzed regioselective hydration of γ-acetoxy-α,β-acetylinic ester by the assistance of a neighboring carbonyl group has been developed. Varieties of simple primary, secondary, and tertiary γ-acetoxy-α,β-acetylinic esters, even those bearing sensitive functional group in the remote reaction sites, are selectively hydrated to the corresponding β-keto esters. The reaction tolerates a wide variety of other carboxylates, such as benzoates, propionates, acrylates, and pivalates, including chiral carboxylates with retention of the configuration. The broad substrate scope, including the derivatization of complex natural products and neutral and open air conditions, makes this atom economical approach very practical. ¹⁸O labeling experiments disclose that the oxygen transposition occurs from the carboxylate group to the triple bond, not from water.

Full text of DOI:10.1021/acs.joc.5b00400

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Article
Synthesis of gamma-Acetoxy beta-Keto Esters Through
Regioselective Hydration of gamma-Acetoxy alpha,beta-Alkynoates
Tapas Ranajn Pradhan, Kishore L. Mendhekar, and Debendra Kumar Mohapatra
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 05 May 2015
Downloaded from http://pubs.acs.org on May 5, 2015
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Synthesis of γ-Acetoxy β-Keto Esters Through Regioselective Hydration of γ-Acetoxy α,β-
Alkynoates
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Tapas R. Pradhan, Kishor L. Mendhekar and Debendra K. Mohapatra
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Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500 007, INDIA; mohapatra@iict.res.in
Abstract: The Au(I)-catalyzed regioselective hydration of γ-acetoxy-α,β-acetylinic ester by the
assistance of a neighboring carbonyl group has been developed. Varieties of simple primary,
secondary and tertiary γ-acetoxy-α,β-acetylinic esters, even bearing sensitive functional group in
the remote reaction sites, are selectively hydrated in to the corresponding β-keto esters. The
reaction tolerates a wide variety of other carboxylates such as benzoates, propionates, acrylates,
pivalates including chiral carboxylates with retention of the configuration. The broad substrate
scope including the derivatization of complex natural products, neutral and open air conditions
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make this atom economical approach very practical. O labeling experiments disclose that the
oxygen transposition occurs from the carboxylate group to the triple bond not from water.
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INTRODUCTION
β-keto esters are a class of unique functionalized and highly valuable intermediates, not only for
the synthesis of various biologically active compounds such as 3,4-dihydropyrimidines, 4-alkyl
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or arylcoumarins, 1,4-dihydropyridines but also for a variety of complex natural products. Their
popularity is based on several factors, one of which is facile bond formation with the two
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differentiable, electrophilic carbonyls and either of the nucleophilic α or γ sp carbons. Most of
the general methods for the synthesis of β-keto esters include traditional base mediated
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condensation and the Ti-Claisen condensation. Besides these, a plethora of other strategies
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have been developed for the synthesis of β-keto esters. In particular, modifiable functional
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group present in the β-keto esters make them more versatile for further organic transformations.
Despite the tremendous successes of above meritorious methods deficiency exists to prepare
modifiable functionalized β-keto esters. As β-keto esters are more prone to electrophilic
substitution either at α- or γ-carbons, further substitution of a modifiable nucleophilic functional
group at the γ-carbon becomes difficult. A direct procedure for the synthesis of γ-hydroxy or γ-
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acetoxy β-keto esters involves the acylation of ester enolates by the acid derivatives. The
disadvantage of this method is the use of strong base for the enolate generation which possibly
limits the preparation of a chiral γ-functionalized β-keto ester. On the other hand, Pd(II)
mediated oxidative cyclization–carbonylation of propargylic esters followed by acidic hydrolysis
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relies on the use of poisonous CO gas as well as on acid catalysis, rendering it unsuitable for
the large scale synthesis and also in terms of functional groups tolerance. Thus, it was thought
that propargylic alcohol i.e. γ-hydroxy-α,β-alkynoate can become surrogates for the synthesis of
modifiable β-keto ester provided that the regioselective hydration of alkyne carbon α to the
alcohol can be performed.
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In the past few years, there has been significant progress in the devlopement of gold catalyzed
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regioselective hydration of both symmetrical and unsymmetrical internal alkynes. During the
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course of literature survey on gold catalyzed trasformation, Au(III)-catalyzed hydration has
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been reported by Hammond et al. for accessing both γ- or β-keto ester. This method of
hydration has not been generalized in a broader scope, particularly for the synthesis of multi-
functionalized β-keto ester. In 2010, Zhang and co-workers reported an intermolecular oxidation
Scheme 1. Gold(I)-Catalyzed Functinalization of γ-Hydroxy/Acetoxy-α,β- Alkynoates
of γ-hydroxy-α,β-acetylinic ester in presence of gold catalyst and pyridine N-oxide for the
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synthesis of oxetan-3-ones through α-oxo gold carbene intermediate (Scheme 1A, eq. 1).
Alternatively, Nolan’s group studied the Au(I)-catalyzed tandem alkoxylation/lactonization of γ-
1
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hydroxy-α,β-acetylinic ester to obtain 4-alkoxy-2(5H)-furanones (Scheme 1A, eq. 2). Although
the direct hydration of γ-hydroxy-α,β-alkynoate is a potential attractive solution, the difficulty of
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obtaining regioselectivity using gold catalyzed condition led us to another approach. We
therefore hoped to harness the electronic bias or perhaps catalytic chelation of a neighboring
carbonyl group in the form of a carboxylate to introduce regioselectivity in the gold catalyzed
hydration. Herein, we report a successful implementation of neighboring carbonyl group assisted
regioselective hydration of γ-acetoxy α,β-alkynoate to access easily modifiable
multifunctionalized γ-acetoxy β-keto ester.
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RESULTS AND DISCUSSION
Initially, it was envisioned that the electron withdrawing carboxylate function of γ-hydroxy α,β-
alkynoate would cause a hydration to afford the corresponding β-keto ester. So, the reaction
under the catalytic conditions (NaAuCl .H O, EtOH/ H O) reported by Hammond’s group was
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e
pursued. To test the feasibility of this hydration process, ethyl 4-hydroxybut-2-ynoate was
subjected to the same catalytic conditions. To our delight the expected β-keto ester was formed
but in a very low yield after 24 h at room temperature. Disappointingly, the same catalytic
conditions for the secondaray and tertiary alcohols led to complete recovery of the starting
material. Prolonged heating of the reaction led to the decomposition of the starting material.
Changing the catalyst or solvent had neither any improvement nor significant impact in the yield
of the reaction. It was presumed that the propargylic substitution might be the cause of difficulty
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for alkyne hydration, reasonably due to the formation of five-membered transition state
involved in the complexation of gold catalyst with –OH and the alkyne bond (Scheme 2), thereby
leading to low yield (at room temprature) and decomposition (on heating). To overcome
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Scheme 2: The Inhibition of Hydration Process Due to The Propargylic Nucleophilic
Substitution
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this substrate scope limit, it was contemplated that the exchange of hydroxyl group with an
acetoxy group might facilate the regioselective hydration by the assistance of the carbonyl
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3a, b
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group
via 1,2-acyloxy migration. Accordingly, the hydration of primary γ-acetoxy α,β-
alkynoic ester 1a, which can be easily accessed by the acetylation of ethyl 4-hydroxybut-2-
ynoate was attempted first.
