Organocatalytic Reductive Propargylation: Scope and Applications

Article abstract of DOI:10.1021/acs.joc.9b02415

An amino acid-catalyzed three-component reductive coupling protocol has been developed for the selective high-yielding synthesis of nearly fifty examples of propargylated cyclic/acyclic systems from the various propargyl aldehydes, cyclic/acyclic CH acids, and Hantzsch ester under ambient conditions. It is an economical, efficient, catalytic, metal-free protocol for the quick gram-scale synthesis of propargylated cyclic/acyclic compounds, and many of these coupling compounds were purified by a simple precipitation-filtration technique instead of column chromatography. Functionally rich propargylated cyclic-1,3-diketones were specifically transformed into dihydropyrans found in natural products and drugs through an annulative etherification reaction by using Lewis-acid (AgOTf) catalysis. Further, we developed the C-methylation reactions on propargylated cyclic-1,3-diketones, which are prolific synthons in natural products and medicinal chemistry.

Full text of DOI:10.1021/acs.joc.9b02415

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Article
Organocatalytic Reductive Propargylation: Scope and Applications
Mohammed Anif Pasha, A. Vamshi Krishna, Etikala Ashok, and Dhevalapally Buchi Ramachary
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02415 • Publication Date (Web): 07 Nov 2019
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Organocatalytic Reductive Propargylation: Scope
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Mohammed Anif Pasha, A. Vamshi Krishna, Etikala Ashok and Dhevalapally B.
Ramachary*
Catalysis Laboratory, School of Chemistry, University of Hyderabad, Hyderabad-500 046, India
Fax: +91-40-23012460, E-mail: ramsc@uohyd.ac.in and ramchary.db@gmail.com
Homepage: http://chemistry.uohyd.ac.in/~dbr/index.htm
KEYWORDS: annulation; cyclic-1,3-diones; organocatalysis; propargylation; reductive
coupling
ABSTRACT: An amino acid-catalyzed three-component reductive coupling protocol has
developed for the selective high-yielding synthesis of nearly fifty examples of propargylated
cyclic/acyclic systems from the various propargyl aldehydes, cyclic/acyclic CH-acids, and
Hantzsch ester at the ambient conditions. It is an economical, efficient, catalytic, metal-free
protocol for the quick gram scale synthesis of propargylated cyclic/acyclic compounds and many
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of these coupling compounds were purified by simple precipitation-filtration technique instead of
column chromatography. Functionally rich propargylated cyclic-1,3-diketones were specifically
transformed into dihydropyrans found in natural products and drugs through an annulative
etherification reaction by using Lewis-acid (AgOTf) catalysis. Further we developed the C-
methylation reactions on propargylated cyclic-1,3-diketones, which are prolific synthons in
natural products and medicinal chemistry.
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. Introduction
Reaction engineering is all about constructing different bonds in a highly selective, efficient and
greener mode, which is a key supporting technique for the synthesis of structurally important
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molecules including natural products, drugs and materials. One such reaction is the
chemoselective propargylation of cyclic 1,3-diones at C-2 position. Owing to its numerous
potential applications in the synthesis of drugs and natural products, chemoselective C-
propargylation drew the attention of many research groups.2
In the previous methods, the C-2 selective propargylation was performed using base in
solvent with or without phase transfer catalyst, but it suffered competition with O-
propargylation. It is evident from the literature that many researchers succeeded in double
2
propargylation at C-2 position of cyclic 1,3-diones. But, when it comes to mono propargylation
at C-2 position, it has always ended up in low yields and sometimes even failed in introducing
the functionally rich propargyl groups. As of today, there is no perfect high-yielding protocol for
C-2 selective mono propargylation of cyclic 1,3-diones.
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Scheme 1: Previous Reports on the Selective C-Propargylation of Cyclic-1,3-diketones
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Earlier in 1998, Mattay et al. and later in 2017, Christmann et al. reported mono
propargylation of 1,3-cyclohexanedione with propargyl bromide induced by KOH at 25-45 °C in
water with longer reaction times and poor yields (40% and 29% respectively, Scheme 1a/d).3a,d
In 2010, Yoshimatsu et al. reported a regioselective mono propargylation of 1,3-
cyclohexanedione using sterically crowded 3-sulfanylpropargyl alcohol catalyzed by the
scandium triflate in MeNO
2
-H O (10:1) at reflux conditions to furnish propargylated 1,3-
2
diketone in good yields (Scheme 1b).3b Later, Luo et al. in 2014 reported the mono
propargylation of 1,3-cyclohexanedione at C-2 position by using propargyl bromide, induced by
sodium methoxide in methanol at 60 °C with longer reaction time and poor yield (42%, Scheme
3
c
1c). In these mono-propargylation methods, either the process lacks favorable yield or was
performed only on some special substrates (Scheme 1).3
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Scheme 2: Selected Applications from 2-(Prop-2-yn-1-yl)cyclic-1,3-diones as Synthons
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The significance of the chemoselective mono propargylation on cyclic 1,3-diketones is
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comprehensible from the few reports enlisted in Scheme 2. In 2019, Meek et al. reported the
asymmetric borylative cyclization of alkynes with ketones by using propargylated cyclic 1,3-
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4a
diones as starting materials (Scheme 2a). For the stereoselective racemic synthesis of complex
carbocyclic compounds by Lam et al. in 2017/2014 and asymmetric synthesis of carbocyclic
propellanes by Christmann et al. in 2017, the propargylated cyclic 1,3-diones were used as the
key staring materials (Scheme 2b-c).4b-d Later in 1999, Prunet et al. synthesized interesting seco-
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e
taxane from 2-methyl-2-propargylcyclohexane-1,3-dione (Scheme 2d). In 1992, Schore et al.
synthesized metal-complexation with macrocyclic lactones starting from 2-(hydroxybutynyl)
4
f
derivatives of 1,3-cyclohexanedione (Scheme 2e). In 1971, Buchi et al. reported the synthesis
of methyl jasmonate which is a valuable raw material in modern perfumery, starting from simple
4
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mono propargylated 1,3-cyclohexanedione (Scheme 2f). By considering the shortcomings of
the available procedures for the chemoselective mono propargylation on cyclic-1,3-diketones
and the importance of the requirement for an efficient method (Scheme 1), we decided to take up
the challenge of developing a simple protocol through which one can access various cyclic 1,3-
diones possessing different functionalized propargyl groups at C-2 position (Scheme 3).
