Reaction of methyl diazoacetate with amines catalyzed by Ru 2(OAc)4Cl

Article abstract of DOI:10.1134/S1070428010100039

Reactions of primary and secondary amines with methyl diazoacetate in the presence of Ru₂(OAc)₄Cl gave the corresponding N-substituted glycine methyl esters in almost quantitative yield. Catalytic decomposition of methyl diazoacetate

Full text of DOI:10.1134/S1070428010100039

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 10, pp. 1461–1465. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.V. Maidanova, A.D. Bakeeva, R.M. Sultanova, R.Z. Biglova, V.A. Dokichev, 2010, published in Zhurnal Organicheskoi Khimii,
2010, Vol. 46, No. 10, pp. 1458–1462.
Reaction of Methyl Diazoacetate with Amines
Catalyzed by Ru2(OAc)4Cl
A. V. Maidanovaa, A. D. Bakeevab, R. M. Sultanovaa, R. Z. Biglovab, and V. A. Dokicheva
a Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: dokichev@anrb.ru
b Bashkir State University, Ufa, Bashkortostan, Russia
Received January 11, 2010
Abstract—Reactions of primary and secondary amines with methyl diazoacetate in the presence of
Ru2(OAc)4Cl gave the corresponding N-substituted glycine methyl esters in almost quantitative yield. Catalytic
decomposition of methyl diazoacetate generates methoxycarbonylcarbene which is inserted into the N–H bond
of amines with high regioselectivity.
DOI: 10.1134/S1070428010100039
Catalytic insertion of alkoxycarbonylcarbenes gen-
erated from diazo esters into N–H bonds of amines
provides a convenient method for the synthesis of
physiologically active N-substituted glycine esters and
heterocyclic compounds [1–3]. For example,
Rh2(OAc)4-catalyzed intramolecular insertion into
N–H bond with participation of α-acyl diazoacetates
containing an azetidine fragment is used in the synthe-
sis of bicyclic β-lactam antibiotics [1, 4]. Traditional
catalysts are Cu, CuSO4, CuCl, CuCN, TpXCu, and
Rh2(OAc)4 [1, 5–8]. However, these catalysts are not
always effective and regioselective. In some cases,
they promote intra- and intermolecular reactions of
diazocarbonyl compounds at C–H, O–H, C=C, and
C=O bonds [1, 9]. In the recent years, ruthenium(II)
complexes were shown to effectively catalyze insertion
of carbenes generated from diazocarbonyl compounds
into heteroatom–hydrogen bonds [10, 11].
50:50:1. Regardless of the amine nature, insertion
of methoxycarbonylcarbene was regioselective, and
insertion products into the N–H bond were formed in
20–85% yield (Scheme 1; see table). Methyl diazo-
acetate failed to react with amines in the absence of
catalyst.
Scheme 1.
OMe
R1
OMe
[Ru]
R1R2NH
+
N
N2
O
R2
O
Ia–Ij
IIa–IIj
R1 = R2 = Et (a); R1 = H, R2 = Bu (b); R1 = R2 = Bu (c);
R1R2 = (CH2)4 (d), (CH2)5 (e), (CH2)2O(CH2)2 (f); R1 = All,
R2 = C5H11 (g); R1 = Et, R2 = HO(CH2)2 (h); R1 = H, R2 =
N
Ph (i); R1R2 =
(j).
N
In the present article we report on the results of our
study on Ru2(OAc)4Cl-catalyzed reaction of methyl di-
azoacetate with primary and secondary amines, namely
with diethylamine (Ia), butylamine (Ib), dibutylamine
(Ic), pyrrolidine (Id), piperidine (Ie), morpholine (If),
N-allylpentan-1-amine (Ig), 2-amino-N-ethylethanol
(Ih), aniline (Ii), and (–)-cytisine (Ij). The reactions
were carried out at 75°C by adding a solution of
methyl diazoacetate in benzene over a period of
30 min to a mixture of amine with the catalyst, the
molar ratio amine–N2CHCO2Me–Ru2(OAc)4Cl being
O
In the reaction of methyl diazoacetate with butyl-
amine (Ib), product of double carbene insertion into
the N–H bond, BuN(CH2COOMe)2 (IIIa), was ob-
tained in 33% yield together with ester IIb. The reac-
tion of methyl diazoacetate with N-allylpentan-1-
amine in the presence of Ru2(OAc)4Cl gave N-allyl-N-
pentylglycine methyl ester (IIg) in 70% yield. No cy-
clopropanation products or those resulting from intra-
molecular rearrangement of ammonium ylide were
1461

MAIDANOVA et al.