Table 1. Optimization of the Gold Catalyzed Hydration Reaction
a
b
entry
catalyst/s
NaAuCl . 2H O
solvent/s
time (h)
24
yield (%)
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1
2
3
4
5
6
7
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9
1
1
1
EtOH/ H O (4:1)
4
2
2
AuCl3
HAuCl . 4H O
EtOH/ H O (4:1)
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12
24
10
08
06
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06
06
06
06
12
12
06
01
06
20
NR
14
18
20
2
EtOH/ H O (4:1)
4
2
2
AuCl / AgOTf
MeOH/ H O (10:1)
3
2
AuCl / AgSbF
MeOH/ H O (10:1)
3
6
2
AuCl / AgNTf
MeOH/ H O (10:1)
3
2
2
AuCl/ AgOTf
AuCl/ AgBF4
DCE
DCE
THF
THF
THF
DCE
DCE
38
28
48
46
46
62
73
78
72
c
Au(PPh )Cl/ AgBF
3
4
c
0
1
2
Au(PPh )Cl/ AgNTf
3
2
c
Au(PPh )Cl/ AgSbF
3
6
c
Au(PPh )Cl/ AgOTf
3
c
13
Au(PPh )Cl/ AgNTf
3
2
c
1
1
1
1
4
5
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7
Au(PPh )Cl/ AgOTf
CH CN
3
3
d,e
Au(PPh )Cl/ AgOTf
CH NO2
3
3
e
Au(PPh )Cl/ AgOTf
1,4-dioxane
1,4-dioxane
96
32
3
e
AgOTf
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Au(PPh )Cl
PtCl2
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toluene
toluene
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NR
NR
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f
PdCl (CH CN)
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NR
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a
The reactions were performed with 1a (0.5 mmol) and water (1.5 equiv.) in solvent (approx. 1
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mL) at room temperature under ambient atmosphere. Yield of isolated product after column
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chromatography. 4 mol% of each of the catalyst was used. 4 mol % of silver catalyst was used.
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mol% of each of the catalyst was used. The reaction was also continued for 48 h.
The attempt towards hydration of 1a involved the use of various gold catalysts (4 mol%), 1.5
equivalents of water (except entries 1-6) and different solvents (Table 1). Hammond’s conditions
of hydration led to only 21% of 2a with the recovery of starting precursor 1a (72%, entry 1). In
case of entries 1-6, the expected alkoxylation of triple bond by the use of alcohols as co-solvent
was not observed. In the presence of other Au(III) catalysts, more disappointing results were
obtained (entries 2-6). Gratifyingly, the reaction proved to be efficient with various Au(I)
catalysts. Combination of Au(I) catalyst with silver catalysts such as AgBF , AgSbF , AgOTf ,
4
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AgNTf (4 mol% of each) was helpful in improving the yield of 2a (entries 7-12). Screening
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with different solvents (THF, acetonitrile, dichloroethane, 1,4-dioxane, nitromethane) led to
further improvement in the yield (entries 9-15). Hydration under Zhang’s condition using water
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gave moderate yield (entry 13). Best results were obtained with PPh AuCl in combination with
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AgOTf in 1,4-dioxane as solvent and also allowed to reduce the amount of each of the catalyst
to 2 mol% (entry 16). The reaction with only AgOTf afforded 32% of 2a, even after prolonged
reaction time and more catalyst loading (entry 17). Furthermore, the only Au(I) catalyst,
PPh AuCl did not afford any hydration product (entry 18). Finally, no reaction occurred in the
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presence of PtCl , PdCl (CH CN) (entries 19 and 20).
2
2
3
2
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SCOPE OF THE HYDRATION REACTION
Having established the optimized conditions (PPh AuCl, AgOTf, 1,4-dioxane, rt), we
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proceeded to investigate the scope of the reaction for different γ-acetoxy α,β-alkynoates. In
general, a wide variety of primary, secondary and tertiary, aliphatic or aromatic substrates were
subjected to this conditions to obtain the corresponding hydration products in good to high yields
after purification by column chromatography on silica gel (Scheme 3). All of the reactions
proceeded smoothly and were completed within 1-2 h. The process readily provided γ-acetoxy β-
keto ester regardless of the electronic properties of the substituents on the arenes positioned α- to
the acetoxy group. The substitution of electron donating and withdrawing groups at any position
(ortho, meta, para) of the aromatic ring had no impact on the rate as well as the yield of the
reaction (2b-f). Multiple substituents (either
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Scheme 3. Hydration of γ-Acetoxy α,β-Alkynoate
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mixture of 1q (dr = 7:3, determined from H NMR and HPLC analysis) was taken for the
d
hydration reaction. Reaction of 1s (0.5 mmol) was carried under the standard conditions as well
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as at a low temperature (10 C).
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donating or withdrawing or both) on the aromatic ring also had no adverse effect on the
regioselective hydration (2g and 2h). The presence of reactive functionalities such as double
bond and triple bond on the aromatic ring did not inhibit the hydration and the desired products
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2
i and 2j were isolated in good yields (90% and 86%, respectively). Protecting groups like TBS,
MOM ether of the phenolic hydroxyl were well tolerated to this catalytic conditions affording the
corresponding keto esters, 2k and 2l in a satisfactory yield. Only for tertiary substrates 2f, 2l and
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m, slightly extended time was required which might be due to the steric effects. Heteroaryl
substrates 2n and 2o were well compatible with the optimized reaction conditions. Not only aryl
but also alkyl substrates 2p-2r gave β-ketoester products with satisfactory yield. Aliphatic
substrates 2q, 2r and 4b containing acid sensitive protecting groups (OTBS, OTBDPS and
OPMB, respectively) also underwent smooth hydration without any disturbance of the existing
functionality. However, unidentified results were obtained for substrate 2s, likely due to the
acidity of the gold catalysis towards the acetal group.
Encouraged by the results from the acetate assisted hydration, we were subsequently interested
in the hydration of other type of easily accessible alkynoates, having less nucleophilic and higher
steric hindered carbonyl oxygen. The reaction proceeded equally well for both primary and
secondary pivalates, benzoates and propionates, providing the keto esters with excellent yields
(Scheme 4). However, a longer reaction time was required for the tertiary substrates 3f and 3g,
presumably due to the steric hindrance. Hydration of both secondary and tertiary o-acrylates (3e
and 3f) also proceeded well when the reaction was carried out at lower temperature (i.e. at 10
o
C). Polyaryl substrates also delivered the corresponding hydration products 4c and 4d in high
yields. Unfortunately, 2,4,6-trichlorobenzoate ester 3h did not
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Scheme 4. Effect of Hydroxyl Protecting Groups (Other than Acetate)
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(
0.5 mmol each) was carried under the standard conditions but at a low temperature (10 C).
give the desired product under the reaction conditions and unprecedented results were obtained.
Groups such as Boc, Cbz, THP, MOM, Bn, Ts, OMe were inert to direct the regioselective
hydration even after a longer time (3aiv-3axi). Similarly, reactions of propargylic vinyl ether 3i
also did not afford any hydration product. The regiochemical outcomes of the successful
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substrates were similar to those of acetates, thus confirming the validity of the neighboring
carbonyl assisted hydration.