Our reaction design as depicted in Scheme 3 suggests that amino acid 4 would catalyze three-
component reductive coupling between cyclic 1,3-diones 1, propargyl aldehydes 2 and Hantzsch
ester 3 at the ambient conditions in DCM. First, amino acid (S)-proline 4 would selectively react
with propargyl aldehydes 2 to generate the iminium ion A formation by 1,2-addition. Secondly,
in situ generated iminium ion A intermediate may undergo reaction with both of the nucleophiles
1
or/and 3 through 1,2- or 1,4-additon. In situ reaction of iminium ion A with cyclic 1,3-diones 1
can produce the intermediates B and D through 1,2-addition (Knoevenagel condensation) and
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,4-addition (Michael addition), respectively (see Scheme 3).
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Scheme 3: Reaction Design for the Chemoselective C-Propargylation of CH-Acids
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In a similar manner, reaction of iminium ion A with 3 can produce olefin-aldehydes C
through 1,4-additon. Thirdly, reduction or transfer hydrogenation of intermediates B with
Hantzsch ester 3 could result in the formation of products 5 or/and E through 1,4-addition or 1,6-
addition, respectively. In a similar manner, reduction or transfer hydrogenation of other
intermediates C and D with 3 could produce the products F and G through 1,4-addition,
respectively. Possible formation of four products 5, E, F, and G from the three-component
coupling reaction under the amino acid-catalysis made more challenging to investigate the
selective synthesis of designed products (Scheme 3).5
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. Results and Discussion
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Table 1: Investigation of the Reductive Propargylation on Cyclohexane-1,3-dione 1aa,b
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a
Reactions were carried out in DCM (1.0 mL) with 2.0 equiv of 2a (0.6 mmol) and 1.0 equiv
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of 3 (0.3 mmol) relative to the 1a (0.3 mmol) in the presence of 5 mol% of (S)-4. Yield refers to
the column-purified product. 1.5 equiv amount of 2a used. 1.0 equiv amount of 2a used.
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As proposed in the reaction design, we decided to investigate the three-component reductive
coupling reaction by choosing 1,3-cyclohexanedione (1a), 3-(trimethylsilyl)propiolaldehyde (2a)
and Hantzsch ester (3) as the substrates. Accordingly, when we treated 1a with 2a under (S)-
proline 4 catalysis, a Knoevenagel condensation product was formed, which upon further
sequential treatment with Hantzsch ester (3) resulted in 70% of the reductive coupling product
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aa (not mentioned in Table 1). Surprisingly, when we performed one-pot reaction of 1.0 equiv.
of 1a, 2.0 equiv. of 2a and 1.0 equiv. of 3 in the presence of 20 mol% of (S)-proline (4) in DCM
at room temperature furnished the reductive coupling product 5aa in 93% yield within 5 minutes
(Table 1, entry 1), which opened a new window for the ‘three-component reductive
propargylation’ (TCRP) reaction. Notably, we are not observed formation of other possible
products Eaa, Faa, Gaa and 2,2'-(3-(trimethylsilyl)prop-2-yne-1,1-diyl)bis(cyclohexane-1,3-
dione) in the above reaction.
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We proceeded with further optimization, by reducing the catalyst loading to 15, 10 and 5
mol%, which resulted in 90%, 90% and 93% yield of 5aa with 35, 50 and 60 minutes of reaction
times, respectively (Table 1, entries 2-4). Though, there is no discernible effect of the catalyst
loading on the reaction yield, it does have a visible effect on the reaction times which are
inversely proportional to the catalyst loadings. As the reaction is satisfactorily facile in the
presence of 5 mol% of catalyst 4, we considered it to be the optimal catalyst loading. Next, we
tried to minimize the equivalents of 2a (1.5 equiv. and 1.0 equiv.) which showed a negative
impact on the reaction, with sluggish reaction times (180 and 300 min.) and yields (76% and
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0%, respectively) which are comparatively low (Table 1, entries 5-6). Same time TCRP
reaction of 1a (0.3 mmol), 2a (0.6 mmol) and 3 (0.3 mmol) in DCM at 25 °C under the 5 mol%
of piperidine-catalysis for 45 minutes furnished the 5aa in 87% yield and under the 10 mol% of
piperidine-catalysis for 30 minutes furnished the 5aa in 81% yield, respectively (results not
shown in Table 1) and these results are inferior to (S)-4-catalysis. Thus, the optimization process
came to an end inferring entry 4 of Table 1 to be the best optimized condition.
With optimized conditions in hand, we continued our studies of three-component reductive
propargylation on various CH-acids or active methylene compounds in order to prove the
strength and generality of the coupling reaction (Table 2). The 3-(trimethylsilyl)propiolaldehyde
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a reacted with various functionalized cyclic 1,3-diones 1b-m under the (S)-proline 4-catalysis in
the presence of 3 to afford the corresponding reductive propargylation products 5ba-5ma with
good to excellent yields (Table 2). Many of these coupling reactions completed within the range
of 9 min. to 60 min. and few of the reactions took 2-3 h may be due to the solubility issues.
These results are showing that the coupling reaction is compatible with a variety of
functionalities including ring size on the cyclic 1,3-dione 1b-m substrates. The yield of the
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product 5ka is comparatively low and reaction conversion is not 99% even after longer reaction
times, which may be due to low reactivity of CH-acid 1k as enolic double bond is in conjugation
with internal double bond. To expand the CH-acids scope, we further carried out the coupling
studies on different acyclic active methylene compounds (1n-1q) with 2a or 2b (Table 2).
