Catalytic Reaction of Ethyl 2-Diazo-3-oxobutanoate with Alcohols

Article abstract of DOI:10.1134/S1070428018030016

The effect of the structure of alcohols on their reaction with ethyl 2-diazo-3-oxobutanoate catalyzed by copper(II) trifluoromethanesulfonate has been studied. The corresponding ethyl 2-alkoxy-3-oxobutanoates were obtained in quantitative yield from primary alcohols. Introduction of a 1,3-dioxolane or 1,3-dioxane fragment into the alcohol molecule changes the reaction direction toward the formation of polyoxa macrocycles that are products of formal insertion of the diazo ester into the carbon–oxygen bond.

Full text of DOI:10.1134/S1070428018030016

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 3, pp. 373–376. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © G.N. Sakhabutdinova, I.P. Baikova, G.Z. Raskil’dina, S.S. Zlotskii, R.M. Sultanova, 2018, published in Zhurnal Organicheskoi
Khimii, 2018, Vol. 54, No. 3, pp. 369–372.
Dedicated to Full Member of the Russian Academy of Sciences
I.P. Beletskaya on her jubilee
Catalytic Reaction of Ethyl 2-Diazo-3-oxobutanoate
with Alcohols
G. N. Sakhabutdinovaa, I. P. Baikovab, G. Z. Raskil’dinaa,*
S. S. Zlotskiia, and R. M. Sultanovaa, b
a Ufa State Petroleum Technological University, ul. Kosmonavtov 1, Ufa, 450062 Bashkortostan, Russia
*e-mail: graskildina444@mail.ru
b Ufa Institute of Chemistry, Russian Academy of Sciences, pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
Received January 25, 2018
Abstract—The effect of the structure of alcohols on their reaction with ethyl 2-diazo-3-oxobutanoate catalyzed
by copper(II) trifluoromethanesulfonate has been studied. The corresponding ethyl 2-alkoxy-3-oxobutanoates
were obtained in quantitative yield from primary alcohols. Introduction of a 1,3-dioxolane or 1,3-dioxane
fragment into the alcohol molecule changes the reaction direction toward the formation of polyoxa macrocycles
that are products of formal insertion of the diazo ester into the carbon–oxygen bond.
DOI: 10.1134/S1070428018030016
Transition metal-catalyzed insertion of α-diazo-
carbonyl compounds into the O–H bond of alcohols,
phenols, and carboxylic acids underlies selective and
convenient methods of synthesis of the corresponding
α-alkoxy, α-aryloxy, and α-acyloxycarbonyl com-
pounds [1–5]. In particular, primary alcohols readily
react with α-aryl-α-diazo esters in the presence of
copper/bisazaferrocene catalyst [6] to give α-alkoxy
derivatives. Rhodium-containing catalysts proved to be
quite efficient in the reaction of diazoacetone with
substituted phenols [7]; rhodium(II)-catalyzed three-
component reaction of aryldiazoacetates with alcohols
and aldehydes (imines) afforded α,β-dihydroxy car-
boxylic acids and α-hydroxy-β-amino acids [8] which
are important as building blocks in the synthesis of
biologically active compounds [9–16].
We previously revealed general and specific
features of catalytic reactions of diazocarbonyl com-
pounds with cyclic acetals in the presence of copper
and rhodium catalysts [17–21]. These reactions can be
utilized in the synthesis of functionally substituted
1,4-diheterocycloalkanes and macroheterocycles.
Scheme 1.
O
O
2a–2e
Me
OEt
OR
O
O
Cu(OTf)2 (1 mol %)
PhH, 80°C, 6 h
3a, 3b, 3e
+
OEt
ROH
Me
Me
O
O
N2
O
O
1
2a–2f
O
HO
OEt
O
+
O
2f
O
O
Me
3f
OEt
Me
Me
Me
Me
4f
R = Bu (a), i-Bu (b), s-Bu (c), t-Bu (d), PhCH2 (e), 2,2-dimethyl-1,3-dioxolan-4-yl (f).
373