To test the hypothesis, studies were initiated by modifying the substituents on the alkyne
terminus of propargylic carboxylate (Scheme 5). Methyl and ethyl prpoargylic esters readily
participated in the hydration (Scheme 3 and 4). Likewise, tert-butyl (5a) and benzyl ester (5b)
were also well amenable to this reaction to afford the corresponding ketoesters 6a and 6b in good
yield. The transfomation of propargylic ketone 5c formed 6c in 88% yield, which left enough
room for further transformation. No reaction was observed in the case of propargylic amide 5d
even after 24 h, presumably as a result of decreasing electron withdrawing power of amide
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(Scheme 5).
Scheme 5. Effect of the Nature of the Substituent at the Alkyne Terminus of Propargylic
a,b
Acetate
a
Reactions were carried out using 5 (0.5 mmol), Ph PAuCl/AgOTf (0.02 mmol each), H O (1.5
3
2
b
mmol), and 1,4-dioxane (2.0 mL) at ambient temperature. Isolated yields.
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Substitution of other groups such as alkyl or even functionalized aliphatic groups did not lead to
productive reactivity (for examples see Scheme 5, 5e-5h). Unpredictable result was also obtained
for homopropargylic carboxylate 5i. The inertness of the substrates 5d-5i towards hydration,
substantiated the necessity of an electron deficient group on the alkyne terminus as well as the
presence of a carboxylate functionality at the other end, for the directed hydration reaction.
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a,b
Scheme 6. Effect of Sustituents Directly Attached to Acetate/Benzoate Bearing Carbon
a
Reactions were carried out on a scale of 0.5 mmol of 7 in 2 mL of solvent under standard
b
c
o
condition. Yield of isolated product. Reaction was carried out at 10 C and the starting diyne
7d (30%) was recovered.
With this set of conditions for the hydration based on the use of Au(I) catalyst [PPh AuOTf]
3
and water (Table 1). The generality of our procedure in a series of substrates containing sensitive
functionalities was evaluated next (Scheme 6). To this end, a set of ethyl 4-acetoxyhex-5-en-2-
ynoates 7a-c possessing both secondary and tertiary acetates were subjected to the hydration
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conditions. Unfortunately, the corresponding hydration product was not obtained even in
traceable amount, albeit some unidentified mixture was obtained. This result of hydration might
1
6
be due to the competitive Rautenstrauch rearrangement in presence of Au(I) catalyst. However,
the tertiary skipped diyne 7d underwent hydration to give the mono hydration product 8d albeit
in 54% yield, by controlling the reaction temperature.
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Scheme 7. Mode of Reactivities of Au(I) and (III) Catalysts for Oxiranyl Carboxylate
It is noteworthy to mention here that the hydration of ethyl 4-acetoxy-4-(oxiran-2-yl)-2-
alkynoates proceeded smoothly in all cases forming the corresponding β-keto esters in 8ei and ii
in good to excellent yield without affecting the epoxide functionality. The switching of the
1
7a,17b
product selectivity from furan synthesis
to β-keto esters might be attributed to the reason
that the presence of electron withdrawing (CO Me/ CO Et) group makes 1,2-acyloxy migration
2
2
more favorable in contrast to the reaction through epoxide chelation (Scheme 7).
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In order to examine the chirality retention in the hydration process, enantio-enriched
1
8
propargyl acetate 10 was prepared according to the literature procedure. Hydration of enantio-
enriched acetate 10 (70% ee) under the standard conditions cleanly afforded 11 without any loss
of the enantioselectivity (70% ee). Importantly, the hydration is not limited to the small scale (ca
100 mg) used for the scope and limitation studies described above as it could be conveniently
performed on a 2.5 gram scale in excellent yield, under the same standard conditions.
Scheme 8. Scalable Hydration of Chiral Substrate 10
0
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The late stage modifications of natural products is highly valuable in medicinal chemistry. We
were delighted to figure out that the current hydration reaction was also capable of tolerating a
wide range of γ-acetoxy/benzoyloxy α,β-alkynoate derived from the natural products (Scheme
1
9
8). For instance, the derivatized γ-acetoxy acetylinic ester of (+)-carvone 12a bearing an
olefinic bond closer to the reaction site, was proved to be competent (56%). Notably, both γ-
acetoxy/benzoyloxy acetylinic ester derived from (+)-menthone (12b and 12c) and cholesterol
(12d) participated in the present transformation, highlighting the broad substrate scope and
potential utility of this protocol. In addition, the oxiranyl derivative 12e underwent the carbonyl
assisted hydration in acceptable yield without the disturbance of epoxide ring.
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a,b,c
Scheme 9. Synthetic Utility of the Hydration Through Natural Produts Derivatization
10
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a
Reactions were carried out on a scale of 0.4 mmol of 12 in 1.5 mL of solvent under standard
b
c
condition. Yield of isolated product. *mark in substrates represents the undetected stereocenter.
Mechanistic Investigation
Having demonstrated the efficiency of our carbonyl assisted hydration reaction, we next
focused our efforts on gaining more insights into the mechanism of this reaction. A plausible
scenario for the regioselective formation of β-keto ester comprises two possible pathways, which
are illustrated in Scheme 10. A traditional and more obvious pathway involves the nucleophilic
attack of water to the β-carbon which may be the result of strong electron withdrawing effect of
8
e
the ester group as assumed by Hammond’s group (Scheme 10, path b).
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Scheme 10. Plausible Mechanisim for the Formation of Hydration Product
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In contrast to the aforementioned pathway, an alternative plausible route is the 5-exo dig attack
of carbonyl oxygen of the γ-carbon to generate a five membered vinyl gold intermediate A. The
formation of this intermediate could be attributed to the electron withdrawing nature of the ester
group which selectively renders such attack by developing a negative charge at the proximal
1
3b, 20
end.
The nucleophilic addition of water to this electrophilic gold intermediate results in B,
which follows subsequent protodeauration to yield the keto ester.
To test the proposed mechanisms and also to determine the source of carbonyl oxygen, the
18
reaction was performed under the present reaction condition using 5 mmol of H O under
2
anhydrous condition. Analysis of the isolated produt by HRMS(ESI) reveals a peak at 289.0931
+
21
[M + Na] , 2 mass unit more than the regular hydration product 2b. However, deacetylation of
+
18
the isotopic hydration product 2b' gave 2b" (245.0780 [M + Na] ) with the loss of O, which
favors the proposed mechanism (Scheme 10, path a).
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CONCLUSIONS
In summary, a remarkably mild, regioselective hydration and atom economical process has
been developed for the synthesis of a series of γ-acetoxy β-keto esters that relies on simultaneous
oxygen transposition from a neighboring carboxylate group to the C≡C bond and water to
carboxylate group in good to excellent yields. The mild catalytic conditions readily tolerate
remote sensitive functional groups and protecting groups as well. This method provides an
efficient masking of easily modifiable electrophilic and nucleophilic carbons as acetylinic ester,
offering a practical solution to construct a C4 carbon skeleton. The utility of this method was
demonstrated by further transformation of the natural product derivatized alkynoates without loss
of enantiomeric purity.
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EXPERIMENTAL SECTION
General Information: All reactions were carried out under ambient atmosphere, unless
otherwise stated. All starting materials and reagents were obtained from commercial producers
and are used without further purification. Solvents were generally used as supplied by the
manufacturer except THF (THF was freshly distilled over sodium/ benzophenone under inert
atmosphere). Column chromatography was carried out by using silica gel (60–120 mesh) unless
otherwise mentioned. Reactions were monitored by TLC on silica gel GF254 (0.25 mm).