Surprisingly, reaction between malononitrile 1n, 2a and 3 under the 4-catalysis didn’t furnished
the coupling product 5na and even Knoevenagel product Bna not formed may be due to the
different electronic nature of substrates. Further when malononitrile 1n reacted with 3-
phenylpropiolaldehyde 2b under the optimized condition, followed by treatment with 3 at the 25
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C for within 25 min. furnished the coupling product 5nb in 97% yield (Table 2). In a similar
manner, treatment of the active methylene compounds 1o-1q with 2b and 3 under the 4-catalysis
in DCM at 25 °C for longer reaction times didn’t furnished the expected coupling 5ob-5qb
products. But the coupling products 5ob-5qb were furnished in good yields from the
corresponding substrates of 1o-1q with 2b and 3 under the 4-catalysis in DCE at 50 °C for 3 h as
shown Table 2. Temperature has become key factor to provide the reductive coupling 5ob-5qb
products in good yields may be due to the less acidity of acyclic compounds 1o-q compared to
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cyclic 1,3-diones 1a-m (Table 2). Based on the many applications of lawsone derivatives in
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medicinal to material chemistry, we performed three-component reductive coupling between
lawsone 1d, 3-phenylpropiolaldehyde 2b and Hantzsch ester 3 under the 4-catalysis in DCM at
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5 °C for 30 min. to furnish the coupling product 5db in 98% yield (Table 2). As lawsone 1d is a
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versatile synthon in organic reactions, we have also done the quick optimization on this
particular coupling reaction of 1d, 2b and 3 to find the correlation between reaction rate/yield
versus catalyst 4 loading, our observations are similar to the cyclohexane-1,3-dione 1a (Table
S1, see SI).
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Table 2: Scope of Reductive C-Propargylation with Various CH-acidsa
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After successful understanding of the organocatalytic reductive propargylation of different
CH-acids 1a-q with 2a/2b, we further shown interest to synthesize the library of 2-(3-
aryl/alkylprop-2-yn-1-yl)cyclohexane-1,3-diones 5ab-aq from the corresponding 3-
aryl/alkylpropiolaldehydes 2b-q and cyclohexane-1,3-dione 1a (Table 3). Because there are
numerous synthetic applications starting from the 2-(3-aryl/alkylprop-2-yn-1-yl)cyclohexane-
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1
,3-diones 5ab-aq (see Scheme 2).2-4 The reported 2-(3-aryl/alkylprop-2-yn-1-yl)cyclohexane-
,3-diones 5ab-aq were obtained in good‐to‐excellent yields through a coupling reaction of
simple cyclohexane-1,3-dione 1a with a variety of 3-aryl/alkylpropiolaldehydes (2b-q)
containing halogen atoms, electron‐withdrawing, electron‐donating, neutral, and heteroatom‐
substituted aryl moieties as well as achiral alkyl groups (Table 3). Organocatalytic three-
component reductive coupling of 1a with 2b and 3 in DCM at 25 °C for 60 minutes followed by
precipitation in cold 10% ethyl acetate in hexanes and quick filtration gave the analytically pure
coupling product 2-(3-phenylprop-2-yn-1-yl)cyclohexane-1,3-dione 5ab in 85% yield without
further column purification (Table 3). Strikingly, the coupling reaction of 1a with 4‐halophenyl‐,
4
‐cyanophenyl‐, and 4‐nitrophenyl-substituted 3-arylpropiolaldehydes 2c-g and 3 under the
catalysis of 4 in DCM at 25ꢀ°C for relatively longer reaction times (5.0–2.0 h) furnished the
products 5ac–ag in 95–78% yields (Table 3). Surprisingly, the reductive coupling reaction of 3-
n
arylpropiolaldehydes 2h-k containing 4‐methoxyphenyl-, 4-methylphenyl-, 4- butylphenyl-, and
naphthalen‐1‐yl with 1a and 3 under the catalysis of 4 in DCM at 25ꢀ°C for shorter reaction times
(60-20 min.) furnished the expected coupling products 5ah-ak in excellent yields (90%, 90%,
8
5% and 95%, respectively, Table 3). In a similar manner, the coupling reaction of 3-
heteroarylpropiolaldehydes 2l-n containing furan‐2‐yl, thiophen‐2‐yl, and N‐Boc‐indolyl‐3‐yl
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with 1a and 3 under the catalysis of 4 in DCM at 25ꢀ°C for 20 min. to 2.0 h furnished the
coupling products 5al-an in very good yields (90%, 88% and 86%, respectively, Table 3).
Table 3: Scope of Reductive C-Propargylation with Cyclohexane-1,3-dione and Various 3-
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Aryl/Alkylpropiolaldehydesa
a
Reactions were carried out in DCM (1.0 mL) with 2.0 equiv of 2b-q (0.6 mmol) and 1.0
equiv of 3 (0.3 mmol) relative to the 1a (0.3 mmol) in the presence of 5 mol% of (S)-4 and yield
refers to the product obtained from simple precipitation-filtration technique.
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Interestingly, the reductive coupling reaction of 1a and 3 with the 3-alkylpropiolaldehydes 2o-
q containing n-butyl, n-pentyl, and n‐hexyl under the catalysis of 4 at 25ꢀ°C for very short
reaction times (30 min. to 15 min.) furnished the expected domino products 5ao-aq in 85–92%
yields (Table 3). All of these propargylated coupling products 5ab-aq were isolated in pure form
by using a unique and simple precipitation-filtration technique on reaction mixture avoiding
tedious column chromatography.
