Propargyl α-aryl-α-diazoacetates as robust reagents for the effective C–H bond functionalization of 1,3-diketones via scandium catalysis

Article abstract of DOI:10.1016/j.tetlet.2019.06.026

Propargyl α-aryl-α-diazoacetate a new class of reagent is developed for the effective C–H bond functionalization of 1,3-diketones at room temperature. The combination of scandium triflate and propargyl α-aryl-α-diazoacetate proved to be efficient catalyst

Full text of DOI:10.1016/j.tetlet.2019.06.026

Accepted Manuscript
Propargyl α-aryl-α-diazoacetates as robust reagents for the effective C-H bond
functionalization of 1,3-diketones via scandium catalysis
Balu S. Navale, Debasish Laha, Ramakrishna G. Bhat
PII:
S0040-4039(19)30577-5
https://doi.org/10.1016/j.tetlet.2019.06.026
TETL 50867
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 March 2019
12 June 2019
15 June 2019
Please cite this article as: Navale, B.S., Laha, D., Bhat, R.G., Propargyl α-aryl-α-diazoacetates as robust reagents
for the effective C-H bond functionalization of 1,3-diketones via scandium catalysis, Tetrahedron Letters (2019),
doi: https://doi.org/10.1016/j.tetlet.2019.06.026
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Graphical Abstract
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Propargyl α-aryl-α-diazoacetates as robust reagents
for the effective C-H bond functionalization of
1,3-diketones via scandium catalysis
Balu S. Navale, Debasish Laha and Ramakrishna G. Bhat*
O
O
O
R
R
O
N2
O
O
Sc(OTf)3 (5 mol %)
DCE, rt, 4 - 24 h
O
R
R
Ar
Ar
O
H
R = Ar, Me, Et
(up to 97% yield)
Propargyl -aryl--diazoacetates-Robust reagents
Works with deactivated substrates
Less prone for side reactions
Low Catalyst loading (5 mol %)
Total of 27 examples and gram scale synthesis

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Propargyl α-aryl-α-diazoacetates as robust reagents for the effective C-H bond
functionalization of 1,3-diketones via scandium catalysis
Balu S. Navale, Debasish Laha and Ramakrishna G. Bhat*
Department of Chemistry, Main Building, Indian Institute of Science Education and Research (IISER)-Pune, Dr. Homi Bhabha Road, Pashan, Pune, 411008,
Maharashtra, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Propargyl α-aryl-α-diazoacetate a new class of reagent is developed for the effective C-H bond
functionalization of 1,3-diketones at room temperature. The combination of scandium triflate
and propargyl α-aryl-α-diazoacetate proved to be efficient catalyst-reagent system for the
controlled C-H bond functionalization to afford 1,3-dicarbonyl alkylation. The protocol uses
inexpensive Sc(OTf)3 (5 mol%) and the reaction did not require the use of expensive catalysts or
ligands and worked efficiently at room temperature. The practicality of the protocol has been
demonstrated by the gram scale synthesis.
Available online
Keywords:
