Ruthenium(III) chloride-catalyzed efficient protocol for ethyl diazoacetate insertion into the N-H bond of secondary amines

Article abstract of DOI:10.1007/s00706-008-0927-z

Ruthenium(III) chloride (1 mol%) alone can catalyze the insertion of ethyl diazoacetate into N-H bonds of various structurally and electronically diverse secondary cyclic amines under solvent-free conditions to afford the corresponding glycine esters in g

Full text of DOI:10.1007/s00706-008-0927-z

Monatsh Chem 139, 1369–1372 (2008)
DOI 10.1007/s00706-008-0927-z
Printed in The Netherlands
Ruthenium(III) chloride-catalyzed efficient protocol for ethyl
diazoacetate insertion into the N–H bond of secondary amines
Ravi Varala, Ramu Enugala, Srinivas R. Adapa
Indian Institute of Chemical Technology, Hyderabad, India
Received 1 February 2008; Accepted 9 March 2008; Published online 2 June 2008
#
Springer-Verlag 2008
Abstract Ruthenium(III) chloride (1mol%) alone can
catalyze the insertion of ethyl diazoacetate into N–H
bonds of various structurally and electronically di-
verse secondary cyclic amines under solvent-free con-
ditions to afford the corresponding glycine esters in
good yields under ambient conditions. Reactions with
various aliphatic primary and aromatic amines exam-
ined, however, were unsuccessful.
action of diazo compounds into X–H bonds (X ¼
heteroatom) [6]. Simonneaux et al. reported this re-
action using ruthenium complexes [7]. Morilla et al.
rediscovered Cu(I) homoscorpionate complex for the
reaction of different amines and diazo compounds
under mild conditions [8]. Perez and co-workers re-
ported the {[HC(3,5-Me pz) ]Cu(NCMe)}BF com-
2
3
4
plex catalyzed transfer of the:CHCO Et unit from
2
ethyl diazoacetate (EDA) to several saturated and
unsaturated substrates with very high yields and un-
der biphasic conditions using ionic liquid [bmim]-
Keywords Ruthenium(III) chloride; Insertion; Amines; Ethyl
diazoacetate; Solvent-free conditions.
[PF ] and n-hexane as the reaction medium [9].
6
Kantam et al. reported the insertion of ꢀ-diazo com-
Introduction
pounds into N–H bonds of amines using Cu(acac)2
The insertion of in situ generated metallocarbenoid
species as the catalytic active species for the transfer
of a carbene moiety from a diazo source into hetero-
atom–H bonds [1], which are valuable synthons in the
synthesis of ꢀ-amino acids, peptides, and ꢁ-lactam
antibiotics [2], remains of considerable attention in
organic synthesis.
The N–H insertion reaction particularly reported
by Yates using copper bronze [3], has received much
attention in the last few decades. Saegusa et al. [4]
and Kagan and Nicoud [5] employed CuCN as a
catalyst for the insertion of diazo compounds into
immobilized in ionic liquids [10]. Very recently, an
elegant procedure was developed by Woo et al. using
iron porphyrin as catalyst for the N–H insertion
reactions with EDA [11]. Keeping in the view of
limited procedures so far for the effective insertion
of ethyl diazoacetate into N–H bonds of amines,
there is further scope to explore and understand the
present reaction.
Another promising synthesis approach to environ-
mentally friendly chemistry is to minimize or elimi-
nate the use of harmful organic solvents. Organic
reactions under solvent-free conditions are advanta-
geous because of their enhanced selectivity and effici-
ency, ease of manipulation, cleaner product formation,
and toxic or often volatile solvents are avoided [12].
Very recently, we have reported an aldol-type
reaction of aldehydes with EDA using quaternary
N–H bonds. Later Rh(OAc) and its derivatives have
2
proved to be excellent catalysts for the insertion re-
Correspondence: Dr. Srinivas R. Adapa, Indian Institute of
Chemical Technology, Hyderabad 500 007, India. E-mail:
rvarala_iict@yahoo.co.in