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After successful high-yielding synthesis of important library of 2-(3-aryl/alkylprop-2-yn-1-
yl)cyclohexane-1,3-diones 5ab-aq from the cyclohexane-1,3-dione 1a, we further shown interest
to investigate the similar library synthesis from cyclopentane-1,3-dione 1e as corresponding
synthon for reductive coupling reactions to show more applications (see Scheme 2).2-4 In a
similar manner, 2-(3-aryl/alkylprop-2-yn-1-yl)cyclopentane-1,3-diones 5eb-eq were obtained in
excellent yields and shorter reaction times through a reductive coupling reaction of
cyclopentane-1,3-dione 1e with a variety of 3-aryl/alkylpropiolaldehydes (2b-q) containing
halogen atoms, electron‐withdrawing, electron‐donating, neutral, and heteroatom‐substituted aryl
moieties as well as alkyl groups (Table 4). Exceptionally, amino acid 4-catalyzed three-
component reductive coupling of cyclopentane-1,3-dione 1e with phenyl‐, 4‐halophenyl‐, 4‐
n
cyanophenyl‐, 4‐nitrophenyl-, 4‐methoxyphenyl-, 4-methylphenyl-, 4- butylphenyl-, naphthalen‐
1
‐yl, furan‐2‐yl, thiophen‐2‐yl, N‐Boc‐indolyl‐3‐yl, n-butyl, n-pentyl, and n‐hexyl substituted 3-
aryl/alkyl-propiolaldehydes 2b-q and Hantzsch ester 3 in DCM at 25 °C for 15 min. to 2.5 h
furnished the coupling products 2-(3-aryl/alkylprop-2-yn-1-yl)cyclopentane-1,3-diones 5eb-eq in
8
0-96% yields as shown in Table 4. Formation of TCRP products 5ac-ag/5ec-eg took longer
reaction times compared to other products 5 (see Tables 3-4), may be due to the shift in the
direction of the polarization of double bond between electron-withdrawing group substituted
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aryls or 1,3-dicarbonyls in the in situ generated Knoevenagel condensation intermediates Bac-
ag/Bec-eg (see Scheme 3), which delayed transfer hydrogenation. Herein, all of these coupling
products were purified by simple precipitation of reaction mixture in cold 10% ethyl acetate in
hexanes and followed by quick filtration gave the analytically pure coupling products 5eb-eq
straightway, in very good yields (Table 4).
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Table 4: Scope of Reductive C-Propargylation with Cyclopentane-1,3-dione and Various 3-
Aryl/Alkylpropiolaldehydesa
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a
Reactions were carried out in DCM (1.0 mL) with 2.0 equiv of 2b-q (0.6 mmol) and 1.0
equiv of 3 (0.3 mmol) relative to the 1e (0.3 mmol) in the presence of 5 mol% of (S)-4 and yield
refers to the product obtained from simple precipitation-filtration technique.
In order to investigate the sustainability of the reductive coupling reaction in bulk scale, we
planned grams scale reaction of cyclohexane-1,3-dione 1a (1.0 g, 8.918 mmol) with reduced
equivalents of 3-phenylpropiolaldehyde 2b (1.39 g, 10.7 mmol, 1.2 equiv.) and Hantzsch ester 3
1
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(
2.26 g, 8.918 mmol) under the catalysis of (S)-proline 4 (51.33 mg, 5 mol%) in DCM (30.0 mL,
0.3 M) at 25 °C for 3.0 h followed by precipitation-filtration technique furnished the coupling
product 5ab in 91% (1.836 g) yield (Scheme 4). In a similar mode, reaction of cyclopentane-1,3-
dione 1e (1.0 g, 10.19 mmol) with 2b (1.59 g, 12.22 mmol, 1.2 equiv.) and 3 (2.58 g, 10.19
mmol) under the catalysis of (S)-proline 4 (58.66 mg, 5 mol%) in DCM (34.0 mL, 0.3 M) at 25
°
C for 3.0 h followed by precipitation-filtration technique furnished the coupling product 5eb in
7% (1.88 g) yield (Scheme 4). This clearly proves the simplicity and significance of the metal-
8
free coupling reaction for industrial applications.
Scheme 4: Gram-Scale Synthesis of Reductive C-Propargylation Products 5ab/5eb
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3
. Applications of C-Propargylation Products 5:
As discussed earlier, there are plentiful potential applications for the propargylated coupling
products 5 and few of them are demonstrated herein. Deprotection of the TMS group on the
propargylated compound 5aa with tetra-n-butylammonium fluoride (TBAF) was performed in
sequential one-pot manner starting from 1a, 2a, 3 and 4 in DCM followed by next reaction in
THF furnished the 2-(prop-2-yn-1-yl)cyclohexane-1,3-dione 6aa in 98% yield containing the
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terminal alkyne, which is a versatile unit that can be used in different type of organic reactions
3d
(Scheme 5, eq.1). Copper-catalyzed azide–alkyne [3+2]-cycloaddition of 6aa with PhN
3
7 in
water and tert-BuOH at 25 °C for 24 h furnished the click product 8aa in 75% yield (Scheme 5,
eq.2). It is a popular fact that 1,2,3-triazoles are biologically and medicinally important
compounds and 1,2,3-triazoles containing cyclic-1,3-diketones will be interesting intermediates
8
for medicinal to material chemistry. Subsequently, we thought of executing an intramolecular
cyclization of coupling products 5 under the Lewis acid-catalysis, as compounds 5 contain the
9
requisite active functional groups. First, we engineered the cyclization reaction of propargylated
coupling compound 5eb with 10 mol% of AgOTf in dry methanol at 25 °C for 5 h, which
resulted in the annulative etherification product 9eb in 75% yield with high selectivity (Scheme
9
5
, eq.3). During the course of intramolecular cyclization, even though there is a chance for the
formation of either substituted dihydrofuran or dihydropyran rings, but only substituted
dihydropyran ring was formed exclusively. Observed high selectivity can be explained based on
the stability of the carbocation formed during the course of reaction as shown in Scheme 5, eq. 3.
Scheme 5: TMS-Deprotection, Click and Annulative Etherification Reactions on the
Reductive Coupling Products 5
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With annulative etherification protocol in hand, we further investigated the scope of this
reaction by developing a library of functionally rich dihydropyrans 9 from the various coupling
products 5 (Table 5).10 Reaction of 2-(3-arylprop-2-yn-1-yl)cyclohexane-1,3-diones 5ab-ai
containing phenyl‐, 4‐bromophenyl‐, 4‐cyanophenyl‐, 4‐nitrophenyl-, and 4-methylphenyl-,
under the catalysis of AgOTf in dry methanol at 25 °C for within 50 min. to 60 min. furnished
the expected dihydropyrans 9ab-ai in very good yields (85-76%) with high selectivity as shown
in Table 5. In a similar manner, cyclization reaction of 2-(3-aryl/alkylprop-2-yn-1-
yl)cyclopentane-1,3-diones 5eb-eq containing phenyl‐, 4‐bromophenyl‐, 4‐cyanophenyl‐, 4‐
nitrophenyl-, 4-methoxyphenyl-, 4-methylphenyl-, and n-hexyl- under the catalysis of 10 mol%
AgOTf in dry methanol at 25 °C for longer reaction times (5 h to 12 h) furnished the expected
dihydropyrans 9eb-eq in good to excellent yields (85-69%) with high selectivity as shown in
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Table 5. Gratifyingly, the various substituents present on the propargylated products 5 seems not
to have much effect on the Lewis acid-mediated annulative etherification reaction (Table 5).