C-H bond functionalization
1,3-Diketones
Propargyl α-aryl-α-diazoacetate
Scandium Triflate
2009 Elsevier Ltd. All rights reserved.
1. Introduction
Selective C-H bond functionalization for the construction of new C-C bonds presents an alternative and powerful
strategy to the traditional methods in organic synthesis. The direct C-H bond functionalization has several advantages and has
attracted a great attention from the synthetic community.1,2 The direct C-H bond functionalization reduces the number of
synthetic steps and the pre-activation of starting materials could be avoided to increase the overall atom-efficiency. It has
rapidly become one of the powerful tools for the synthesis and modification of complex molecules.3 A great progress has been
made in this field using different transition metal catalysts.4 However, identifying and developing a suitable combination of
catalyst and reagent system for the selective C-H bond functionalization is always a challenging task. The diazo compounds
have been established as versatile reagents for various metal-catalyzed reactions.5 Davies is one of the pioneers who embarked
on comprehensive investigations of the scope of intermolecular C-H bond functionalization using diazo compounds.6 The C-
H bond functionalization using α-diazo esters normally proceeds via transient metal-carbenoid species, which are usually
formed by the reaction with transition-metal complexes.7 The transition metals such as rhodium,8 copper,9 silver10 and
recently gold11 have been successfully explored for the decomposition of α-diazo esters to achieve the C-H bond
functionalization. Different carbon nucleophiles have been explored for the intermolecular C-H bond functionalization with
donor/acceptor type α-diazo esters.11g,12
 Dr. Ramakrishna G. Bhat; Tel.: +91-20-25908092; fax: + 91-20-25898022; e-mail: rgb@iiserpune.ac.in
A) Lan and Shi's Report
O
O
(ArO)3PAuNTf2 (5 mol%)
R
R
Reactive 1,3-dicarbonyl compounds are very useful scaffolds
and they have been utilized for the transition-metal catalyzed
oxidative C-H bond functionalization to access useful
compounds.13 However, these useful protocols need oxidants,
excess substrates and high temperature for the effective
transformation. In the year 2014, Lan and Shi, and co-workers
N2
CO2Me
O
O
CO2Me
+
Ph
DCM, rt
Ph
R
R
(Gold Catalysis)
(up to 90% yield)
(0.2 mmol)
(1 mmol)
B) Bi's Report
O
O
Sc(OTf)3 (30 mol%)
N2
O
O
R
R
DCE, 80 o
C
+
elegantly
presented
the
first
gold-catalyzed
C-H
CO2R
Ar
R
R
CO2Me
Ph
(Scandium Catalysis)
(0.6 mmol)
(0.3 mmol)
functionalization of 1,3-dicarbonyl compounds with α-aryl-α-
diazoacetate (see Fig 1A).14
(up to 90% yield)
R = Me, Bn, iPr, Allyl
O
O
C) This Work
Sc(OTf)3 (5 mol%)
N2
O
O
O
Fig.1 C-H bond functionalization of 1, 3-dicarbonyl compounds with α-
aryl-α-diazoacetates-Influence of ester groups
It was demonstrated that the reaction followed the gold
catalyzed decomposition of α-aryl-α-diazoacetate via the
R
R
O
+
DCE, rt
(Scandium Catalysis)
Ar
R
R
Ar
O
O
(0.5 mmol)
(0.75 mmol)
R = Ar, Me
(up to 97% yield)
Propargyl aryl-diazoacetate-Robust reagent
C-H functionalization at room temperature
Works with deactivated substrates
Less prone for Side reactions
Low Catalyst loading (5 mol%)

2
Tetrahedron Letters
formation of a carbophilic carbocation. However, there is a great challenge to develop novel catalyst and reagent systems
that are easily available and less expensive. A lot more efforts is needed to avoid the use of any expensive catalysts and ligands to
make the protocol simple and practical which work at room temperature under mild conditions. Although, coinage metals and few of
the heavy transitional-metals have been successfully explored for the C-H bond functionalization of α-diazo esters, alternative yet
useful catalyst systems are desirable. Group 3 transition metals, e.g., scandium and lanthanides, have been used as environmentally
friendly Lewis acid catalysts or promoters for a variety of chemical transformations.15
Scandium catalysis has been promising and scandium triflate has been explored for the reactions of diazo compounds to achieve the
successful C-H bond functionalization.16 It would be very interesting to study the efficiency of scandium catalyst on the C-H bond
functionalization of 1,3-dicarbonyl compounds with α-aryl-α-diazo esters. The main challenges of this type of reaction are to avoid the
side reactions such as dimerization of α-diazo esters, formation of α-oxoesters and to minimize the catalytic amount of the metal
catalyst. It would also be a challenging task to have a catalyst control over insertion processes such as C-H insertion over O-H insertion.
While this manuscript was under preparation, Bi and Co-workers disclosed the C-H bond functionalization of 1,3-dicarbonyl
compounds with α-aryl-α-diazoacetates via scandium catalysis using higher catalyst loading and excess of α-aryl-α-diazoacetates at
elevated temperature (see Fig. 1B).10e Our group has been independently pursuing the development of catalyst-reagent system to expand
the scope of C-H bond functionalization of α-diazo esters using early transition elements and lanthanides.17 Despite many advances, still
there are numerous limitations such as high reaction temperature, high substrate-reagent ratio, use of excess catalytic amount and
expensive catalysts etc. Some of these limitations need to be overcome to make the protocols more practical and affordable. Herein, we
report the discovery of propargyl α-aryl-α-diazoacetates as robust and useful new class of reagents for the C-H bond functionalization.
