Preparation of γ,δ-unsaturated-β-ketoesters: Lewis acid-catalysed C[sbnd]H insertion of ethyl diazoacetate into α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tetlet.2017.07.095

The synthesis of γ,δ-unsaturated-β-keto esters was achieved by the Lewis acid-catalysed direct C[sbnd]H insertion of an α-diazoester into various α,β-substituted-unsaturated aldehydes. C[sbnd]H insertion of ethyl diazoacetate into alkyl- and aryl-substituted α,β-unsaturated aldehydes was performed under mild conditions to afford the corresponding γ,δ-unsaturated-β-keto esters in moderate to high yields as a mixture of keto/enol tautomers.

Full text of DOI:10.1016/j.tetlet.2017.07.095

Accepted Manuscript
Pr eparation of γ,δ-unsaturated-β-ketoesters: Lewis acid-catalysed C-H inser-
tion of ethyl diazoacetate into α,β-unsaturated aldehydes
Hirenkumar Gandhi, Timothy P. O'Sullivan
PII:
S0040-4039(17)30964-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.095
TETL 49177
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 June 2017
25 July 2017
28 July 2017
Please cite this article as: Gandhi, H., O'Sullivan, T.P., Pr eparation of γ,δ-unsaturated-β-ketoesters: Lewis acid-
catalysed C-H insertion of ethyl diazoacetate into α,β-unsaturated aldehydes, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.07.095
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Preparation of γ,δ-unsaturated-β-ketoesters: Lewis acid-catalysed C-
H insertion of ethyl diazoacetate into α,β-unsaturated aldehydes
Hirenkumar Gandhi1,2, Timothy P. O’Sullivan1,2,3*
1School of Chemistry, University College Cork, Cork, Ireland
2Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
3School of Pharmacy, University College Cork, Cork, Ireland
Abstract: The synthesis of γ,δ-unsaturated-β-keto esters was achieved by the Lewis acid-catalysed
direct C-H insertion of an α-diazoester into various α,β-substituted-unsaturated aldehydes. C-H
insertion of ethyl diazoacetate into alkyl- and aryl-substituted α,β-unsaturated aldehydes was
performed under mild conditions to afford the corresponding γ,δ-unsaturated-β-keto esters in
moderate to high yields as a mixture of keto/enol tautomers.
Keywords: γ,δ-Unsaturated-β-ketoesters, C-H insertion, ethyl diazoacetate
1Other methods include the Lewis acid-
1.
Introduction
catalysed C-H insertion of α-diazoesters into
aldehydes under mild conditions.11a-d In
contrast, the synthesis of γ,δ-unsaturated-β-
keto esters has traditionally been achieved
using Wittig12 and Horner-Wadsworth-
Emmons (HWE) chemistry.13a-b Herein, we
report a general process for the Lewis acid-
catalysed C-H insertion of α-diazoesters into
α,β-unsaturated aldehydes for the preparation
of γ,δ-unsaturated-β-keto esters in moderate to
high yields.
β-Keto esters are important building blocks in
organic synthesis and are used for the
construction of a variety of biologically
relevant molecules.1a,
1b
They are excellent
substrates for the synthesis of heterocyclic
compounds including dihydroxypyridines,
pyrroles, dihydropyrimidines, indoles, and
quinolines.2,3 As a subfamily of β-keto esters,
γ,δ-unsaturated-β-keto esters are important
intermediates
in
the
pure
preparation
of
enantiomerically
γ,δ-unsaturated-β-
hydroxy esters that act as chiral building blocks
for the synthesis of many biologically active
compounds and pharmaceutical products such
2.
Results and discussion
Several Lewis acids, such as BF3·OEt2,
MoOCl4, SnCl2, TiCl4, NbCl5, and ZrCl, have
been successfully utilised in the C-H insertion
of α-diazoesters into aldehydes.14a-f However,
only one, low yielding example involving an
α,β-unsaturated aldehyde has previously been
reported.15 Accordingly, we conducted an
4
as (-)-CP2-disorazole C1 , turnagainolides A
and B5, epothilones6 and seimatopolide A.7
Many methods have been developed for the
synthesis of β-keto esters using strong bases
or alkali metals, e.g. Claisen condensation,8a-b
Blaise reaction,9a-b Dieckmann condensation.10
1* Corresponding author: Tel.: 353 21 4901655; fax: 353 21
4901656; e-mail: tim.osullivan@ucc.ie