Table 5: Scope of Annulative Etherification Reactiona
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a
Reactions were carried out in dry MeOH (1.0 mL) with 1.0 equiv of 5 (0.2 mmol) in the
presence of 10 mol% of AgOTf and yield refers to the product obtained from column
chromatography.
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9
In order to increase the versatility of the annulation reaction, we investigated few synthetic
applications of annulation products 9. Delightfully, treatment of dihydropyrans 9eb or 9ab with
1.0 equiv. of K
2
CO in dry methanol at room temperature for 1.5 h resulted in nucleophilic 1,4-
3
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addition of methanol followed by pyran ring opening to furnish the products 10eb or 10ab in
excellent yields (92% and 76% respectively, Scheme 6, eq.4). On the other hand, epoxidation of
9eb with 1.2 equiv. of m-CPBA in DCM at 25 °C for 1 h furnished the selective epoxide product
1
1eb in 71% yield (Scheme 6, eq.5). While oxidation of 9eb with 5.0 equiv. of 30% aqueous
in the presence of 6.0 M aqueous NaOH in methanol at 50 °C for 12 h furnished the 4-oxo-
H
2
O
2
4-phenylbutanoic acid 12eb in 50% yield through a sequence of epoxidation/epoxide ring
opening with hydroxide/Baeyer-Villiger oxidation reactions (Scheme 6, eq.6). These reactions
not only for diversifying of dihydropyrans 9, but gave strong support to the structural analysis of
regioselective formation of 9 from Ag(I)-catalysis on 5 (see Table 5).
Scheme 6: Controlled Experiments on the Annulative Etherification Products 9
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Further, we shown interest to synthesize the 2-methyl-2-(3-aryl/alkylprop-2-yn-1-
yl)cyclopentane-1,3-diones and 2-methyl-2-(3-aryl/alkylprop-2-yn-1-yl)cyclohexane-1,3-diones
from the corresponding coupling products 5 through C-methylation, as these compounds are
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4
prolific starting materials in various organic transformations (see Scheme 2). Same time, base-
mediated selective C-methylation of the propargylated coupling products 5 with methyl iodide is
a challenging task as O-methylation will be a dominating side reaction. Firstly, reaction of 5eb or
5
ab with 3 equiv. of MeI in the presence of 1.1 equiv. of NaOH in acetonitrile at 60 °C for 10 h,
furnished only O-methylation products 13eb or 13ab in 63% and 30% yield, respectively and
surprisingly didn’t find the C-methylation products (Scheme 7, eq.7). These results gave
inspiration to study some more details about methylation reactions on 5 (Scheme 7). Reaction of
5
eb with 2.0 equiv. of propargyl bromide in the presence of 1.0 equiv. of sodium bicarbonate in
water at 80 °C for 48 h, furnished only C-propargyl product 14eb in 31% yield (Scheme 7, eq.8),
which gave insight to install methyl group on C-2 position of 5. Strikingly, reaction of 5eb or
5
ab with 3 equiv. of MeI in the presence of 1.0 equiv. of sodium bicarbonate in water at 80 °C
for 36 h, furnished only C-methylation products 15eb or 15ab in moderate (40% and 34%)
yields, respectively and we didn’t find the O-methylation products (Scheme 7, eq.9). To improve
yields and diversity of methylation reactions, we have tested next conditions on different
substrates. Fortunately, reaction of 2-(3-(trimethylsilyl)prop-2-yn-1-yl)cyclohexane-1,3-diones
5
aa, 5ba or 2-(3-(trimethylsilyl)prop-2-yn-1-yl)cyclopentane-1,3-dione 5ea with 3 equiv. of MeI
in the presence of 1.2 equiv. of potassium carbonate in acetone at 60 °C for 4 h, furnished C-
methylation products 15aa in 76%, 15ba in 87% and 15ea in 40% yields, respectively and in last
case we observed the O-methylation product 13ea in 60% yield (Scheme 7, eq.10). In a
continuation, when we performed the methylation reaction of 5ba with 3 equiv. of MeI in the
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presence of 2.0 equiv. of potassium carbonate in methanol at 45 °C for 16 h, furnished domino
C-methylation/TMS-deprotection product 16ba in 30% yield (Scheme 7, eq.11). Definitely these
methylation reactions on reductive coupling products 5 will give inspiration for organic chemists
to make useful library of 14-16 and use them as starting materials to investigate new annulation
reactions.
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Scheme 7: Methylation Reactions on the Reductive Coupling Products 5
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5
6
The structure and relative stereochemistry of the reductive coupling 5 and their application
products 6, and 8-16 were established by IR, NMR, and mass analysis and also finally confirmed
by correlation with the X-ray crystal structure of 5eh (Figure S1, see the SI).11
0
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. Conclusions
In summary, we effectively established a new synthetic methodology named ‘organocatalytic
three-component reductive propargylation’ for the selective coupling of propargyl aldehydes
with CH-acids or active methylene compounds under the 5 mol% of (S)-proline in presence of
Hantzsch ester as hydrogen source. The metal-free reductive coupling method has wide substrate
tolerance in generating the mono-propargylated cyclic and acyclic products and which has lot
more applications in total synthesis of natural products, drugs and designed materials. We have
also shown applications of reductive coupling products 5 into synthesizing click 1,2,3-triazoles
8
, functionally rich dihydropyrans 9, and methylation products 13-16, which act as excellent
building blocks for many natural products and pharmaceuticals. Further, more applications
toward this ‘organocatalytic three-component reductive propargylation’ is currently underway.