SAKHABUTDINOVA et al.
374
4
Me
Table 1. Catalytic reaction of alcohols 2a–2f with ethyl
2-diazo-3-oxobutanoate (1) in the presence of Cu(OTf)2
O
Me
O
O
3
2
(S)
(R)
5"
O
O
4"
2'
Run no.
Initial alcohol
Product
Yield, %
O
1"O
O
1
O3"
OEt
O
OEt
2"
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
3a
3b
85
83
–
Me
Me
Me
Me
S-3f
R-3f
–
These data are very consistent with published data
[22] suggesting stepwise mechanism of the reaction of
diazocarbonyl compounds with alcohols, according to
which oxonium ylide (A or B) generated by attack of
carbenoid species on alcohol is stabilized by trans-
formation to α-alkoxy derivative C, and the presence
of prochiral centers in the molecule leads to the forma-
tion of two diastereoisomers (Scheme 2).
–
–
3e
96
59
3f + 4f
The goal of the present work was to study how the
structure of alcohols affects their reaction with ethyl
2-diazo-3-oxobutanoate (1) catalyzed by copper(II)
trifluoromethanesulfonate Cu(OTf)2. As substrates we
selected primary (2a, 2b, 2e–2g), secondary (2c), and
tertiary alcohols (2d) (Scheme 1). In fact, the result of
the reaction clearly depended on the substrate struc-
ture. Diazo ester 1 readily reacted with primary ali-
phatic alcohols 2a, 2b, 2e, and 2f in benzene at 80°C
in the presence of 1.0 mol % of Cu(OTf)2 to give the
corresponding ethyl 2-alkoxy-3-oxobutanoates 3a, 3b,
3e, and 3f in 50–96% yield (Table 1). Secondary and
tertiary alcohols, namely butan-2-ol (2c) and 2-methyl-
propan-2-ol (2d) failed to react with ester 1 under the
given conditions (Table 1; run nos. 3, 4), presumably
due to steric and electronic factors [5].
Alcohol 2g containing a 1,3-dioxane fragment
(5-ethyl-1,3-dioxan-5-ylmethanol) reacted with diazo
ester 1 under analogous conditions in a more com-
1
plicated manner. H NMR analysis of the reaction
mixture revealed formation of a number of products,
the major ones being two carbenoid insertion products
into the C–O bond of the 1,3-dioxane fragment.
According to the 1H NMR data, the overall yield of 4g
and 5g was 40% (Scheme 3).
Thus, the direction of the Cu(OTf)2-catalyzed reac-
tion of ethyl 2-diazo-3-oxobutanoate (1) with primary
alcohols, including those containing a 1,3-dihetero-
cyclic fragment, is determined by the substrate nature.
This reaction makes it possible to obtain the corre-
sponding ethyl 2-alkoxy-3-oxobutanoates in good
yield. The reaction of 5-ethyl-1,3-dioxan-5-ylmethanol
with diazo ester 1 involves the endocyclic C–O bond.
The moderate yield of 3f (50%) is determined in
part by concurrent insertion of intermediate alkoxy-
carbonylcarbene into the C–O bond with formation of
trioxacyclooctene 4f. Compounds 3f and 4f were
1
isolated as an inseparable mixture. Analysis of the H
and 13C NMR spectra of that mixture allowed us to
identify ester 3f as a mixture of two diastereoisomers
at a ratio of 1:1, as followed from the presence of
double sets of proton and carbon signals. The chemical
shifts of C4″ and C2 of the S and R isomers of 3f were
appreciably different: δC 74.1 and 75.1 ppm (C4″), 77.8
and 80.1 ppm (C2), respectively.
EXPERIMENTAL
The H and 13C NMR spectra were recorded on
a Bruker Avance III 500 high-resolution mass spec-
trometer operating at 500 (1H) or 125.76 MHz (13C);
CDCl3 was used as solvent, and tetramethylsilane, as
1
Scheme 2.
A
C
O
A
C
O
A
B
A
B
ROH
:
ML + N2
C
LM
C
LM
BH2
B
+ ML
–N2
H
R
H
R
A
B
A
H
C
B
OR
C
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 3 2018