−1
2 −1
Specific optical rotations [α] were given in 10 degcm g . Infrared spectra were recorded in
D
−
1
CHCl /neat (as mentioned) and reported in wave number (cm ). HRMS spectra were recorded
3
using a Q-TOF mass spectrometer. HPLC was performed on HPLC systems consisting of the
following; detector, 875-UV or UV-970, measured at 210 nm and 254 nm; column, ATLANTIS
C18 (4.6 × 150 mm, 5μ) and LUX AMISOSE (4.6 × 250 mm, 5μ); mobile phase, acetonitrile,
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1
water, isopropanol and hexane; flow rate, 1 mL/min. H NMR spectra were recorded at 300, 400,
13
5
00 and C NMR spectra 75, 100, 125 MHz in CDCl solution unless otherwise mentioned,
3
chemical shifts are in ppm downfield from tetramethylsilane and coupling constants (J) are
reported in hertz (Hz). The following abbreviations are used to designate signal multiplicity: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad.
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2
2
Procedure for Synthesis of 1a and 3a (P-1)
To a solution of 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran 1a'" (5.0 g, 35.71 mmol), n-BuLi
(4.28 mL, 2.5 M in hexane, 35.71 mmol) was added dropwise using a syringe at −78 °C under
nitrogen atmosphere and stirred at this temperature for 20 min. Then ethyl chloroformate (6.76
mL, 71.42 mmol) was added dropwise to this ylide solution. Reaction mixture was slowly (10
min) brought to room temperature and continued to stir until the complete consumption of alkyne
(
monitored by TLC). The reaction was quenched with saturated aqueous NH Cl solution (75 mL)
4
and diluted with ethyl acetate (100 mL). The organic layer was separated and the aqueous layer
extracted with ethyl acetate (3 × 75 mL). The combined organic layer was washed with brine
(
100 mL), dried over anhydrous Na SO and concentrated under reduced pressure to get the
2 4
crude ethyl 4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-ynoate (1aʹʹ) (6.8 g, 90%) as a thick yellow
liquid.
The crude THP-ether 1aʹʹ obtained was treated with catalytic amount of PTSA in ethanol (30
mL) and stirred for 5 h. EtOH was then removed and the reaction was quenched with saturated
aqueous NaHCO solution (30 mL) and diluted with CH Cl (50 mL). The organic layer was
3
2
2
separated and the aqueous layer extracted with CH Cl (3 × 50 mL). The combined organic layer
2
2
was washed with brine (2 × 75 mL), dried over anhydrous Na SO and concentrated under
2
4
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reduced pressure to get the crude compound, which on purification by column chromatography
(ethyl acetate/hexane = 1:4) afforded the ethyl 4-hydroxybut-2-ynoate (1aʹ) (3.36 g, 82%) as
colorless oil.
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Hydration precursors 1a and 3a were synthesized from 1aʹ by following the procedures (P-2b,
2
c, 2d, 2e) as described below.
Representative Procedure for Synthesis of Hydration precursors (P-2)
(a) General procedure for synthesis of secondary or tertiary γ-hydroxy α,β-acetylinic ester
23
(P-2a)
A flame-dried, round-bottom flask was charged with anhydrous THF (20 mL) and methyl/ethyl
propiolate (7.50 mmol). The solution was cooled to −78 °C and LHMDS (7.50 mmol, 1.0 M in
THF) was added slowly over 10 min. The solution was allowed to stir for 30 min at −78 °C and
then aldehyde/ketone (5.0 mmol) was added slowly over 5 min. The mixture was stirred for an
additional 45 min at same temperature and was allowed to warm to 23 °C. After complete
consumption of the starting material (monitored by TLC), saturated aqueous NH Cl solution (25
4
mL) was added slowly and continued to stir for 15 min. The mixture was diluted with ethyl
acetate (30 mL). The aqueous layer was extracted with ethyl acetate (2 × 30 mL) and the
combined organic layer was washed with brine and dried over Na SO . The crude propargylic
2
4
alcohol obtained after evaporation of the solvent under reduced pressure was directly used for the
preparation of hydration precursor by following the procedures as described below.
(b) General procedure for acetylation of primary, secondary or tertiary γ-hydroxy α,β-
2
4
acetylinic ester (P-2b)
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To a solution of the crude propargyl alcohol (1.0 mmol) in anhydrous CH Cl (15 mL) was added
2
2
triethylamine (0.28 mL, 2.0 mmol), acetic anhydride (0.18 mL, 2.0 mmol), and DMAP
catalytic) under a nitrogen atmosphere at 0 °C. The resultant mixture was stirred at room
(
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temperature until the complete consumption of starting material (monitored by TLC). Then the
reaction mixture was washed with brine solution (2 × 15 mL), dried over MgSO and the solvent
4
was removed under reduced pressure. The residue was purified by column chromatography to
obtain the acetylated hydration precursor (up to 95% yield).
(c) General procedure for benzoylation of primary, secondary or tertiary γ-hydroxy α,β-
2
4
acetylinic ester (P-2c)
To a solution of the crude propargyl alcohol (1.0 mmol) in anhydrous CH Cl (15 mL) was added
2
2
triethylamine (0.28 mL, 2.0 mmol), benzoyl chloride (1.74 mL, 1.5 mmol), and DMAP
(catalytic) under nitrogen atmosphere at 0 °C. The resultant mixture was stirred for 5 h and then
quenched with aqueous NH Cl solution (15 mL). The aqueous layer was extracted with CH Cl
4
2
2
(
2 × 20 mL) and the combined organic layer was washed with brine and dried over MgSO . The
4
crude residue obtained after evaporation of the solvent under reduced pressure, was purified by
column chromatography to obtain the pure benzoate ester (up to 90% yield).
(d) General procedure for acryloylation of primary, secondary or tertiary γ-hydroxy α,β-
2
5
acetylinic ester (P-2d)
To a solution of the crude propargyl alcohol (1.0 mmol) in anhydrous CH Cl (15 mL) was added
2
2
triethylamine (0.28 mL, 2.0 mmol), followed by acryloyl chloride (0.16 mL, 2.0 mmol), and
DMAP (cat.) under a nitrogen atmosphere at 0 °C. The resultant mixture was stirred for 1 h and
then quenched with aqueous NH Cl solution (15 mL). The aqueous layer was extracted with
4
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CH Cl (2 × 15 mL).The combined organic layer was washed with brine and dried over Na SO .
2
2
2
4
The crude residue obtained after evaporation under reduced pressure, was purified by flash
column chromatography to obtain the pure acrylate ester (up to 85% yield).
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(
e) General procedure for pivaloylation of primary, secondary or tertiary γ-hydroxy α,β-
2
6
acetylinic ester (P-2e)
(This procedure is a minor modification of the literature procedure)
To a solution of the crude propargyl alcohol (1.0 mmol) in anhydrous CH Cl (15 mL), was
2
2
added triethylamine (0.28 mL, 2.0 mmol)) followed by pivaloyl chloride (0.24 mL, 2.0 mmol),
and DMAP (catalytic) under a nitrogen atmosphere at 0 °C. The resultant mixture was stirred for
2 h and then quenched with aqueous NH Cl solution (15 mL). The aqueous layer was extracted
4
with CH Cl (2 × 15 mL). The combined organic layer was washed with brine and dried over
2
2
Na SO . The crude residue obtained after evaporation of solvent under reduced pressure, was
2
4
purified by column chromatography to obtain the pure pivaloate ester (up to 80% yield).