Results and discussion
At the outset, we began our investigation by choosing ethyl α-(4-methoxyphenyl)-α-diazoacetate 1a’ and 1,3-diketone 2a (1,3-
diphenyl-1,3-propanedione) as model substrates. The reaction of ethyl α-(4-methoxyphenyl)-α-diazoacetate 1a’ and 1,3-diketone 2a in
presence of Cu(OTf)2 (5 mol%) in DCE at room temperature afforded the corresponding desired C-H functionalized product 3a’a in
52% yield in 6 h (Entry 1, Table 1). While, the reaction in presence of gold catalyst [(ArO)3PAuNTf2 (5 mol%)] afforded the 3a’a in
moderate yield (36%, Entry 2, Table 1). Interestingly, Sc(OTf)3 (5 mol%) catalyzed the reaction of ethyl α-(4-methoxyphenyl)-α-
diazoacetate 1a’ (0.5 mmol) and 1,3-diketone 2a (0.75 mmol) to afford the desired product 3a’a in 51% yield in 6 h at room
temperature (See Entry 3, Table 1). A slight excess of unreacted 2a was recovered during the purification. It was very encouraging that
desired reaction worked at room temperature under scandium catalysis. Likewise, allyl α-(4-methoxyphenyl)-α-diazoacetate 1a’’ (0.5
mmol) and 1,3-diketone 2a (0.75 mmol) reacted in presence of Sc(OTf)3 (5 mol%) to afford the desired product 3a’’a in 53% yield in 6
h at room temperature (See, Entry 4, Table 1). The reactions in presence of gold catalyst [(ArO)3PAuNTf2 (5 mol%)] afforded the
desired products in modest yields (see Entries, 5, 6 Table 1). It is known in the literature that propargyl moiety is a weakly electron
withdrawing group18 and in this regard we planned to explore the effect of propargyl group in C-H bond functionalization of 1,3-
dicarbonyl compounds. Propargyl α-(4-methoxyphenyl)-α-diazoacetate 1a upon treatment with 2a in presence of Sc(OTf)3 (5 mol%) in
DCE at room temperature afforded the corresponding 3aa in relatively shorter reaction time with an excellent yield (96%, Entry 7,
Table 1). Later, we screened various catalysts to explore the reactivity of propargyl α-(4-methoxyphenyl)-α-diazoacetate 1a (see Entries
8-14). Cu(OTf)2 catalyzed the desired reaction affording 3aa in 71% yield in 6 h, where as other catalysts found to be not useful. In
order to confirm the catalytic efficiency of Sc(OTf)3, and to rule out the possibility of the formation of trace amount of triflic acid in situ
by the hydrolysis of Sc(OTf)3 if any due to the moisture and its subsequent catalysis, we carried out the reaction of 1a and 2a in
presence of catalytic amount triflic acid (Entry 15, Table 1).
Table 1 Optimization of the reaction conditions for C-H functionalizationa-d
O
O
O
N2
O
O
Ph
Ph
OR
Catalyst (5 mol%)
DCE, rt, 4-6 h
OR
Ph
Ph
O
MeO
H
MeO
3aa
3a'a
3a''a
1
2a
3
(0.5 mmol)
(0.75 mmol)
1a
1a'
= R = Propargyl
= R = Ethyl
= R = Propargyl
= R = Ethyl
= R = Allyl
1a''
= R = Allyl
1a'''
= R = Homopropargyl
3a'''a
= R = Homopropargyl

3
Substrate (1) Time Yieldb
Entry Catalyst
aReaction conditions: α-Aryl-α-diazoacetate 1 (1 equiv., 0.5 mmol), 1,3-
diketone 2a (1.5 equiv., 0.75 mmol), DCE (3 mL) at room temperature,
bIsolated yield after purification by column chromatography. cDC-Decomposed,
dNR-no reaction.