1
370
R. Varala et al.
ammonium hydroxide as base [13]. During the course
of our target to synthesize ꢀ-amino acids and having
been interested in exploring novel synthesis protocols,
particularly for carbon–carbon, carbon–heteroatom
bond forming reactions [14], we undertook a study
on the insertion of EDA into N–H bonds of various
structurally and electronically divergent amines.
as Ru(acac) , Co(acac) , Pd(acac) , VO(acac) ,
3
3
2
2
Nd(NO ) , RhCl , RuCl , Zn(OTf) , PrCl , TbCl ,
3
3
3
3
3
2
3
SmCl , FeCl , and CeCl ꢀ 7H O using 1 mmol EDA
3
3
3
2
as carbene source with morpholine (1.2 mmol) un-
der solvent-free conditions at ambient temperature.
Among the reagents screened, RuCl proved to be
3
the best catalyst for the model reaction both in terms
of yields and reaction times. To our delight, we
observed the formation of the corresponding N–H
insertion product in 95% yield of isolated product
Results and discussion
1
Initially, we screened the catalytic activity of sev-
eral reagents chosen (5 mol% as standard) such
after 1 h (Scheme 1). The H NMR spectroscopic
analysis revealed the formation of a new signal at
Scheme 1
Table 1 RuCl -catalyzed insertion of EDA into funtionalized amines
3
a,b
Formula number
Amine
Product
Time=h
Yields=%
Ref.
[8]
1
1.0
95
2
3
4
5
6
7
1.5
1.0
8.0
3.5
4.5
3.0
60
88
45
78
85
68
–
[11]
–
–
–
–
8
9
12.0
3.0
4.5
4.5
4.5
38
82
85
72
92
–
–
1
1
1
0
1
2
–
c
[10]
–
a
b
c
Yields refer to isolated pure products after column chromatography
1
All new compounds were characterized by H NMR, IR, and mass spectra
2
mmol EDA were used