Ethyl 4-acetoxybut-2-ynoate (1a): Following the general procedure P-2b, 1a was obtained from
1
a' (200 mg, 1.56 mmol) as a colorless liquid (249 mg, 94%); R 0.48 (9:1 hexane/EtOAc); IR
f
−1
1
(neat) νmax 2954, 2852, 2249, 1763, 1740, 1376, 1244, 1056, 772 cm ; H NMR (300 MHz,
1
3
CDCl ) δ 4.79 (s, 2H), 4.25 (q, J = 7.2 Hz, 2H), 2.13 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H) ppm; C
3
NMR (75 MHz, CDCl ) δ 169.7, 152.7, 80.7, 77.8, 62.2, 51.4, 20.4, 13.8 ppm; HRMS (EI-TOF)
3
+
[
M] calcd. for C H O 170.0574; found: 170.0565.
8
10
4
Ethyl 4-acetoxy-4-phenylbut-2-ynoate (1b): Following the general procedure P-2a and 2b, 1b
236 mg, 73%) was obtained from benzaldehyde as light yellow liquid. R 0.52 (9:1
(
f
−
1
hexane/EtOAc); IR (neat) νmax 2955, 2924, 2853, 2244, 1744, 1711, 1368, 1216, 1054, 771 cm ;
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1
H NMR (300 MHz, CDCl ) δ 7.54-7.46 (m, 2H), 7.44-7.37 (m, 3H), 6.53 (s, 1H), 4.25 (d, J =
3
1
3
7
1
.2 Hz, 2H), 2.1 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H) ppm; C NMR (75 MHz, CDCl ) δ 169.2,
3
52.8, 134.9, 129.3, 128.7, 127.6, 82.6, 78.1, 64.6, 62.2, 20.6, 13.8 ppm; HRMS (ESI-TOF) m/z:
0
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0
+
[
M + Na] calcd for C H O Na 269.0784; found: 269.0783.
14
14
4
Methyl 4-acetoxy-4-(4-methoxyphenyl)but-2-ynoate (1c): Following the general procedure P-
2
0
a and 2b, 1c (210 mg, 79%) was obtained from 4-methoxybenzaldehyde as yellow liquid. Rf
.65 (9:1 hexane/EtOAc); IR (neat) νmax 2926, 2949, 2376, 2246, 1747, 1720, 1515, 1217, 959,
−
1 1
837 cm ; H NMR (500 MHz, CDCl ) δ 7.43 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.48
3
13
(s, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 2.10 (s, 3H) ppm; C NMR (75 MHz, CDCl ) δ 169.4, 160.5,
3
1
53.4, 129.4, 127.2. 114.2, 83.5, 77.7, 64.5, 55.3, 52.8, 20.8 ppm; HRMS (ESI-TOF) m/z: [M +
+
Na] calcd for C H O Na 285.0742; found: 285.0737.
14
14
5
Methyl 4-acetoxy-4-(2-bromophenyl)but-2-ynoate (1d): Following the general procedure P-2a
and 2b, 1d (220 mg, 72%) was obtained from 2-bromobenzaldehyde as yellow liquid. R 0.55
f
−
1 1
(9:1 hexane/EtOAc); IR (neat) νmax 2984, 2246, 1736, 1372, 1235, 1043, 772 cm ; H NMR
(500 MHz, CDCl ) δ 7.70 (dd, J = 1.7, 7.8 Hz, 1H), 7.60 (dd, J = 1.2 Hz, 7.9 Hz, 1H), 7.39 (td, J
3
= 1.2, 7.6 Hz, 1H), 7.27 (td, J = 1.7, 8.1 Hz, 1H), 6.80 (s, 1H), 3.79 (s, 3H), 2.15 (s, 3H) ppm;
1
3
C NMR (125 MHz, CDCl ) δ 168.9, 153.1, 134.2, 133.1, 130.9, 129.5, 127.9, 123.0, 82.1, 77.9,
3
+
6
4.3, 52.8, 20.5 ppm; HRMS (ESI-TOF) m/z: [M + Na] calcd for C H O BrNa 332.9732; found:
1
3
11
4
332.9729.
Methyl 4-acetoxy-4-(4-fluorophenyl)but-2-ynoate (1e): Following the general procedure P-2a
and 2b, 1e (150 mg, 76%) was obtained from 4-fluorobenzaldehyde as yellow liquid. R 0.56 (9:1
f
hexane/EtOAc); IR (neat) νmax 3009, 2957, 2246, 1748, 1722, 1511, 1436, 1259, 1219, 1016, 751
−1
1
cm ; H NMR (500 MHz, CDCl ) δ 7.50-7.46 (m, 2H), 7.11-7.05 (m, 2H), 6.50 (s, 1H), 3.79 (s,
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1
H), 2.11 (s, 3H) ppm; C NMR (75 MHz, CDCl ) δ 169.2, 164.8, 161.5, 153.1, 129.8, 129.7,
3
+
15.9, 115.6, 82.8, 77.9, 63.9, 52.8, 20.6 ppm; HRMS (ESI-TOF) m/z: [M + H] calcd for
C H O F 251.0714; found: 251.0718.
1
3
12
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 4-acetoxy-4-(3-nitrophenyl)pent-2-ynoate (1f): Following the general procedure P-2a
and 2b, 1f (180 mg, 69%) was obtained from 3-nitroacetphenone as yellow liquid. R 0.35 (9:1
f
−
1
hexane/EtOAc); IR (neat) νmax 3083, 2957, 2852, 2243, 1752, 1722, 1524, 1067, 857, 751 cm ;
1
H NMR (500 MHz, CDCl ) δ 8.28-8.20 (m, 2H), 7.76-7.66 (m, 2H), 3.83 (s, 3H), 2.12 (s, 3H),
3
1
3
1
7
3
.92 (s, 3H) ppm; C NMR (75 MHz, CDCl ) δ 168.3, 156.2, 147.8, 147.5, 125.7, 123.9, 84.1,
3
+
9.3, 73.7, 52.9, 31.0, 21.1 ppm; HRMS (ESI-TOF) m/z: [M + Na] calcd for C H O NNa
1
4
13
6
14.0635; found: 314.0630.
Methyl 4-acetoxy-4-(3,4,5-trimethoxyphenyl)but-2-ynoate (1g): Following the general
procedure P-2a and 2b, 1g (185 mg, 74%) was obtained from 3,4,5-trimethoxybenzaldehyde as
colorless liquid. R 0.62 (9:1 hexane/EtOAc); IR (neat) νmax 2929, 2851, 2377, 2313, 1749, 1729,
f
−
1 1
1510, 1225, 922 cm ; H NMR (300 MHz, CDCl ) δ 6.72 (s, 2H), 6.45 (s, 1H), 3.89 (s, 6H),
3
13
3
1
.85 (s, 3H), 3.80 (s, 3H), 2.14 (s, 3H) ppm; C NMR (75 MHz, CDCl ) δ 169.2,153.3, 153.1,
3
38.7, 130.3, 104.8, 83.0, 77.7, 64.7, 60.6, 56.0, 52.7, 20.7 ppm; HRMS (ESI-TOF) m/z: [M +
+
H] calcd for C H O 323.1125; found: 323.1126.