initial screen to identify a suitable catalyst for
this transformation. Using trans-2-pentenal
(1a) as our test substrate, a number of Lewis
acids were examined for their ability to
catalyse the C-H insertion of ethyl
diazoacetate (EDA, Table 1). As the reaction
of EDA with the Lewis acids was found to be
exothermic, EDA was added at 0-5 °C before
subsequent stirring at room temperature to
avoid reagent degradation. CuI (Entries 1, 2),
Ti(O-iPr)4 (Entries 3, 4), and Ce(SO4)2
(Entries 5, 6) were each found to be
ineffective catalysts. The addition of BF3·OEt2
(Entry 7) was accompanied by a vigorous
reaction with the liberation of nitrogen gas,
however, no product formation was observed.
In contrast, CuBr2 (Entry 8), TiCl4 (Entry 9),
PdCl2 (Entry 10), and FeCl3 (Entry 11) did
effect the C-H insertion of EDA into trans-2-
pentenal, but the conversions and yields were
low even after prolonged reaction times. Both
AlCl3 (Entry 12) and NbCl5 (Entry 13)
resulted in complete conversion of the starting
aldehyde. However, use of AlCl3 afforded the
target γ,δ-unsaturated-β-ketoester with a lower
52% yield in comparison to a 63% yield with
NbCl5. The reaction was further optimised by
increasing the equivalents of EDA from 1.1 to
1.2 and the catalyst loading to 7 mol%,
leading to an improved yield of 68% and a
reduction in reaction time from 10 h to 8 h
(Entry 8), or increasing the temperature to 40
°C (Entry 9) resulted in lower yields.
Table 1. Screening of suitable Lewis acids
Lewis
acid
Loading
(mol%)
EDA Time Yield
Entry
1
(eq.)
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.2
1.2
(h)
32
42
28
44
32
44
24
28
24
24
24
24
10
8
(%)
--
CuI
CuI
5
10
5
2
--
3
Ti(O-iPr)4
Ti(O-iPr)4
Ce(SO4)2
Ce(SO4)2
BF3·OEt2
CuBr2
TiCl4
--
4
10
5
--
5
--
6
10
5
--
7
--
8
5
33
44
31
27
52
63
68
59
9
5
10
11
12
13
14
15
PdCl2
FeCl3
AlCl3
5
5
5
NbCl5
NbCl5
NbCl5
5
7
10
8
Reagents and conditions: trans-2-pentenal (0.9 mmol),
CH2Cl2 (5 mL), r.t.
Table 2. Solvent and temperature study
Entry
Solvent
Temp Time Yield
(°C)
r.t.
r.t.
50
(h)
16
18
14
42
28
8
(%)
54
59
43
--
1
2
3
4
5
6
7
8
9
THF
Toluene
Toluene
CHCl3
(Entry
14).
Higher
loadings
were
r.t.
r.t.
r.t.
-10
0
accompanied by a decreased yield (Entry 15).
A subsequent solvent and temperature screen
identified dichloromethane as the optimal
reaction medium (Table 2, Entry 6). No
reaction occurred in chloroform (Entry 4)
while lower yields were observed in
tetrahydrofuran (Entry 1), toluene (Entries 2,
3), and acetonitrile (Entry 4). For the reactions
conducted in dichloromethane, lowering the
temperature to either 0 °C (Entry 7) or -10 °C
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
36
68
30
38
48
36
24
6
40
Reagents and conditions: trans-2-pentenal (0.9 mmol),
EDA (1.08 mmol), NbCl5 (7 mol%), solvent (5 mL).
A series of aliphatic and aromatic α,β-
unsaturated aldehydes was next subjected to
the C-H insertion reaction under the optimised

conditions (Table 3). In general, it was found
that longer reaction times were required for
the complete conversion of α,β-unsaturated
aldehydes compared to their saturated
equivalents.14e Yields of the target γ,δ-
unsaturated-β-keto esters were comparable
regardless of the aldehyde chain length
(Entries 1-12). The C-H insertion with
aromatic aldehydes also afforded similar
yields, albeit at the cost of longer reaction
times (Entries 15-19). Noticeably higher
yields were observed with electron-poor
aromatic substrates (Entries 17-19) in contrast
to aldehydes containing electron-rich rings
(Entry 16). The presence of a methyl group at
the γ- or δ-positions resulted in lower yields
(Entries 10-12) most likely as a result of
increased steric hindrance. β-Keto esters with
more highly unsaturated side-chains were also
tolerated under these conditions (Entry 12).
initial attack of the carbene species, generated
from ethyl diazoacetate, on the aldehyde is
followed
by a 1,2-hydride shift and
concomitant loss of nitrogen.14e
In conclusion, reaction conditions for the
NbCl5-catalysed C-H insertion of ethyl
diazoacetate into α,β-unsaturated aldehydes
were successfully optimised to produce γ,δ-
unsaturated-β-keto esters in moderate to high
yields. The outlined methodology tolerates
both aliphatic, aromatic and unsaturated
substrates equally well.
Acknowledgments
HG is grateful for funding by way of a
Government of Ireland Postgraduate Research
Scholarship (GOIPG/2013/113) provided by the
Irish Research Council.
The mechanism is likely similar to that
proposed by Yadav and co-workers whereby
Table 3. Synthesis of γ,δ-unsaturated-β-ketoesters under optimised conditionsa
Time
(h)
Yield
(%)
Entry Aldehyde
R1
R2
R3
Product
Keto:enolb
1
2
3
4
5
CH3CH2
CH3
H
H
H
H
H
H
H
H
H
H
8
8
68
56c
71
72
65
60:40
68:32
49:51
59:41
71:29
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
CH3(CH2)2
CH3(CH2)3
CH3(CH2)4
8
8
7.5