R
(h)
(%)
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Ethyl
6
52
(ArO)3PAuNTf2
Sc(OTf)3
Ethyl
Ethyl
4
6
6
6
4
4
6
6
36
51
Interestingly, the reaction led to the decomposition of propargyl α-
(4-methoxyphenyl)-α-diazoacetate 1a in presence of triflic acid.
The reaction of homopropargyl α-(4-methoxyphenyl)-α-
diazoacetate 1a’’’ (0.5 mmol) and 1,3-diketone 2a (0.75 mmol) in
presence of Sc(OTf)3 (5 mol%) afforded the corresponding product
3a’’’a in 73% yield in 6 h at room temperature (See, Entry 16,
Table 1). The reaction did not work in absence of any catalyst
(Entry 17, Table 1).
Sc(OTf)3
Allyl
53
(ArO)3PAuNTf2
(ArO)3PAuNTf2
Sc(OTf)3
Allyl
39
Propargyl
Propargyl
Propargyl
Propargyl
37
96
Table 2. Scope of propargyl α-aryl-α-diazoacetates for the effective C-
Bi(OTf)3
trace
71
H bond functionalization of 1,3-diketonesa-d
Cu(OTf)2
O
O
O
N2
O
O
R
R
O
Dichloro(p-
cymene)ruthenium(II)
dimer
O
Sc(OTf)3 (5 mol %)
DCE, rt, 4-24 h
10
Propargyl
6
DCc
Ar
R
R
O
Ar
H
2
1
3
(0.5 mmol)
(0.75 mmol)
R = Ar, Alkyl
11
12
Y(OTf)3
Propargyl
Propargyl
6
6
18
68
OMe OMe
In(OTf)3
Ph Ph
Ph Ph
13
14
15
16
Rh2(OAc)4
Yb(OTf)3
Triflic acid
Sc(OTf)3
Propargyl
Propargyl
4
6
6
6
DC c
Trace
DCc
73
O
O
O
O
O
O
O
O
O
O
MeO
MeO
O
O
O
O
O
O
MeO
MeO
MeO
Propargyl
3ab
(4 h, 97%)
3ac
3ba
(4 h, 85%)
3aa
(4 h, 97%)
(4 h, 96%)
OMe OMe
Homopropargyl
17
No Catalyst
Propargyl
6
NRd
Ph Ph
O
O
O
O
O
O
O
O
O
O
O
MeO
MeO
MeO
O
O
O
O
O
MeO
3bc
3bb
(4 h, 97%)
3cb
(6 h, 80%)
(4 h, 96%)
3ca
(6h, 91%)
OMe OMe
OMe OMe
Ph Ph
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
3dc
(6 h, 81%)
3db
3da
(6 h, 78%)
3cc
(6 h, 78%)
(6 h, 70%)
OMe OMe
Ph Ph
Ph
O
Ph
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Cl
Br
Br
Br
3eb
3fa
3ea
(24 h, 62%)
OMe OMe
(24 h, 60%)
(24 h, 79%)
3ec
(24 h, 62%)
Ph Ph
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
F
F
Cl
Cl
3fc
3ga
(24 h, 63%)
(24 h, 39%)
3fb
3gb
(24 h, 40%)
(24 h, 45%)
OMe OMe
O
O
O
O
O
O
O
O
Ph
Ph
O
O
O
O
O
O
O
MeO
MeO
O
F3C
F
c
c
d
3ae
(1.5 h, 55%)
3ad
3ha
(10 h, 51%)
(1.5 h, 57%)
3gc
(24 h, 56%)
OMe OMe
O
O
O
O
O
O
O
O
O
O
O
(10 h, 53%)
O
3aa
F3C
F3C
O
d
d
d
3ia
(10 h, 51%)
3hc
(10 h, 52%)
3hb

4
Tetrahedron Letters
aReaction conditions: α-aryl-α-diazoacetate 1 (1 equiv., 0.5 mmol), 1,3-diketone 2 (1.5 equiv., 0.75 mmol), Sc(OTf)3 (5 mol%) in DCE (3 mL) at room
temperature under inert atmosphere, bIsolated yield after purification by column chromatography (Time and Yield are given in parenthesis), creaction was carried
out at 50 oC, dSc(OTf)3 (10 mol%) in DCE at 70 oC under inert atmosphere
Later, in order to optimize the reaction condition further, we carried out the reaction of 1a and 2a in presence of Sc(OTf)3 in different solvents
and among all the solvents, DCE proved to be the optimal solvent (See Appendix 1, ESI). The combination of propargyl α-aryl-α-diazoacetate
1 and scandium triflate as reagent-catalyst system proved to be efficient for the effective C-H bond functionalization of 1,3-diketones.