1
6
19
7
Methyl 4-acetoxy-4-(4-bromobenzo[d][1,3]dioxol-5-yl)but-2-ynoate (1h): Following the
general procedure P-2a and 2b, 1h (160 mg, 70%) was obtained from 4-
bromobenzo[d][1,3]dioxole-5-carbaldehyde as colorless liquid. R 0.48 (9:1 hexane/EtOAc); IR
f
−1
1
(
neat) νmax 2925, 2851, 2376, 2315, 1752, 1719, 1480, 1254, 1212, 1036, 939 cm ; H NMR
(500 MHz, CDCl ) δ 7.16 (s, 1H), 7.02 (s, 1H), 6.73 (s, 1H), 6.03 (s, 2H), 3.79 (s, 3H), 2.19 (s,
3
13
3
H) ppm; C NMR (125 MHz, CDCl ) δ 169.0, 153.2, 149.3, 147.8, 127.3, 114.3, 112.8, 109.1,
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2
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2
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3
3
3
3
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5
5
5
5
5
5
5
5
6
+
1
02.3, 82.3, 77.7, 64.3, 52.9, 20.6 ppm; HRMS (ESI-TOF) m/z: [M + Na] calcd for
C H O BrNa 376.9631; found: 376.9641.
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6
Methyl 4-acetoxy-4-(2-(allyloxy)phenyl)but-2-ynoate (1i): Following the general procedure P-
a and 2b, 1i (160 mg, 74%) was obtained from 2-(allyloxy)benzaldehyde as a pale yellow
liquid. R 0.50 (9:1 hexane/EtOAc); IR (neat) ν 2923, 2852, 2377, 1743, 1719, 1447, 1219,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
f
max
−
1 1
9
1
52 cm ; H NMR (500 MHz, CDCl ) δ 7.59 (dd, J = 1.5, 7.6 Hz, 1H), 7.34 (td, J = 1.5, 7.6 Hz,
3
H), 7.01 (brt, J = 7.6 Hz, 1H), 6.93 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.08-5.95 (m, 1H), 5.45-
1
3
5.37 (m, 1H), 5.31-5.24 (m, 1H), 4.62-4.55 (m, 2H), 3.77 (s, 3H), 2.10 (s, 3H) ppm; C NMR
(
125 MHz, CDCl ) δ 169.2, 155.5, 153.4, 132.5, 130.7, 128.8, 123.3, 120.8, 117.3, 112.0, 83.6,
3
+
7
7.1, 68.9, 59.7, 52.7, 20.7 ppm; HRMS (ESI-TOF) m/z: [M + Na] calcd for C H O Na:
16 16
5
311.0889; found: 311.0891.
Methyl 4-acetoxy-4-(2-(prop-2-ynyloxy)phenyl)but-2-ynoate (1j): Following the general
procedure P-2a and 2b, 1j (170 mg, 69%) was obtained from 2-(prop-2-ynyloxy)benzaldehyde as
a colorless liquid. R 0.48 (9:1 hexane/EtOAc); IR (neat) νmax 2923, 2246, 1732, 1492, 1220,
f
−1
1
1
043, 772, 685 cm ; H NMR (300 MHz, CDCl ) δ 7.61 (dd, J = 1.5, 7.5 Hz, 1H), 7.38 (td, J
3
= 1.5, 7.5 Hz, 1H), 7.06 (t, J = 7.5 Hz, 2H), 6.88 (s, 1H), 4.75 (d, J = 2.3 Hz, 2H), 3.78 (s, 3H),
1
3
2
1
.51 (t, J = 2.3 Hz, 1H), 2.11 (s, 3H) ppm; C NMR (75 MHz, CDCl ) δ 169.3, 154.6, 153.4,
3
30.7, 129.0, 123.9, 121.7, 112.6, 83.5, 78.0, 77.2, 75.9, 59.6, 56.3, 52.8, 20.7 ppm; HRMS
+
(ESI-TOF) m/z: [M + Na] calcd for C H O Na 309.0733; found: 309.0734.
1
6
14
5
Methyl 4-acetoxy-4-(2-(tert-butyldimethylsilyloxy)phenyl)but-2-ynoate (1k): Following the
general procedure P-2a and 2b, 1k (220 mg, 72%) was obtained from 2-(tert-butyldimethyl-
silyloxy)benzaldehyde as a colorless liquid. R 0.65 (9:1 hexane/EtOAc); IR (neat) ν 2955,
f
max
−1
1
2
859, 2245, 1720, 1215, 1017, 747 cm ; H NMR (300 MHz, CDCl ) δ 7.30-7.21 (m, 1H), 7.11-
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.05 (m, 1H), 6.98-6.94 (m, 1H), 6.89-6.52 (m, 1H), 6.46 (s, 1H), 3.79 (s, 3H), 2.12 (s, 3H), 0.99
13
(s, 9H), 0.21 (s, 6H) ppm; C NMR (75 MHz, CDCl ) δ 169.3, 155.9, 153.2, 136.2, 129.8,
3
1
21.0, 120.5, 119.3, 83.1, 77.7, 64.4, 52.8, 25.6, 20.7, 18.1, -4.5 ppm; HRMS (ESI-TOF) m/z:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
[
M + H] calcd for C H O Si 363.1622; found: 363.1625.
1
9
27
5
Methyl 4-acetoxy-4-(2-(methoxymethoxy)phenyl)pent-2-ynoate (1l): Following the general
procedure P-2a and 2b, 1l (180 mg, 68%) was obtained from 1-(2-(methoxymethoxy)phenyl)-
ethanone as a yellow liquid. R 0.55 (9:1 hexane/EtOAc); IR (neat) νmax 3021, 2956, 2243, 1731,
f
−
1 1
1374, 1256, 1045, 744 cm ; H NMR (300 MHz, CDCl ) δ 7.60-7.51 (m, 1H), 7.33-7.13 (m,
3
2
H), 7.07-6.36 (m, 1H), 5.29-5.18 (m, 2H), 3.78 (s, 3H), 3.51 (s, 3H), 2.11 (s, 3H), 2.04 (s, 3H)
13
ppm; C NMR (75 MHz, CDCl ) δ 168.4, 153.9, 140.0, 129.7, 127.9, 126.9, 121.5, 115.1, 94.5,
3
+
86.7, 77.1, 73.9, 56.1, 52.6, 27.7, 21.3 ppm; HRMS (ESI-TOF) m/z: [M + Na] calcd for
C H O Na 329.0995; found: 329.0994.
16
18
6
Methyl 4-acetoxy-4-phenylpent-2-ynoate (1m): Following the general procedure P-2a and 2b,
m (140 mg, 73%) was obtained from acetophenone as a pale yellow liquid. R 0.50 (9:1
1
f
−1
1
hexane/EtOAc); IR (neat) νmax 3033, 2938, 2247, 1752, 1716, 1373, 753, 702 cm ; H NMR
(300 MHz, CDCl ) δ 7.55-7.52 (m, 2H), 7.39-7.35 (m, 2H), 7.33-7.29 (m, 1H), 3.81 (s, 3H), 2.09
3
13
(
s, 3H), 1.92 (s, 3H) ppm; C NMR (75 MHz, CDCl ) δ 168.3, 153.6, 140.8, 128.5, 128.2,
3
+
1
24.6, 85.9, 78.7, 74.5, 52.7, 31.1, 21.4 ppm; HRMS (ESI-TOF) m/z: [M + Na] calcd for
C H O Na 269.0784; found: 269.0774.