Ruthenium(III) chloride-catalyzed efficient protocol for ethyl diazoacetate insertion
1371
ꢂ ¼ 3.15 ppm for the N–CH and the disappearance
range of secondary cyclic amines under mild condi-
tions at ambient temperature with moderate to excel-
lent yields under atmospheric conditions. Although
this protocol offers limited applicability, it is the first
example using a simple Ru salt as the catalyst for
diazo N–H insertion. Further exploration of the full
applicability for the EDA insertion into various pri-
mary aliphatic and aromatic amines using anchored
ruthenium salts is currently underway.
2
of N ¼CH proton of EDA at ꢂ ¼ 4.72 ppm.
2
Further studies revealed that 1 mol% of catalyst
was also efficient to carry forward the insertion pro-
cess (1 mol%, 1 h, ꢁ95% yield). We also screened
several solvents (EtOH, THF, H O, CH CN, toluene,
2
3
DCM, DMF, and DMSO), interestingly no insertion
product was observed. The optimum yields of the
product were obtained when a ratio of substrate to
EDA (1.1:1) is used. When equimolar ratios of EDA
to amine were used trace amounts of side products,
such as diethyl fumarate, diethyl maleate (due to
dimerization of EDA), or ethyl glyoxalate azine were
observed. Based on literature reports by Simonneaux
et al. [7a, c] we took amines slightly in excess to
EDA in order to prevent the formation of the side
products [15]. The addition of EDA to the amine
was done slowly so as to prevent the dimerization
of EDA.
Experimental
1
H NMR spectra of CDCl solutions were recorded on Varian
3
FT-200MHz (Gemini) and Bruker UXNMR FT-300 MHz
(Avance) instruments. The chemical shifts are reported as
parts per million downfield from tetramethylsilane. Mass spec-
tra were recorded on a VG 7070H Micro mass spectrometer.
The purity of the compounds was checked by TLC on precoat-
ed SiO gel (HF254, 200 mesh) aluminum plates (E. Merck)
2
using n-hexane:ethyl acetate (8:2) as mobile phase and com-
pounds were visualized by iodine vapors.
Having optimized the reaction conditions, we dem-
onstrated the generality and scope of this method for
the reaction between EDA and structurally divergent
functionalized secondary cyclic amines and the re-
sults are summarized in Table 1. Moderate to excel-
lent isolated yields were observed for all substrates
employed. The present protocol is very clean and
free from side reactions and does not require inert
conditions. In the absence of the catalyst, the desired
product was not formed. It is interesting to note that
for entries 4 and 8, the isolated yields of the corre-
sponding insertion products were low and required
longer reaction times. Whereas in case of piperazine
General procedure for the insertion of EDA into amines
To a stirred solution of 1.1 mmol amine and 1 mol% RuCl3
was added EDA (1mmol) slowly at room temperature under
solvent-free conditions (Table 1). After completion of the re-
action as indicated by TLC, the crude product was extracted
3
with 2ꢂ5 cm diethyl ether. The combined products were
concentrated in vacuo and the crude residue was purified by
silica gel column chromatography to afford the corresponding
pure addition product in good yields. The known compounds
in Table 1 were found to be identical with respect to the
1
published H NMR and mass data [8, 10, 11] and novel com-
1
pounds were characterized by H NMR and mass spectral
analyses.
(
1.1 equiv., entry 11), 2 mmol of EDA were employ-
Ethyl 2-(1,4-thiazinan-4-yl)acetate (2, C H NO S)
8
15
2
ed by adding stepwise for the double insertion to
occur. Satisfied by these results, we extended our
RuCl catalyzed protocol for various aliphatic prima-
1
Oil; H NMR (200MHz, CDCl ): ꢂ ¼ 1.31 (t, J ¼ 7.51 Hz,
3
3
H), 2.84 (t, J ¼ 4.53Hz, 4H), 3.18 (s, 2H), 3.38 (t, J ¼
3
4.53Hz, 4H), 4.22 (q, J ¼ 7.55Hz, 2H) ppm; MS (EI): m=z ¼
þ
ry and aromatic amines, such as cyclohexyl amine, n-
butyl amine, allyl amine, aniline, and benzyl amine
etc., but these experiments were unsuccessful.
Based on the report by Simonneaux et al. [7], we
presume that the active intermediate in the catalyzed
ethyl diazoacetate insertion into the N–H bond is a
ruthenium carbene complex. EDA was then added to
the carbene complex which thereafter leads to the
formation of the expected glycine ester.
189 (M ).
Ethyl 2-(4-methylpiperidino)acetate (4, C H NO )
2
1
0
19
1
Oil; H NMR (300MHz, CDCl ): ꢂ ¼ 0.96 (d, 3H), 1.23–1.28
3
(
2
m, 5H), 1.26 (t, J ¼ 7.24 Hz, 3H), 2.52–2.58 (m, 4H), 3.15 (s,
þ
H), 4.17 (q, J ¼ 7.03 Hz, 2H) ppm; MS (EI): m=z ¼ 185 (M ).
Ethyl 2-(4-benzylpiperazino)acetate (5, C H N O )
5 22 2 2
1
1
Oil; H NMR (300MHz, CDCl ): ꢂ ¼ 1.27 (t, J ¼ 6.79 Hz,
3
3
2
5
H), 2.37–2.58 (m, 4H), 2.87 (t, J ¼ 4.53 Hz, 4H), 3.15 (s,
H), 3.47 (s, 2H), 4.18 (q, J ¼ 6.79 Hz, 2H), 7.25–7.27 (m,
þ
H) ppm; MS (EI): m=z ¼ 262 (M ).
Conclusion
Ethyl 2-(4-methylpiperazino)acetate (6, C H N O )
9
18 2 2
In conclusion, we have preliminary demonstrated
that RuCl (1 mol%) alone is sufficient for a facile
N–H insertion of ethyl diazoacetate into a wide
1
Oil; H NMR (300MHz, CDCl ): ꢂ ¼ 1.29 (t, J ¼ 6.79 Hz,
3
3
3H), 2.26 (s, 3H), 2.36–2.58 (m, 8H), 3.16 (s, 2H), 4.16 (q,
J ¼ 6.79 Hz, 2H) ppm; MS (EI): m=z ¼ 185 (Mþ).