We observed that propargyl α-aryl-α-diazoesters and scandium catalyst worked synergistically to bring about desired C-H bond
functionalization very efficiently at room temperature. Based on the exhaustive screening, propargyl α-aryl-α-diazoacetate 1 (0.5
mmol), 1,3-diketone 2 (0.75 mmol), Sc(OTf)3 (5 mol%) in DCE at room temperature proved to be the optimum reaction condition.
Encouraged by the initial success, we planned to explore the reactivity and scope of different propargyl α-aryl-α-diazoacetates for the
effective C-H bond functionalization of 1,3-diketones. In order to study the protocol in more detail we synthesized various propargyl α-
aryl-α-diazoacetates (1a-1g). Relatively, electron rich propargyl α-aryl-α-diazoacetates (1a-1d) reacted smoothly with different 1,3-
diketones under the optimum reaction conditions to afford the corresponding desired products (3aa-3dc) in good to excellent yields
(Table 2). Mildly electron deactivated substrates such as bromo-, chloro-, fluoro-propargyl α-aryl-α-diazoacetates (1e-1g) reacted
smoothly with nucleophilic acyclic 1,3-diketones (2a-2c) successfully to afford the corresponding tricarbonyl compounds (3ea-3ec, 3fa-
3fc, 3ga-3gc) in moderate to good yields (Table 2). It is very important to note that mildly electron deactivated substrates such as
chloro-, fluoro-propargyl α-aryl-α-diazoacetates reacted under the reaction conditions at room temperature. Further, the treatment of
propargyl α-(4-methoxyphenyl)-α-diazoacetate 1a with aliphatic 1,3-diketones (2d, 2e) afforded the corresponding desired products
(3ad, 3ae) at slightly elevated temperature in moderate yields (Table 2). While, the reactions of few propargyl α-aryl α-diazoacetates
(1h, 1i) containing electron withdrawing groups (CF3, Ac) with different 1,3-diketones in presence of Sc(OTf)3 (10 mol %) afforded the
o
corresponding desired products (3ha-3hc, 3ia) in moderate yields at elevated temperature (70 C). Surprisingly, the reactions of
propargyl α-(4-methoxyphenyl)-α-diazoacetate 1a with cyclic 1,3-diketones (1,3-cyclohexanedione and 1,3-cyclopentanedione) under
the optimum reaction conditions exclusively furnished the corresponding O-H insertion products. Based on the earlier findings,10e it is
believed that the formation of cis enol is crucial for the formation of bidentate complex with the metal for facilitating the C-H insertion
reaction of acyclic 1,3-diketones. While the cyclic ketone such as 1,3-cyclohexanedione may not be able to form effective bidentate
complex as it is known to form trans enol19 thus leading to O-H insertion product.
We observed that relatively electron rich propargyl α-aryl-α-diazoacetates (1a-1d) showed better reactivity in terms of yields under
standard conditions. Both electron-rich and electron -deactivated/withdrawing propargyl α-aryl-α-diazoacetates tolerated the reaction
conditions. We did not observe any side products such as carbene dimerization, α-oxoesters and azines during the C-H bond
functionalization of 1,3-diketones under the optimal reaction conditions.
In order to extend the scope the methodology we carried out the reaction of propargyl α-(4-methoxyphenyl)-α-diazoacetate 1a and 1,3-
diketone 2a on a gram scale under optimum reaction conditions.The protocol proved to be scalable and worked smoothly to afford the
corresponding desired product 3aa in 87% yield (Scheme 1).
Scheme 1. Gram scale synthesis
Further, the structure of the compound 3aa was unambiguously confirmed by single crystal X-ray analysis.20 Based on the earlier
literature report,10e we proposed the plausible reaction pathway.21 The 1,3-diketone 2 interacts with the Sc(OTf)3 to form the scandium
enolate I and triflic acid as by-product. This eventually acts as a proton source to protonate the propargyl α-aryl-α-diazoacetate 1 to
generate the intermediate diazonium ion II, which undergoes a facile nucleophilic attack by the scandium enolate I to afford the
complex III (Scheme 2).