1462
Scheme 2.
Et
N
OH
OMe
H
[Ru]
N
OMe
N2
+
HO
Et
N
–MeOH
O
O
O
Et
O
Ih
A
IIh
detected in the reaction mixture [1]. The formation of
a stable complex by Ru2(OAc)4Cl with alkaloid cyti-
sine (Ij) is likely to be responsible for the poor yield
(20%) of methyl cytisinylacetate (IIj) [10–12]. The
C=C bonds in the pyridine ring of Ij remained intact in
the reaction with methyl diazoacetate in the presence
of Ru2(OAc)4Cl under the above conditions.
displayed in the mass spectrum (electron impact) the
molecular ion peak with a precise m/z value of
129.0833, which corresponded to the composition
C6H11NO2. In addition, a number of fragment ion
peaks were present due to elimination of methyl
(m/z 114.0609), ethyl (m/z 100.0667), and vinyloxyl
radicals (m/z 86.0353), as well as of C4H9N radical
cation (m/z 71.0446). Fragment ion with an m/z value
of 85.0628 was formed as a result of elimination of
neutral CO2 molecule, which unambiguously con-
firmed the assumed lactone structure of IIh. Scheme 3
illustrates the main fragmentation pathways of the
molecular ion of compound IIh.
The reaction of N-ethyl-2-aminoethanol (Ih) with
N2CHCO2Me in benzene at 75°C, catalyzed by
Ru2(OAc)4Cl, regioselectively occurred at the N–H
bond (Scheme 2), and the primary insertion product,
N-ethyl-N-(2-hydroxyethyl)glycine methyl ester A
underwent intramolecular cyclization to N-ethylmor-
pholin-2-one (IIh, yield 85%). As noted in [13, 14],
intramolecular insertion of aminoalkoxycarbonyl-
carbenes into N–H bond in the presence of Rh2(OAc)4
gives oligomeric products. N-Ethylmorpholin-2-one
(IIh) was isolated as individual substance by column
chromatography. Its IR spectrum contained an absorp-
tion band at 1735 cm–1, which is typical of carbonyl
stretching vibrations in cyclic lactones. Compound IIh
Butylamine (Ib) reacted with an equimolar amount
of methyl diazoacetate to give products of insertion of
both one and two methoxycarbonylcarbene molecules
into the N–H bonds, compounds IIb (17%) and IIIb
(33%). Unlike butylamine, the reaction with aniline
selectively afforded methyl (phenylamino)acetate (IIi)
in 71% yield. Catalytic reactions of primary amines Ib
and Ii with 2 equiv of methyl diazoacetate led to
Scheme 3.
CH2
N
–Me
–Et
O
O
m/z 114 (5%)
N
+·
Et
N
O
O
m/z 100 (3%)
Et
N
Et
O
O
+
N
Et
M+, m/z 129 (35%)
CH2
N
·
·
H2C
–CO2
H2C
CH2
O
O
M+, isomerized
m/z 86 (20%)
m/z 41 (100%)
m/z 57 (50%)
H2C
C
O
H
–H2
m/z 43 (60%)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 10 2010

REACTION OF METHYL DIAZOACETATE WITH AMINES CATALYZED BY Ru2(OAc)4Cl
1463
Yields of N-substituted glycine methyl esters IIa–IIj and IIIa, relative rate constants krel, ionization potentials IP, and basicity
constants pKa of amines Ia–Ij
pKa
Compound
Yield, %
65
krel
IP, eV [18]
no.