CATALYTIC REACTION OF ETHYL 2-DIAZO-3-OXOBUTANOATE WITH ALCOHOLS
375
Scheme 3.
Et
O
O
OH
Et
OH
O
O
O
O
O
Cu(OTf)2, PhH, 80°C
O
1
+
+
EtO
Me
EtO
Me
OH
O
O
Et
2g
4g
5g
internal standard. GLC analysis was performed with
a Kristall-2000M chromatograph equipped with
a 2.0-m column packed with 5% SE-30 on Chromaton
N-AW; oven temperature 50–250°C; carrier gas
helium. Silica gel plates (Sorbfil, Russia) were used for
analytical TLC. The products were isolated by column
chromatography on silica gel (70–230 mesh; Lancaster,
UK). The solvents used (benzene, ethyl acetate) were
purified according to standard procedures [23, 24].
Compounds 3a and 3b were reported previously [25].
Ethyl 2-[(2,2-dimethyl-1,3-dioxolan-4-yl)me-
thoxy]-3-oxobutanoate (3f) was a mixture of two
1
diastereoisomers at a ratio of 1:1. H NMR spectrum,
δ, ppm: S-3f: 1.20 t (3H, CH3, J = 7 Hz), 1.44 s (3H,
CH3), 1.55 s (3H, CH3), 2.14 s (3H, CH3), 3.72–3.76 m
and 3.86–3.89 m (1H each, 2′-H), 3.94 s (1H, 2-H),
3.97 t (1H, 5″-H, J = 8.6 Hz), 4.17 q (2H, OCH2CH3,
J = 7 Hz), 4.25 d.d (1H, 5″-H, J = 8.6, 3.8 Hz), 4.40–
4.44 m (1H, 4″-H); R-3f: 1.20 t (3H, CH3, J = 7 Hz),
1.44 s (3H, CH3), 1.55 s (3H, CH3), 2.14 s (3H, CH3),
3.72–3.76 m and 3.86–3.89 m (1H each, 2′-H), 4.09 s
(1H, 2-H), 4.15 m (1H, 5″-H), 4.17 q (2H, OCH2CH3,
J = 7 Hz), 4.50 d (1H, 5″-H, J = 11.5 Hz), 4.45–4.47 m
(1H, 4″-H). 13C NMR spectrum, δC, ppm: S-3f: 14.07
(CH3), 20.12 (CH3), 20.74 (CH3), 31.86 (CH3), 61.08
(OCH2), 67.50 (C5″), 68.45 (C2′), 74.09 (C4″), 77.84
(C2), 104.76 (C2″), 169.60 (C1), 207.30 (C3); R-3f:
14.07 (CH3), 20.12 (CH3), 20.74 (CH3), 31.86 (CH3),
61.29 (OCH2), 65.27 (C5″), 68.79 (C2′), 75.13 (C4″),
80.10 (C2), 105.04 (C2″), 169.60 (C1), 207.30 (C3).
General procedure for the Cu(OTf)2-catalyzed
reaction of alcohols 2a–2g with ethyl 2-diazo-3-oxo-
butanoate. A solution of 0.1 g (0.6 mmol) of diazo
ester 1 in 10 mL of benzene was added with vigorous
stirring over a period of 15 min to a solution of
1.2 mmol of alcohol 2a–2g and 4 mg (0.012 mmol) of
Cu(OTf)2 in benzene, heated to 80°C. The mixture was
stirred for 6 h at 80°C. When the reaction was com-
plete (GLC), the mixture was cooled to room tempera-
ture and passed through a thin layer of silica gel. The
solvent was removed under reduced pressure, and the
residue was purified by silica gel chromatography
using benzene–ethyl acetate (9:1) as eluent or distilled
under reduced pressure.
Ethyl (Z)-8-(hydroxymethyl)-2,2,4-trimethyl-