5
. Experimental Section
General Experimental Procedures for the Organocatalytic Reductive Propargylation:
1
13
General Methods: The H NMR and C NMR spectra were recorded at 400 MHz and 100
1
MHz, respectively. The chemical shifts are reported in ppm downfield to TMS (δ = 0) for H
1
3
13
NMR and relative to the central CDCl
spectra, the nature of the carbons (C, CH, CH
35 experiment, and is given in parentheses. The coupling constants J are given in Hz. Column
3
resonance (δ = 77.0) for C NMR. In the C NMR
2
or CH ) was determined by recording the DEPT-
3
1
chromatography was performed using Acme’s silica gel (particle size 0.063-0.200 mm). High-
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resolution mass spectra were recorded on micromass ESI-TOF MS. IR spectra were recorded on
JASCO FT/IR-5300 and Thermo Nicolet FT/IR-5700. The X-ray diffraction measurements were
carried out at 298 K on an automated Enraf-Nonious MACH 3 diffractometer using graphite
monochromated, Mo-Kα (λ = 0.71073 Å) radiation with CAD4 software or the X-ray intensity
data were measured at 298 K on a Bruker SMART APEX CCD area detector system equipped
with a graphite monochromator and a Mo-Kα fine-focus sealed tube (λ = 0.71073 Å). For thin-
layer chromatography (TLC), silica gel plates Merck 60 F254 were used and compounds were
visualized by irradiation with UV light and/or by treatment with a solution of p-anisaldehyde (23
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
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2
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2
3
4
5
6
7
8
9
0
mL), conc. H
2
SO (35 mL), acetic acid (10 mL), and ethanol (900 mL) followed by heating.
4
Materials: All solvents and commercially available chemicals were used as received without
further purification unless otherwise stated.
(S)-Proline Catalysed Cascade Three-Component Reductive Propargylation (TCRP)
Reactions (Procedure A): For Table 1 and 2: In an ordinary glass vial equipped with a
magnetic stirring bar, to 2.0 equiv. of the 3-alkyl/arylpropiolaldehydes 2 (0.6 mmol), 1.0 equiv.
of 1,3-diketones or active methylene compound 1 (0.3 mmol) and 1.0 equiv. of Hantzsch ester 3
(
0.3 mmol, 76.0 mg) was added 1.0 mL of DCM (0.3 M), and then the catalyst (S)-proline 4
0.015 mmol, 1.73 mg, 5 mol%) was added, the resulting reaction mixture was stirred at 25 °C
(
for the time indicated in Tables 1 and 2. The crude reaction mixture was directly loaded onto a
silica gel column chromatography without aqueous workup, and pure coupling products 5 were
obtained in 70–98% yield (eluent: mixture of hexanes/ethyl acetate). For Table 3 and 4:
Reaction was performed as similar to above method and pure coupling products 5 were obtained
through precipitation-filtration technique instead of column-chromatography. The crude reaction
mixture was precipitated with cold 10% ethyl acetate in hexanes and washed with 10% cold
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1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ethyl acetate/hexanes (3 x 10 mL) and analytically pure coupling products 5 was obtained in 78-
9
9% yield.
General Procedure for the Trimethylsilyl Deprotection of Coupling Products 5 (Procedure
B): In an ordinary glass vial equipped with a magnetic stirring bar, to 1.5 equiv. of TBAF (0.45
mmol, 117.66 mg) and 1.0 equiv. of coupling product 5aa (0.3 mmol, 66.71 mg) was added 1.0
mL of THF (0.3 M) and the reaction mixture was stirred at room temperature for 2 h. The crude
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
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2
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4
5
6
7
8
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reaction was quenched with aqueous NH
4
Cl solution, and the aqueous layer was extracted with
SO ), filtered, and
ethyl acetate (3 x 10 mL). The combined organic layers were dried (Na
2
4
concentrated. Pure product 6aa (98%, 44.15 mg) were obtained by column chromatography
(silica gel, mixture of hexanes/ethyl acetate).
General Procedure for the Click Reaction of 2-(Prop-2-yn-1-yl)cyclohexane-1,3-dione 6aa
(Procedure C): In an ordinary glass vial equipped with a magnetic stirring bar, 1.0 equiv. of 2-
(prop-2-yn-1-yl)cyclohexane-1,3-dione 6aa (0.3 mmol, 45.05 mg) and 1.0 equiv. of phenyl azide
7 (0.3 mmol, 35.74 mg) was added to 0.2 equiv. of 1.0 M aqueous sodium ascorbate (0.06 mmol,
1.89 mg, 60.01 μL), 0.4 equiv. of copper sulfate pentahydrate (0.12 mmol, 29.96 mg) in 1.0 mL
of water and tertiary-butanol solvent (1:1 mixture, 0.3 M), then the reaction mixture was stirred
at room temperature for 24 h. The crude reaction mixture was quenched with aqueous NH Cl
solution, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined
organic layers were dried (Na SO ), filtered, and concentrated. Pure click product 8aa (75%,
0.59 mg) were obtained by column chromatography (silica gel, mixture of hexanes/ethyl
acetate).
1
4
2
4
6
General Procedure for the Annulative Etherification of 2-(3-Arylprop-2-yn-1-yl)cyclic-1,3-
diones 5 (Procedure D): In an ordinary glass vial equipped with a magnetic stirring bar, 0.1
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equiv. of silver triflate (0.02 mmol, 5.14 mg, 10 mol%) was added to 1.0 equiv. of propargyl
cyclic-1,3-diones 5 (0.2 mmol) in 1.0 mL of dry methanol (0.2 M) solvent and the reaction
mixture was stirred at room temperature for 1-12 h. The crude reaction mixture was quenched
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
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2
3
4
5
6
7
8
9
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2
3
4
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8
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4
5
6
7
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1
2
3
4
5
6
7
8
9
0
with aqueous NH
4
Cl solution, and the aqueous layer was extracted with ethyl acetate (3 x 10
SO ), filtered, and concentrated. Pure
mL). The combined organic layers were dried (Na
2
4
products 9 were obtained by column chromatography (silica gel, mixture of hexanes/ethyl
acetate).