H2O [15]
10.93
MeCN [16]
18.75
DMSO [16]
10.50
IIa
–
8.01
8.71
IIb
IIIa
17
33
0.505
10.60
–
–
IIc
IId
IIe
IIf
IIg
IIh
IIi
55
67
77
85
70
85
71
20
1.000
1.845
2.040
1.140
0.744
0.745
1.183
–
7.69
8.00
8.20
8.20
–
[16] 11.25 [16]
11.27
–
19.58
18.92
16.61
–
–
10.80
10.50
08.50
–
11.12
08.70
0(9.99)
09.96
–
–
–
7.72
–
04.58
10.56
–
03.6
–
IIj
09.89
quantitative formation of N-butyl-N-(methoxycar-
bonylmethyl)glycine methyl ester (IIIa) and N-(me-
thoxycarbonylmethyl)-N-phenylglycine methyl ester
(IIIb) (Scheme 4).
It should be also noted that, unlike copper and
rhodium compounds [1–3], no dimerization products
of methoxycarbonylcarbene (dimethyl maleate or di-
methyl fumarate) were detected in the reaction mix-
tures in the presence of Ru2(OAc)4Cl.
Scheme 4.
We can conclude that Ru2(OAc)4Cl is an effective
catalyst for regioselective synthesis of N-substituted
glycine methyl esters by reaction of primary or secon-
dary amines with methyl diazoacetate.
OMe
N
2
RNH2
+
2
O
Ib, Ii
MeO
OMe
[Ru]
N
R
EXPERIMENTAL
O
O
IIIa, IIIb
1
The H and 13C NMR spectra were recorded on
R = Bu (a), Ph (b).
a Bruker AM-300 spectrometer at 300.13 and
75.47 MHz, respectively, using CDCl3 or C6D6 as
solvent and tetramethylsilane as internal reference. The
IR spectra were measured on a Specord M82-63 instru-
ment from thin films. GLC analysis was performed on
a Kristall-2000m chromatograph equipped with
a flame ionization detector (1200 ×5-mm column
packed with 5% of SE-30 on Inerton N-AW DMCS,
0.125–0.160 mm; carrier gas helium). The mass spec-
tra were obtained on a Thermo Finnigan MAT 95 XP
mass spectrometer (electron impact, 70 eV; ion source
temperature 250°C, batch inlet probe temperature 50–
250°C, heating rate 10 deg/min). The progress of reac-
tions was monitored by TLC on silica gel plates
(Merck) using chloroform–methanol (9:1) as eluent.
There are almost no published quantitative data on
the relative reactivity of amines in catalytic insertion of
methoxycarbonylcarbene at the N–H bond. We
examined the competing reactions of dibutylamine (Ic)
and amines Ib and Id–Ii with methyl diazoacetate in
the presence of Ru2(OAc)4Cl (see table). The relative
reactivity of amines was determined at 75°C by adding
a solution of N2CHCO2Me in benzene to a mixture of
dibutylamine (Ic) and amine Ib or Id–Ii, the molar
ratio Ic–Ib (Id–Ii)–N2CHCO2Me–Ru2(OAc)4Cl being
50:50:50:1. Aniline Ii and cyclic amines Id–If were
found to be the most reactive. Unfortunately, we failed
to obtain satisfactory correlations between the relative
reactivity of amines and their basicity constants
[14–16] or ionization potentials [17]. Only amines
Ic–Ie gave rise to a linear relation between the relative
rate constants krel and ionization potentials IP.
Aniline, butylamine, diethylamine, dibutylamine,
morpholine, N-allylpentan-1-amine, N-ethyl-2-amino-
ethanol, piperidine, pyrrolidine, and plant alkaloid
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 10 2010

MAIDANOVA et al.
1464
(–)-cytisine [(1R,5S)-1,2,3,4,5,6-hexahydro-1,5-
methanopyrido[1,2-a][1,5]diazocin-8-one] were com-
mercial products. Benzene was purified according to
standard procedure [19].