1,3,6-trioxacyclooct-4-ene-5-carboxylate (4f).
1H NMR spectrum, δ, ppm: 1.23 t (3H, CH3, J = 7 Hz),
1.42 s (3H, CH3), 1.52 s (3H, CH3), 2.16 s (3H, CH3),
3.85 d.d (1H, 7-H, J = 12.2, 10 Hz), 4.10–4.30 m (5H,
8-H, 7-H, CH2OH), 4.25 q (2H, CH3CH2, J = 7 Hz),
5.42 s (2H, 2-H). 13C NMR spectrum, δC, ppm: 13.81
(CH3), 20.10 (CH3), 20.80 (CH3), 21.16 (CH3), 61.21
(C7), 61.40 (CH2O), 62.53 (CH3CH2), 76.11 (C8),
94.03 (C2), 142.27 (C5), 157.30 (C4), 163.77 (C=O).
Ethyl-2-benzyloxy-3-oxobutanoate (3e) was
isolated by column chromatography. Yield 0.14 g
(96%), light yellow liquid, Rf 0.44 (benzene–EtOAc,
1
9:1). H NMR spectrum, δ, ppm: 1.15 t (3H, CH3, J =
7.1 Hz), 1.62 s (3H, CH3), 3.78 s (1H, CH), 4.20 q
(2H, OCH2CH3, J = 7.1 Hz), 5.21 s (2H, PhCH2),
7.31–7.43 (5H, Ph). 13C NMR spectrum, δC, ppm: 13.8
(CH3), 21.5 (CH3), 58.8 (CH), 62.5 (OCH2CH3), 67.8
(PhCH2), 128.1 (Cp), 128.5 (Co), 128.6 (Cm), 134.9
(Ci), 170.8 (CO2C2H5), 202.0 (COCH3). Found, %:
C 66.10; H 6.91. C13H16O4. Calculated, %: C 66.09;
H 6.83.
Ethyl (Z)-8-ethyl-8-(hydroxymethyl)-4-methyl-
1,3,6-trioxacyclonon-4-ene-5-carboxylate (4g) and
ethyl (Z)-8-ethyl-8-(hydroxymethyl)-5-methyl-1,3,6-
trioxacyclonan-4-ene-4-carboxylate (5g) (mixture of
isomers) were isolated by column chromatography.
Light yellow liquid, Rf 0.32 (benzene–EtOAc, 9:1).
1H NMR spectrum, δ, ppm: 4g: 0.91 t (3H, CH3, J =
7.2 Hz), 1.31 q (2H, CH2CH3, J = 7.2 Hz), 1.33 t (3H,
CH3, J = 7.3 Hz), 2.06 s (3H, CH3), 3.48 d (1H, 7-H,
J = 13 Hz), 3.87 s (2H, 9-H), 3.95 d (1H, 7-H, J =
13 Hz), 4.22 q (2H, OCH2CH3, J = 7.3 Hz), 4.48 s
(2H, CH2O), 4.64 s and 4.65 s (1H each, 2-H);
5g: 0.84 t (3H, CH3, J = 7.1 Hz), 1.33 t (3H, CH3, J =
Vacuum distillation of the residue obtained in the
reaction of 2,2-dimethyl-1,3-dioxolan-4-yl (2f) with
diazo ester 1 gave 0.09 g (59%) of a mixture of com-
pounds 3f and 4f at a ratio of 7:1. Light yellow liquid,
bp 134°C (3 mm). Found, %: C 55.23; H 7.69.
C12H20O6. Calculated, %: C 55.37; H 7.74.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 3 2018

SAKHABUTDINOVA et al.
376
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CH3), 3.51 d (1H, 7-H, J = 12.9 Hz), 3.89 s (2H, 9-H),
3.87 s (2H, CH2O), 3.91 d (1H, 7-H, J = 12.9 Hz),
4.35 q (2H, OCH2CH3, J = 7.5 Hz), 4.98 s and 4.99 s
(1H each, 2-H). 13C NMR spectrum, δC, ppm: 4g: 6.83
(CH3), 13.92 (CH3), 16.49 (CH3), 23.89 (CH2CH3),
37.57 (C8), 60.80 (CH2OH), 60.79 (CH3CH2O), 71.54
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