14
14
4
tert-Butyl
3-(1-acetoxy-4-methoxy-4-oxobut-2-ynyl)-1H-indole-1-carboxylate
(1n):
Following the general procedure P-2a and 2b, 1n (185 mg, 67%) was obtained from tert-butyl 3-
formyl-1H-indole-1-carboxylate as a thick yellow gel. R 0.64 (9:1 hexane/EtOAc); IR (neat)
f
−1
1
νmax 2924, 2243, 1734, 1728, 1453, 1370, 1219, 1096, 772 cm ; H NMR (300 MHz, CDCl ) δ
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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5
5
5
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8
3
1
2
.16 (d, J = 8.3 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.42-7.24 (m, 2H), 6.81 (s, 1H),
1
3
.79 (s, 3H), 2.12 (s, 3H), 1.68 (s, 9H) ppm; C NMR (75 MHz, CDCl ) δ 169.4, 153.2, 149.1,
3
35.5, 132.5, 127.3, 125.8, 125.0, 123.0, 119.4, 115.4, 114.8, 84.3, 82.3, 76.9, 57.9, 52.8, 27.9,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
0.6 ppm; HRMS (ESI-TOF) m/z: [M + H] calcd for C H O N 372.1442; found: 372.1438.
2
0
22
6
Methyl 4-acetoxy-4-(thiophen-2-yl)but-2-ynoate (1o): Following the general procedure P-2a
and 2b, 1o (147 mg, 66%) was obtained from thiophene-2-carbaldehyde as a light yellow liquid.
R 0.58 (9:1 hexane/EtOAc); IR (neat) ν 3119, 2926, 2247, 1751, 1725, 1514, 1268, 1215,
f
max
−
1 1
1016, 970 cm ; H NMR (300 MHz, CDCl ) δ 7.38 (dd, J = 1.2, 5.2 Hz, 1H), 7.27-7.25 (m, 1H),
3
13
7
.00 (dd, J = 3.7, 5.2 Hz, 1H), 6.77 (s, 1H), 3.81 (s, 3H), 2.12 (s, 3H) ppm; C NMR (75 MHz,
CDCl ) δ 169.2, 153.1, 137.1, 128.3, 126.8, 82.1, 77.2, 59.8, 52.9, 20.6 ppm; HRMS (ESI-TOF)
3
+
m/z: [M + Na] calcd for C H O SNa 261.0201; found: 261.0194.
11
10
4
Methyl 4-acetoxy-6-phenylhex-2-ynoate (1p): Following the general procedure P-2a and 2b,
p (146 mg, 76%) was obtained from 3-phenylpropanal as a colorless liquid. R 0.50 (9:1
1
f
−
1
hexane/EtOAc); IR (neat) νmax 2924, 2856, 2245, 1742, 1731, 1492, 1220, 1033, 772, 685 cm ;
1
H NMR (300 MHz, CDCl ) δ 7.32-7.27 (m, 2H), 7.23-7.17 (m, 3H), 6.42 (t, J = 6.5 Hz, 1H),
3
1
3
3.8 (s, 3H), 2.78 (t, J = 7.8 Hz, 2H), 2.20-2.12 (m, 2H), 2.09 (s, 3H) ppm; C NMR (75 MHz,
CDCl ) δ 169.5, 153.3, 139.9, 128.5, 128.3, 126.3, 84.1, 76.8, 62.5, 52.8, 35.3, 31.0, 20.6 ppm;
3
+
HRMS (ESI-TOF) m/z: [M + Na] calcd for C H O Na 283.0941; found: 283.0934.
1
5
16
4
2
7
(6R)-Ethyl 4-acetoxy-6-(tert-butyldimethylsilyloxy)-8-phenyloct-2-ynoate (1q) : Following
the general procedure P-2a and 2b, 1p (222 mg, 71%) was obtained as an inseparable
1
diastereomeric mixture (dr = 7:3, determined by H NMR and HPLC analysis) from (R)-3-(tert-
28
D
butyldimethylsilyloxy)-5-phenylpentanal. R 0.60 (9:1 hexane/EtOAc); [α] = −8.5 (c 0.6); IR
f
−1
1
(neat) νmax 2929, 2856, 2243, 1751, 1717, 1369, 1255, 1022, 836 cm ; H NMR (300 MHz,
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CDCl ) δ 7.33-7.29 (m, 2H), 7.23-7.18 (m, 3H), 5.62 (dd, J = 6.0, 8.7 Hz, 1H), 4.27 (q, J = 7.2
3
Hz, 2H), 4.00-3.95 (m, 1H), 2.72-2.62 (m, 2H), 2.11 (s, 3H), 2.09-2.02 (m, 2H), 1.89-1.82 (m,
13
2
H), 1.34 (t, J = 7.2 Hz, 3H), 0.94 (s, 9H), 0.12 (d, J = 13.3 Hz, 6H) ppm; C NMR (75 MHz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CDCl ) δ 169.3, 152.9, 141.8, 128.3, 128.2, 125.8, 83.9, 68.0, 67.1, 62.1, 40.7, 39.1, 30.9, 25.8,
3
+
20.7, 17.9, 13.9, −4.4 ppm; HRMS (ESI-TOF) m/z: [M + Na] calcd for C H O SiNa
2
4
36
5
4
55.2234; found: 455.2230.
Methyl 4-acetoxy-6-(tert-butyldiphenylsilyloxy)hex-2-ynoate (1r): Following the general
procedure P-2a and 2b, 1r (246 mg, 72%) was obtained from 3-(tert-butyldiphenylsilyloxy)
propanal as a colorless liquid. R 0.70 (9:1 hexane/EtOAc); IR (neat) ν 2957, 2929, 2856,
f
max
−
1 1
2
376, 1750, 1721, 1431, 1258, 1221, 1108, 741 cm ; H NMR (300 MHz, CDCl ) δ 7.70-7.59
3
(m, 4H), 7.48-7.34 (m, 6H), 5.72 (t, J = 6.8 Hz, 1H), 3.83-3.69 (m, 5H), 2.13-2.03 (m, 5H), 1.04
13
(
s, 9H) ppm; C NMR (75 MHz, CDCl ) δ 169.4, 153.3, 135.5, 133.2, 129.7, 127.7, 84.5, 60.3,
3
+
5
8.9, 52.7, 36.7, 26.7, 20.6, 19.1 ppm; HRMS (ESI-TOF) m/z: [M + Na] calcd for
C H O SiNa 461.1754; found: 461.1762.
25
30
5
Ethyl 4-(pivaloyloxy)but-2-ynoate (3ai): Following the general procedure P-2e, 3ai (201 mg,
95%) was obtained from 1aʹ as a colorless liquid. R 0.65 (9:1 hexane/EtOAc); IR (neat) ν
f
max
−
1 1
2
977, 2931, 2249, 1741, 1719, 1462, 1252, 1137, 772 cm ; H NMR (300 MHz, CDCl ) δ 4.78
3
13
(
s, 2H), 4.25 (q, J = 6.8 Hz, 2H), 1.32 (t, J = 6.8 Hz, 3H), 1.23 (s, 9H) ppm; C NMR (75 MHz,
CDCl ) δ 177.2, 152.7, 80.9, 77.7, 62.0, 51.2, 38.6, 26.9, 26.4, 13.8 ppm; HRMS (ESI-TOF)
3
+
m/z: [M + Na] calcd for C H O Na 235.0948; found: 235.0941.