(C=O), 1670 (C=C), 1465, 1198 (C–N), 1171, 995,
920. H NMR spectrum (CDCl3), δ, ppm: 0.87 t (3H,
1
CH3, J = 6.6 Hz), 1.31 m (2H, CH2), 1.45 m (2H,
CH2), 2.55 t (2H, CH2, J = 7.6 Hz), 3.24 d (2H, CH2,
J = 5.0 Hz), 3.31 s (2H, CH2), 3.71 s (3H, OCH3),
5.17 d.d (2H, CH2=CH, J = 10.5, 12.1 Hz), 5.83 m
(1H, CH=CH2). 13C NMR spectrum (CDCl3), δC, ppm:
14.06 (CH3), 22.52 (CH2), 27.06 (CH2), 29.42 (CH2),
51.06 (OCH3), 53.98 (CH2), 54.04 (CH2), 57.39 (CH2),
117.4 (CH2), 135.64 (CH), 171.49 (SO2). Mass spec-
trum, m/z (Irel, %): 199 (10) [M]+, 140 (100), 114
(14.6), 84 (32), 41 (18). M+ 199.1389. C11H21NO2. Cal-
culated: M 199.30.
( Te t r a a c e t a t o ) d i r u t h e n i u m c h l o r i d e
Ru2(OAc)4Cl. A solution of 2 g (6.1 mmol) of
ruthenium chloride trihydrate and 2.5 g (18.3 mmol) of
sodium acetate trihydrate in a mixture of 50 ml of
glacial acetic acid and 50 ml of anhydrous ethanol was
heated for 4 h under reflux in an argon atmosphere.
The resulting green solution was evaporated to dryness
under reduced pressure, and the residue was extracted
in a Soxhlet apparatus with boiling anhydrous alcohol
until the extract lost its green color. The extract was
cooled and filtered, and the filtrate was evaporated to
dryness. Yield 2.2 g (82%). The properties of the
product were consistent with those reported for
Ru2(OAc)4Cl in [20].
N-Ethylmorpholin-2-one (IIh). Yield 85%. IR
spectrum, ν, cm–1: 2770–3040, 1743 (C=O), 1640,
1450, 1408, 1338, 1238, 1190, 1146, 1072 (C–N), 799.
1H NMR spectrum (CDCl3), δ, ppm: 1.17 t (3H, CH3,
J = 7.08 Hz), 2.48 q (2H, CH2, J = 7.08 Hz), 2.68 t
(2H, CH2N, J = 5.09 Hz), 3.31 s (2H, CH2CO), 4.41 t
(2H, CH2O, J = 5.04 Hz). 13C NMR spectrum (CDCl3),
δC, ppm: 12.16 (CH3), 48.55 (CH2), 53.20 (CH2), 55.22
(CH2), 68.54 (CH2), 167.41 (C=O). Mass spectrum,
m/z (Irel, %): 129 (35) [M]+, 114 (5), 100 (3), 86 (20),
71 (33), 57 (50), 43 (60), 41 (100). M+ 129.083.
C6H11NO2. Calculated: M 129.16.
N-Substituted glycine methyl esters IIa–IIj
(general procedure). A solution of 0.27 g (2.7 mmol)
of methyl diazoacetate and 1.35 mmol of amine Ia–Ij
in 3 ml of benzene was added over a period of 30 min
to a solution of 1.35 mmol of the same amine and
0.055 mmol of Ru2(OAc)4Cl in 3 ml of benzene,
maintaining the temperature at 75°C. The mixture was
stirred for 20 h, the progress of the reaction being
monitored by TLC. When the reaction was complete,
the mixture was passed through a thin layer of silica
gel and evaporated, and the residue was purified by
column chromatography on silica gel using chloroform
as eluent.
N-Substituted N-(methoxycarbonylmethyl)-
glycine methyl esters IIIa and IIIb (general proce-
dure). A mixture of 0.54 g (5.4 mmol) of methyl diazo-
acetate and 1.35 mmol of amine Ib or Ii in 4 ml of
benzene was added over a period of 40 min to a solu-
tion of 1.35 mmol of the same amine and 0.055 mmol
of Ru2(OAc)4Cl in 3 ml of benzene, heated to 75°C,
and the mixture was stirred for 20 h, the progress of
the reaction being monitored by TLC. When the reac-
tion was complete, the mixture was passed through
a thin layer of silica gel and evaporated, and the
residue was subjected to column chromatography on
silica gel using chloroform as eluent.