General Procedure for the Ring Opening of 4H-Pyran Derivatives 9 (Procedure E): In an
ordinary glass vial equipped with a magnetic stirring bar, 1.0 equiv. of potassium carbonate (0.2
mmol, 27.64 mg) was added to 1.0 equiv. of 4H-pyran derivative 9 (0.2 mmol) in 1.0 mL of dry
methanol (0.2 M) solvent and the reaction mixture was stirred at room temperature for 1.5 h. The
crude reaction mixture was quenched with aqueous NH
4
Cl solution, and the aqueous layer was
SO ),
extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried (Na
2
4
filtered, and concentrated. Pure products 10 were obtained by column chromatography (silica
gel, mixture of hexanes/ethyl acetate).
General Procedure for the Epoxidation of 4H-Pyran Derivative 9eb (Procedure F): In an
ordinary glass vial equipped with a magnetic stirring bar, 1.2 equiv. of m-CPBA (0.24 mmol,
4
1.42 mg) was added to 1.0 equiv. of 4H-pyran derivative 9eb (0.2 mmol, 42.45 mg) in 1.0 mL
of dry DCM (0.2 M) solvent and the reaction mixture was stirred at room temperature for 1.0 h.
The crude reaction mixture was quenched with aqueous NH Cl solution, and the aqueous layer
was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried (Na SO ),
4
2
4
filtered, and concentrated. Pure product 11eb (71%, 32.41 mg) were obtained by column
chromatography (silica gel, mixture of hexanes/ethyl acetate).
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
General Procedure for the Fragmentation of 4H-Pyran Derivative 9eb (Procedure G): In an
ordinary glass vial equipped with a magnetic stirring bar, 5.0 equiv. of 30% aqueous H
2
2
O (1.0
mmol, 34.01 mg, 30.64 μL) and 1.0 equiv. of 6.0 M aqueous NaOH (0.2 mmol, 8.0 mg, 33.33
μL) were added to 1.0 equiv. of 4H-pyran derivative 9eb (0.2 mmol, 42.45 mg) in 1.0 mL of
methanol (0.2 M) solvent and the reaction mixture was stirred at 50 °C (oil bath) for 12 h. The
0
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3
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2
3
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5
6
7
8
9
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2
3
4
5
6
7
8
9
0
crude reaction mixture was quenched with aqueous NH
4
Cl solution, and the aqueous layer was
SO ),
extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried (Na
2
4
filtered, and concentrated. Pure product 12eb (50%, 17.82 mg) were obtained by column
chromatography (silica gel, mixture of hexanes/ethyl acetate).
General Procedure for the O-Methylation of TCRP Products 5 (Procedure H): In an
ordinary glass vial equipped with a magnetic stirring bar, 1.1 equiv. of NaOH (0.22 mmol, 8.8
mg), 3.0 equiv. of methyl iodide (0.6 mmol, 37.35 μL) were added to 1.0 equiv. of 1,3-cyclic
diketone propargyl derivative 5 (0.2 mmol) in 1.0 mL of CH
reaction mixture was stirred at 60 °C (oil bath) for 10 h. The crude reaction mixture was
quenched with aqueous NH Cl solution, and the aqueous layer was extracted with ethyl acetate
3 x 10 mL). The combined organic layers were dried (Na SO ), filtered, and concentrated. Pure
3
CN (0.2 M) solvent and the
4
(
2
4
products 13 were obtained by column chromatography (silica gel, mixture of hexanes/ethyl
acetate).
General Procedure for the C-Alkylation Reaction of TCRP Products 5 (Procedure I):
Method 1: In an ordinary glass vial equipped with a magnetic stirring bar, 1.0 equiv. of NaHCO
3
(0.2 mmol, 16.8 mg), 2.0 equiv. of propargyl bromide (80 wt.% in toluene, 0.4 mmol, 35.64 μL)
were added to 1.0 equiv. of 1,3-cyclic diketone propargyl derivative 5 (0.2 mmol) in 1.0 mL of
water (0.2 M) and the reaction mixture was stirred at 80 °C (oil bath) for 48 h. The crude
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reaction mixture was quenched with aqueous NH
4
Cl solution, and the aqueous layer was
extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried (Na
2
SO ),
4
filtered, and concentrated. Pure products 14 were obtained by column chromatography (silica
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
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
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
gel, mixture of hexanes/ethyl acetate).
Method 2: In an ordinary glass vial equipped with a magnetic stirring bar, 1.0 equiv. of NaHCO
3
(0.2 mmol, 16.8 mg), 3.0 equiv. of methyl iodide (0.6 mmol, 37.35 μL) were added to 1.0 equiv.
of 1,3-cyclic diketone propargyl derivative 5 (0.2 mmol) in 1.0 mL of water (0.2 M) and the
reaction mixture was stirred at 80 °C (oil bath) for 36 h. The crude reaction mixture was
quenched with aqueous NH
4
Cl solution, and the aqueous layer was extracted with ethyl acetate
SO ), filtered, and concentrated. Pure
(3 x 10 mL). The combined organic layers were dried (Na
2
4
products 15 were obtained by column chromatography (silica gel, mixture of hexanes/ethyl
acetate).
Method 3: In an ordinary glass vial equipped with a magnetic stirring bar, 1.2 equiv. of K
2
CO
3
(0.24 mmol, 33.17 mg), 3.0 equiv. of methyl iodide (0.6 mmol, 37.35 μL) were added to 1.0
equiv. of 1,3-cyclic diketone propargyl derivative 5 (0.2 mmol) in 1.0 mL of acetone (0.2 M)
solvent and the reaction mixture was stirred at 60 °C (oil bath) for 4 h. The crude reaction
mixture was quenched with aqueous NH
4
Cl solution, and the aqueous layer was extracted with
SO ), filtered, and
ethyl acetate (3 x 10 mL). The combined organic layers were dried (Na
2
4
concentrated. Pure products 15 were obtained by column chromatography (silica gel, mixture of
hexanes/ethyl acetate).