6
CH3(CH2)5
CH3(CH2)6
H
H
H
H
8
9.5
10
10
6.5
8
63
66
60
67
59
54
54
67
73
69
43
69
73
76
50:50
55:45
49:51
39:61
85:15
n.d.c
1f
1g
1h
1i
2f
2g
2h
2i
7
8
CH3(CH2)7
H
H
9
CH3(CH2)8
H
H
10
11
12
13
14
15
16
17
18
19
CH3CH2
H
CH3
H
1j
2j
(CH3)2CH(CH2)2
Farnesal
CH3
1k
1l
2k
2l
8
n.d.c
(CH3)2CH(CH2)2CH(CH3)
C6H5(CH2)2
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6
45:55
58:42
49:51
55:45
9:91
1m
1n
1o
1p
1q
1r
1s
2m
2n
2o
2p
2q
2r
2s
16
5.5
18
16
14
15
4-MeO-C6H4
2-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
26:74
0:100
aReagents and conditions: α,β-unsaturated aldehyde (0.9 mmol), EDA (1.08 mmol), NbCl5 (7 mol %), CH2Cl2 (5 mL), r.t.
See Ref 16 and ESI for full experimental procedure and characterisation data.
bKeto:enol ratio determined by 1H-NMR. cn.d.: not determined due to the presence of (E)- and (Z)-isomers in the starting
material.
References and notes
1. (a) Benetti, S.; Romagnoli, R.; De Risi, C.; Spalluto, G.; Zanirato, V. Chem. Rev. 1995, 95,
1065-1114. (b) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 24,
4957-4980.
2. (a) Ducatti, D. R. B.; Massi, A.; Noseda, M. D.; Duarte, M. E. R.; Dondoni, A. Org. Biomol.
Chem. 2009, 7, 1980-1986. (b) Debache, A.; Boulcina, R.; Belfaitah, A.; Rhouati, S.;
Carboni, B. Synlett. 2008, 4, 509-512. (c) Chitra, S.; Pandiarajan, K. Tetrahedron Lett. 2009,
50, 2222-2224. (d) Singh, O. M.; Devi, N. S. J. Org. Chem. 2009, 74, 3141-3144. (e)
Velezheva, V. S.; Sokolov, A. I.; Kornienko, A. G.; Lyssenko, K. A.; Nelyubina, Y. V.;
Godovikov, I. A.; Peregudov, A. S.; Mironov, A. F. Tetrahedron Lett. 2008, 49, 7106-7109.
(f) Wang, H.-M.; Hou, R.-S.; Cheng, H.-T.; Chen, L.-C. Heterocycles 2009, 78, 487-493. (g)
Thomae, D.; Perspicace, E.; Hesse, S.; Kirsch, G.; Seck, P. Tetrahedron 2008, 64, 9309-
9314.
3. Sridharan, V.; Menéndez, J. C. Org. Lett. 2008, 10, 4303-4306.