The structure of the isolated compounds was con-
firmed by their IR and 1H and 13C NMR spectra. The
physical constants and spectral parameters of com-
pounds IIa, IIb, IId–IIf, and IIh–IIj coincided with
those reported in [21–27].
N,N-Dibutylglycine methyl ester (IIc). Yield 55%.
IR spectrum, ν, cm–1: 2956, 2931, 2872, 1750 (C=O),
1
1676, 1436, 1330, 1215, 1197 (C–N), 1172. H NMR
N-Butyl-N-(methoxycarbonylmethyl)glycine
methyl ester (IIIa). Yield 99%. IR spectrum, ν, cm–1:
2800–2990, 1750 (C=O), 1437, 1260, 1202, 1171,
1016. 1H NMR spectrum (CDCl3), δ, ppm: 0.91 d (3H,
CH3, J = 7.3 Hz), 1.35 m (2H, CH2), 1.47 m (2H,
CH2), 2.60 t (2H, CH2, J = 7.3 Hz), 3.55 s (2H, CH2),
3.73 s (3H, OCH3). 13C NMR spectrum (CDCl3), δC,
ppm: 13.80 (CH3), 20.07 (CH2), 29.86 (CH2), 51.09
(OCH3), 53.40 (CH2), 53.80 (CH2), 171.17 (C=O).
Mass spectrum, m/z (Irel, %): 217 (10) [M]+, 174 (12.5),
158 (100), 146 (9.8), 116 (33), 102 (8), 74 (9.5), 42
(15). M+ 217.1005. C10H19NO4. Calculated: M 217.26.
spectrum (C6D6), δ, ppm: 0.91 t (6H, CH3, J = 7.0 Hz),
1.28–1.40 m (8H, CH2), 2.56–2.64 m (4H, CH2), 3.28 s
(2H, CH2), 3.41 s (3H, OCH3). 13C NMR spectrum
(C6D6), δC, ppm: 14.50 (CH3), 20.72 (CH2), 30.42
(CH2), 50.87 (OCH3), 54.02 (CH2), 54.37 (CH2),
170.93 (C=O). Mass spectrum, m/z (Irel, %): 201 (12.6)
[M]+, 158 (75), 142 (100), 116 (16), 100 (17), 86 (4.5),
74 (5), 58 (8.5), 42 (11.5). M+ 201.1688. C11H23NO2.
Calculated: M 201.31.
N-Allyl-N-pentylglycine methyl ester (IIg). Yield
70%. IR spectrum, ν, cm–1: 2954, 2930, 2859, 1742
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 10 2010

REACTION OF METHYL DIAZOACETATE WITH AMINES CATALYZED BY Ru2(OAc)4Cl
1465
8. Morilla, M.E., Requejo, M.M., Belderrain, T., Nica-
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N-(Methoxycarbonylmethyl)-N-phenylglycine
methyl ester (IIIb). Yield 98%. The 1H and 13C NMR
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previously [27].
9. Wee, A.G.H., Curr. Org. Synth., 2006, vol. 3, p. 499.
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Competing reactions of methyl diazoacetate with
dibutylamine (Ic) and amines Ib and Id–Ii. A solu-
tion of 0.05 g (0.38 mmol) of dibutylamine (Ic),
0.38 mmol of amine Ib or Id–Ii, and 6.7 mg
(0.015 mmol) of Ru2(OAc)4Cl in 1 ml of C6D6 was
heated to 75°C, and a solution of 0.076 g (0.76 mmol)
of methyl diazoacetate, 0.05 g (0.38 mmol) of dibutyl-
amine (Ic), and 0.38 mmol of the same amine (Ib or
Id–Ii) in 1 ml of C6D6 was added over a period of
15 min under vigorous stirring. The mixture was
analyzed by 1H NMR. The relative reactivity of amines
Ib and Id–Ii was calculated by the formula krel = S1/S0,
where S0 is the intensity of the methylene proton signal
of N,N-dibutylglycine methyl ester (IIc), and S1 is the
intensity of the methylene proton signal of methoxy-
carbonylcarbene insertion product into the N–H bond
of amine Ib or Id–Ii.
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