Scheme 2. Plausible reaction pathway for the scandium catalyzed C-H insertion
Eventually the reaction of triflate anion with complex III furnishes the desired product 3 by regenerating the catalyst (Scheme 2). We
presume that unlike electron donating power of ethyl/methyl group in ester, relatively weak electron deactivating propargyl moiety
played a significant role in enhancing the electrophilicity of the diazonium ion which eventually leads to the reactive carbocation
towards the facile C-H insertion at room temperature.
Conclusions
In conclusion, we have developed the new reagent-catalyst controlled effective C-H bond functionalization to afford 1,3-dicarbonyl
alkylation via scandium catalysis. We have developed a new series of α-aryl-α-diazoacetates with propargyl ester as the robust acceptor
group and employed them as reagents for the effective C-H functionalization at room temperature. The protocol avoids the use of
excess, expensive catalysts and ligands under practical conditions at room temperature. Practicality of the protocol has been
demonstrated by the gram scale synthesis.
Acknowledgements

O
O
O
Ph
Ph
O
O
O
N2
Sc(OTf)3 (5 mol%)
DCE, rt, 6 h
O
Ph
Ph
+
H
O
MeO
MeO
5
3aa
(87%)
1a
2a
R. G. B. thanks DST-SERB (EMR/2015/000909), Govt. of
India for the generous research grant. Authors also thank Indian Institute of Science Education and Research (IISER), Pune
for the financial support. B. S. N. thanks CSIR, New Delhi, India and D. L. thanks UGC, New Delhi, India for the fellowship.
Authors also thank Mr. Sandeep Kanade for optimizing the protocol for recording mass spectra of diazoesters.
References and notes
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M.R. Fructos, T.R. Belderrain, P. de Frémont, N.M. Scott, S.P. Nolan, M.M. Díaz-Requejo,
OTf
O
TfO
OTf
O
TfO
Sc
Sc
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Tetrahedron 61 (2005) 5585.
O
O
O
O
OTf
3
Ar
Ar
Ar
Ar
Ar
Ar
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4151.
H
O
I
H
H
O
2
Ar
Sc(OTf)3
N2
N2
Ar
III
H
Sc(OTf)3
HOTf
O
II
O
1
OTf
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functionalization by early transition metal-carbenoid insertion and its applications-EMR/2015/000909, SERB-DST Govt. of India.
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[20] CCDC number of 3aa is 1848209 The number contains all crystallographic details of this publication and is available free of charge at
http://www.ccdc.cam.ac.uk/conts/retrieving.html.
[21] It is believed that the formation of cis enol is crucial for the formation of bidentate complex with the metal for facilitating the C-H
insertion reaction of acyclic 1,3-diketones (See ref 10e).
Supplementary Material
Electronic Supplementary Information (ESI) available: [Experimental details, copies of 1H and 13C NMR spectrum of products]. See DOI:

6
Tetrahedron Letters
Graphical Abstract
Highlights
 Efficient C-H bond functionalization of 1,3-diketones
Leave this area blank for abstract info.
Propargyl α-aryl-α-diazoacetates as robust reagents
for the effective C-H bond functionalization of
1,3-diketones via scandium catalysis
Balu S. Navale, Debasish Laha and Ramakrishna G. Bhat*
O
O
O
R
R
O
N2
O
O
Sc(OTf)3 (5 mol %)
DCE, rt, 4 - 24 h
O
R
R
Ar
Ar
O
H
R = Ar, Me, Et
(up to 97% yield)
Propargyl -aryl--diazoacetates-Robust reagents
Works with deactivated substrates
Less prone for side reactions
Low Catalyst loading (5 mol %)
Total of 27 examples and gram scale synthesis
 Propargyl α-aryl-α-diazoacetate as a robust and novel reagent
 Catalytic amount (5 mol%) of Sc(OTf)3 for the effective transformation
 Practical and scalable on gram scale
 Total of 27 examples with very good yields (up to 97%).