General Procedure for the Domino C-Methylation Followed by Trimethylsilyl Deprotection
of TCRP Product 5ba (Procedure J): In an ordinary glass vial equipped with a magnetic
stirring bar, 2.0 equiv. of K
2
CO
3
(0.4 mmol, 55.28 mg), 5.0 equiv. of methyl iodide (1.0 mmol,
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
41.94 mg, 62.25 μL) were added to 1.0 equiv. of TCRP compound 5ba (0.2 mmol, 50.08 mg)
in 1.0 mL of methanol (0.2 M) solvent and the reaction mixture was stirred at 45 °C (oil bath) for
16 h. The crude reaction mixture was quenched with aqueous NH Cl solution, and the aqueous
layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried
Na SO ), filtered, and concentrated. Pure domino product 16ba (30%, 11.53 mg) was obtained
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
2
4
by column chromatography (silica gel, mixture of hexanes/ethyl acetate).
General Observations during the Recording of NMR Samples:
(
1) Because of solubility problem of 2-propargyl-cycloalkane-1,3-diones 5 in CDCl
have used few drops of CD OD or DMSO-d for recording NMR spectra.
3
, we
3
6
(
2) Due to the keto-enol and enol-enol tautomerism of 2-propargyl-cycloalkane-1,3-diones 5,
13C NMR resulted in the poor resolution of few carbons (2 x CH
2
and 2 x C=O) even
after more than 2000 scans in the solvent system of CDCl
CDCl + DMSO-d (few drops).
3) In few compounds NMR spectra, even after addition of few drops of CD
spectra has shown minor tautomeric mixture of keto-isomer along with major enol-
isomer.
-(3-(Trimethylsilyl)prop-2-yn-1-yl)cyclohexane-1,3-dione (5aa): The title compound was
3
+ CD
3
OD (few drops) or
3
6
(
3
OD or DMSO-
d
6
2
prepared following procedure A, purified by column chromatography using EtOAc/hexanes
(2/8), and isolated as an off-white solid. Mp.: 130-132 °C. Yield: 93% (62.04 mg). IR (Neat):
-1
1
ν
max 2958, 2642, 2172, 1661, 1631, 1556, 1411, 1383, 1266, 997, 841, 800, 759 and 642 cm . H
NMR (CDCl , 500 MHz, 12.8:1 ratio, major enol isomer): δ 8.53 (1H, s, O-H), 3.32 (2H, s), 2.48
3
(2H, t, J = 6.0 Hz), 2.36 (2H, t, J = 6.5 Hz), 1.95 (2H, quintet, J = 6.5 Hz), 0.17 (9H, s,
13
Si(CH
3
)
3
). C NMR (CDCl
3
, DEPT-135, 6.25:1 ratio, major enol isomer): δ 197.0 (C, C=O),
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73.5 (C, C=C-OH), 108.9 (C, C=C-OH), 104.5 (C, acetylenic-C), 103.7 (C, acetylenic-C), 36.4
1
(CH
2
), 29.4 (CH
2
), 20.4 (CH
2
), 14.0 (CH
2
), -0.3 (3 x CH
3
, Si(CH
3
)
3
). H NMR (CDCl
3
, 500
MHz, 12.8:1 ratio, minor diketo isomer): δ 3.70 (1H, t, J = 6.0 Hz, CH), 2.74 (2H, d, J = 6.0 Hz),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
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
.72-2.69 (1H, m), 2.65-2.59 (2H, m), 2.22-2.17 (1H, m), 1.83-1.76 (2H, m), 0.10 (9H, s,
1
3
Si(CH
3
)
3
). C NMR (CDCl , DEPT-135, 6.25:1 ratio, minor diketo isomer): δ 202.4 (2 x C,
3
C=O), 90.2 (C, acetylenic-C), 85.0 (C, acetylenic-C), 66.7 (CH), 39.9 (2 x CH
2
), 18.0 (CH ),
2
1
1
3.6 (CH
2
), 0.02 (3 x CH
3
, Si(CH
3
)
3
). H NMR (CDCl
3
+CD OD (three drops), 500 MHz, only
3
major enol isomer): δ 3.25 (2H, br s), 2.39 (4H, t, J = 6.5 Hz), 1.92 (2H, quintet, J = 6.5 Hz),
1
3
0
.12 (9H, s, Si(CH
3
)
3
). C NMR (CDCl
3
3
+CD OD (three drops), DEPT-135, only major enol
isomer): δ 109.6 (C, C=C−OH), 104.2 (C, acetylenic-C), 87.5 (C, acetylenic-C, broad peak), 33.2
(2 x CH
2
, broad peak), 20.3 (CH
2
), 13.5 (CH
2
), -0.26 (3 x CH
3
, Si(CH
3
3
) ). HRMS (ESI-TOF)
+
m/z: [M + H] Calcd for C12
H
18
2
O SiH 223.1154; Found 223.1157.
5
,5-Dimethyl-2-(3-(trimethylsilyl)prop-2-yn-1-yl)cyclohexane-1,3-dione (5ba):12a The title
compound was prepared following procedure A, purified by column chromatography using
EtOAc/hexanes (1/9), and isolated as an off-white solid. Mp.: 131-132 °C. Yield: 96% (72.11
mg). IR (Neat): νmax 2957, 2922, 2854, 2178, 1551, 1332, 1306, 1249, 1201, 1149, 1042, 1015,
-1 1
840, 757, 604 and 482 cm . H NMR (CDCl
3
+DMSO-D
6
(three drops), 400 MHz): δ 2.95 (2H,
13
br s), 2.03 (4H, br s), 0.79 (6H, s, 2 x CH
3
), -0.15 (9H, s, Si(CH
3
)
3
). C NMR (CDCl
3
+DMSO-
D (three drops), DEPT-135) δ 109.1 (C, C=C−OH), 105.4 (C, acetylenic-C), 81.7 (C,
6
acetylenic-C), 31.31 (C), 27.6 (2 x CH
3
), 12.2 (CH
2
), -0.34 (3 x CH
3
, Si(CH
3
3
) ). HRMS (ESI-
+
TOF) m/z: [M + H] Calcd for C14
H
22
O
2
SiH 251.1467; Found 251.1467.
5
-Phenyl-2-(3-(trimethylsilyl)prop-2-yn-1-yl)cyclohexane-1,3-dione (5ca): The title
compound was prepared following procedure A, purified by column chromatography using
ACS Paragon Plus Environment
2
9