4. Hopkins, C. D.; Schmitz, J. C.; Chu, E.; Wipf, P. Org. Lett. 2011, 13, 4088-4091.
5. D. Li, G. Carr, Y. Zhang, D. E. Williams, A. Amlani, H. Bottriell, A. L. F. Mui, R. J.
Andersen, J. Nat. Prod. 2011, 74, 1093-1099.
6. Reiff, E. A.; Nair, S. K.; Narayan Reddy, B. S.; Inagaki, J.; Henri, J. T.; Greiner, J. F.;
Georg, G. I. Tetrahedron Lett. 2004, 45, 5845-5847.
7. Schmidt, J. B.; Kunz, O; Petersen, M. H. J. Org. Chem. 2012, 77, 10897-10906.
8. (a) Claparede, C. L.; A. Ber. Dtsch. Chem. Ges. 1881, 14, 2460-2468. (b) Claisen, L. Ber.
Dtsch. Chem. Ges. 1887, 20, 655-657.
9. (a) Rao, H. S. P.; Rafi, S.; Padmavathy, K. Tetrahedron 2008, 64, 8037-8043. (b) Wang, F-
D.; Yue, J-M. Synlett. 2005, 13, 2077-2079.
10. Schaefer, J. P.; Bloomfield, J. J. Org. React. 1967, 15, 1-203.
11. (a) Yamamoto, H. Lewis Acids in Organic Synthesis, Wiley-VCH: Weinheim, 2000. (b)
Anastas, P.T.; Kirchhoff, M. M. Acc. Chem. Res. 2002, 35, 686-694. (c) Martin, R. Org.
Prep. Proced. Int. 1992, 24, 369-435. (d) Ford, A.; Miel, H.; Ring, A.; Slattery, C. N.;
Maguire, A. R.; McKervey, M. A. Chem. Rev. 2015, 115, 9981-10080.
12. Hoffmann, R. W. Angew. Chem., Int. Ed. 2001, 40, 1411-1416.
13. (a) Wadsworth, W. Org. React. 1977, 25, 73-253. (b) Wadsworth, W. S., Jr.; Emmons, W.
D. J. Am. Chem. Soc. 1961, 83, 1733-1738.
14. (a) Hirooka, Y.; Ikeuchi, K.; Kawamoto, Y.; Akao, Y. Furuka, T.; Asakawa, T.; Inai, M.;
Wakimoto, T.; Fukuyama, T.; Kan, T. Org. Lett. 2014, 16, 1646-1649. (b) Jeyakumar, K.;
Chand, D. K. Synthesis, 2008, 11, 1685-1687. (c) Albert, P.; Dean, D. C.; Fairfax, D. J.; Xu,
S. L.; J. Org. Chem. 1993, 58, 4646-4655. (d) Clarke, P. A.; Matthew, G.; Ebden, M.;
Wilson, C. Chem. Commun. 2003, 13, 1560-1561. (e) Yadav, J. S.; Subba Reddy, B. V.;
Eeshwaraiah, B.; Reddy, P. N. Tetrahedron, 2005, 61, 875-878. (f) Nomura, K.; Lida, T.;
Hori, K.; Yoshii, E.; J. Org. Chem. 1994, 59, 488-490.
15. Kanemasa, S.; Kanai, T.; Araki, T.; Wada, E. Tetrahedron Lett. 1999, 40, 5055-5058.
16. NbCl5 (0.063 mmol, 7 mol%) was added to a solution of the α,β-unsaturated aldehyde (0.9
mmol, 1.0 equiv) in anhydrous dichloromethane (5.0 mL) at 0 °C under an inert atmosphere.
EDA (1.08 mmol, 1.2 equiv) was added over period of 10 minutes via syringe at 0 °C before
stirring at room temperature until complete consumption of the aldehyde was evident by
TLC. The solvent was removed in vacuo and the remaining residue was subjected to dry
flash chromatography using a mixture of hexane and diethyl ether to afford the target γ,δ-
unsaturated keto ester in moderate to high yields. Ethyl (E)-3-oxohept-4-enoate (2a): The
title compound was isolated as a yellow oil in 68% yield as a mixture of keto-enol
1
tautomers. H-NMR (400MHz, CDCl3) (mixture of keto-enol tautomers): δ 1.08 (m, 6H,
CH3), 1.24-1.33 (m, 6H, CH3, ester), 2.20-2.30 (m, 4H, CH2), 3.58 (s, 2H, α-CH2, keto),
4.20 (m, CH2, ester), 4.98 (s, 1H, α-CH enol), 5.79 (d, 1H, J = 15.6 Hz, CH), 6.16 (d, 1H, J
= 15.6 Hz), 6.70 (m, 1H, CH), 6.94 (m, 1H, CH), 11.90 (d, J = 1.28 Hz, OH); C-NMR
13
(100MHz, CDCl3) : δ 192.26, 173.03, 169.68, 167.47, 151.24, 142.39, 128.72, 123.43,
89.95, 61.31, 60.01, 46.93, 25.63, 22.63, 14.26, 14.07, 12.64, 12.05; vmaz /(NaCl) cm-1: 734,
802, 861, 979, 1031, 1097, 1159, 1203, 1376, 1670, 1737, 2884, 2943, 2983, 3446; HRMS
(ESI+): Exact mass calc for C9H15O3 (M+H+) 171.1016 Found 171.1024.

-We have developed a mild method for the synthesis of γ,δ-unsaturated-β-keto esters
-Niobium chloride was found to be an ideal catalyst for C-H insertions
-Aliphatic and aromatic α,β-unsaturated aldehydes are transformed in good yields

Graphical Abstract
Preparation of γ,δ-unsaturated-β-ketoesters: Lewis acid-catalysed C-H insertion of ethyl
diazoacetate into α,β-unsaturated aldehydes
Hirenkumar Gandhi1,2, Timothy P. O’Sullivan1,2,3*