1
372
R. Varala et al.
Ethyl 2-(4-phenylpiperazino)acetate (7, C H N O )
1
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Oil; H NMR (200MHz, CDCl ): ꢂ ¼ 1.29 (t, J ¼ 6.79 Hz,
3
3
H), 2.73 (t, J ¼ 5.28Hz, 4H), 3.20 (t, J ¼ 5.28 Hz, 4H), 3.22
(s, 2H), 4.18 (q, J ¼ 6.79 Hz, 2H), 6.78–6.99 (m, 2H), 7.17–
þ
3
4
7
.25 (m, 3H) ppm; MS (EI): m=z ¼ 248 (M ).
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1
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1
3 19 3 2
1
Oil; H NMR (300MHz, CDCl ): ꢂ ¼ 1.23 (t, J ¼ 7.55 Hz,
3
3
4
H), 2.88 (t, J ¼ 4.53Hz, 4H), 3.15 (s, 2H), 3.39 (t, J ¼
.53Hz, 4H), 4.12 (q, J ¼ 7.53Hz, 2H), 6.49 (m, 2H), 7.34
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7
8
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(
t, J ¼ 9.03Hz, 1H), 8.07 (d, J ¼ 6.04 Hz, 1H) ppm; MS (EI):
þ
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tert-Butyl 4-(2-ethoxy-2-oxoethyl)-1-piperazinecarboxylate
(
10, C H N O )
12 18 4 2
1
Oil; H NMR (300 MHz, CDCl ): ꢂ ¼ 1.29 (t, J ¼ 7.2 Hz, 3H),
3
1
4
.49 (s, 9H), 2.63–2.75 (m, 4H), 3.18 (s, 2H), 3.20–3.31 (m,
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1
0. Kantam ML, Neelima B, Reddy ChV (2006) J Mol Cat A:
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Ethyl 2-[4-(2-pyrimidinyl)piperazino]acetate
12, C H N O )
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(
1
2 18 4 2
1
Oil; H NMR (300MHz, CDCl ): ꢂ ¼ 1.29 (t, J ¼ 7.55 Hz,
3
3
5
1
H), 2.63 (t, J ¼ 5.28Hz, 4H), 3.21 (s, 2H), 3.85 (t, J ¼
.28Hz, 4H), 4.17 (q, J ¼ 7.55 Hz, 2H), 6.42 (t, J ¼ 5.28 Hz,
þ
H), 8.24 (d, J ¼ 4.53Hz, 2H) ppm; MS (EI): m=z ¼ 250 (M ).
1
3. Varala R, Ramu E, Sreelatha N, Adapa SR (2006) Tetra-
hedron Lett 47:877
Acknowledgements
14. a) Ramu E, Varala R, Sreelatha N, Adapa SR (2007)
Tetrahedron Lett 48:7184; b) Varala R, Nasreen A, Ramu
E, Adapa SR (2007) Tetrahedron Lett 48:69 and refer-
ences cited therein; c) Varala R, Nasreen A, Adapa SR
Ravi Varala thanks DIICT, Dr. J.S. Yadav, and the Council
of Scientific Industrial Research (CSIR, India) for financial
support.
(2007) Can J Chem 85:148; d) Varala R, Ramu E, Adapa
SR (2007) J Braz Chem Soc 18:291; e) Nasreen A, Varala
R, Adapa SR (2007) J Heterocyclic Chem 44:983; f)
Varala R, Ramu E, Vijay K, Adapa SR (2007) Chem
Pharm Bull 55:1254; g) Varala R, Ramu E, Adapa SR
(2007) J Iran Chem Soc 4:370; h) Varala R, Ramu E,
Vijay K, Ganapaty S, Adapa SR (2007) Asian J Chem
19:5435
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