11
16
4
4
-Ethoxy-4-oxobut-2-ynyl benzoate (3aii): Following the general procedure P-2c, 3aii (297
mg, 96%) was obtained from 1aʹ as colorless liquid. R 0.76 (9:1 hexane/EtOAc); IR (neat) ν
f
max
−1
1
2
926, 2854, 2244, 1636, 1385, 1286, 1025, 708 cm ; H NMR (300 MHz, CDCl ) δ 8.08 (d, J =
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2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
4
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4
4
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5
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5
5
5
6
7
2
1
.5 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.5 Hz, 2H), 5.05 (s, 2H), 4.25 (q, J = 6.8 Hz,
13
H), 1.31 (t, J = 6.8 Hz, 3H) ppm; C NMR (75 MHz, CDCl ) δ 165.3, 152.7, 133.4, 130.4,
3
+
29.7, 128.7, 128.4, 80.7, 78.0, 62.2, 51.7, 13.8 ppm; HRMS (ESI-TOF) m/z: [M + Na] calcd
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
for C H O Na 255.0627; found: 255.0626.
1
3
12
4
Ethyl 4-(propionyloxy)but-2-ynoate (3aiii): To a solution of the crude propargyl alcohol 1a'
200 mg, 1.56 mmol) in anhydrous CH Cl (20 mL), was added triethylamine (0.48 mL, 3.12
(
2
2
mmol), propionic anhydride (0.39 mL, 3.12 mmol), and DMAP (catalytic) under nitrogen
atmosphere at 0 °C. The resultant mixture was stirred for 1 h and then quenched with aqueous
NH Cl solution (15 mL). The organic layer was separated and the aqueous layer extracted with
4
CH Cl (2 × 25 mL). The combined organic layer was washed with brine (50 mL) and dried over
2
2
Na SO . The crude residue obtained after evaporation under reduced pressure was purified by
2
4
silica gel column chromatography to obtain the propionate ester 3aiii as colorless liquid (270 mg,
9
1
4%). R 0.55 (9:1 hexane/EtOAc); IR (neat) ν 2923, 2856, 2241, 1756, 1724, 1434, 1219,
f max
−
1 1
062, 772 cm ; H NMR (500 MHz, CDCl ) δ 4.80 (s, 2H), 4.25 (q, J = 7.2 Hz, 2H), 2.40 (q, J
3
13
=
7.6 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.6 Hz, 3H) ppm; C NMR (75 MHz,
CDCl ) δ 173.2, 152.8, 80.9, 77.8, 62.2, 51.1, 27.1, 13.9, 8.8 ppm; HRMS (ESI-TOF) m/z: [M +
3
+
Na] calcd for C H O Na: 207.0628; found: 207.0622.
9
12
4
Ethyl 8-(4-methoxybenzyloxy)-4-(pivaloyloxy)oct-2-ynoate (3b): Following the general
procedure P-2a and 2e, 3b (245 mg, 72%)was obtained from 5-(4-methoxybenzyloxy)pentanal
as pale yellow liquid. R 0.60 (9:1 hexane/EtOAc); IR (neat) ν 2934, 2857, 2243, 1717, 1613,
f
max
−1 1
1
250, 1143, 751 cm ; H NMR (300 MHz, CDCl ) δ 7.25 (d, J = 7.5 Hz, 2H), 6.88 (d, J = 8.3
3
Hz, 2H), 5.43 (t, J = 6.0 Hz, 1H), 4.43 (s, 2H), 4.23 (q, J = 6.8 Hz, 2H), 3.81 (s, 3H), 3.45 (t, J =
6
.0 Hz, 2H), 1.90-1.79 (m, 2H), 1.69-1.48 (m, 4H), 1.31 (t, J = 6.0 Hz, 3H), 1.22 (s, 9H) ppm;
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Page 29 of 58
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13
C NMR (75 MHz, CDCl ) δ 171.1, 159.1, 130.4, 129.2, 113.7, 84.1, 76.6, 72.5, 69.4, 62.8,
3
+
6
2.1, 55.1, 38.7, 33.6, 29.6, 29.0, 26.9, 21.6, 13.9 ppm; HRMS (ESI-TOF) m/z: [M + Na] calcd
for C H O Na 427.2091; found: 427.2095.
2
3
32
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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34
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38
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40
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44
45
46
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51
52
53
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59
60
4
-Methoxy-1-(naphthalen-1-yl)-4-oxobut-2-ynyl benzoate (3c): Following the general
procedure P-2a and 2c, 3c (198 mg, 73%) was obtained from 1-naphthaldehyde as a pale yellow
liquid. R 0.68 (9:1 hexane/EtOAc); IR (neat) ν 2993, 2922, 2852, 2241, 1764, 1717, 1434,
f
max
−1 1
1
242, 1062, 772 cm ; H NMR (300 MHz, CDCl ) δ 8.27 (d, J = 8.3 Hz, 2H), 8.06 (d, J = 7.5
3
Hz, 2H), 7.92 (dd, J =3.8, 8.3 Hz, 2H), 7.85 (d, J = 6.8 Hz, 1H), 7.65-7.45 (m, 3H), 7.42 (t, J =
13
7
1
.5 Hz, 2H), 7.37 (s, 1H), 3.77 (s, 3H) ppm; C NMR (75 MHz, CDCl ) δ 165.0, 153.3, 133.9,
3
33.5, 130.5, 130.4, 130.3, 129.9, 128.9, 128.4, 127.1, 127.0, 126.2, 125.1, 123.4, 83.1, 78.5,
+
63.9, 52.8 ppm; HRMS (ESI-TOF) m/z: [M + H] calcd for C H O 345.1121; found:
2
2
17
4
3
45.1130.
Methyl 4-(naphthalen-1-yl)-4-(pivaloyloxy)but-2-ynoate (3d): Following the general
procedure 2a and 2e, 3d (210 mg, 73%) was obtained from 1-naphthaldehyde as a yellow liquid.
R 0.56 (9:1 hexane/EtOAc); IR (neat) ν 2924, 2856, 2239, 1756, 1721, 1434, 1256, 1220,
f
max
−
1 1
1130, 1062, 773 cm ; H NMR (500 MHz, CDCl ) δ 8.12 (br d, J = 8.4 Hz, 1H), 7.90 (br d, J =
3
8
.4 Hz, 2H), 7.75 (br d, J = 7.0 Hz, 1H), 7.61-7.51 (m, 2H), 7.51-7.46 (m, 1H), 7.10 (s, 1H), 3.76
1
3
(s, 3H), 1.21 (s, 9H) ppm; C NMR (125 MHz, CDCl ) δ 176.9, 153.4, 133.9, 130.6, 130.3,
3
128.8, 126.8, 126.7, 126.1, 125.1, 123.4, 83.3, 78.2, 63.3, 52.8, 38.9, 26.9 ppm; HRMS (ESI-
+
TOF) m/z: [M + Na] calcd for C H O Na 347.1253; found: 347.1253.
2
0
20
4
Methyl 4-(acryloyloxy)-6-phenylhex-2-ynoate (3e): Following the general procedure 2a and
2
d, 3e (170 mg, 70%) was obtained from 3-phenylpropanal as a light yellow liquid. R 0.65 (9:1
f
−1
hexane/EtOAc); IR (neat) νmax 3117, 2937, 2377, 2314, 1786, 1693, 1550, 1514, 1216, 772 cm ;
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