O-H insertion and tandem N-H insertion/cyclization reactions using an iron porphyrin as catalyst with diazo compounds as carbene sources

Article abstract of DOI:10.1142/S1088424610001982

Iron(III) tetraphenylporphyrin chloride, Fe(TPP)Cl, efficiently catalyzed the insertion of carbenes derived from methyl 2-phenyldiazoacetates into O-H bonds of aliphatic and aromatic alcohols, with yields generally above 80%. Although the analogous N-H insertions are rapid at room temperature, the O-H insertion reactions are slower and required heating in refluxing methylene chloride for about 8 hours using 1.0 mol.% catalyst. Fe(TPP)Cl was also found to be effective for tandem N-H insertion/cyclization reactions when 1,2-diamines and 1,2-alcoholamines were treated with diazo reagents to give piperazinones and morpholinones and related analogs such as quinoxalinones and benzoxazin-2-ones. This approach provides a new one-pot route for synthesizing these classes of heterocyclic compounds.

Full text of DOI:10.1142/S1088424610001982

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2010; 14: 284–292
DOI: 10.1142/S1088424610001982
Published at http://www.worldscinet.com/jpp/
O-H insertion and tandem N-H insertion/cyclization reactions
using an iron porphyrin as catalyst with diazo compounds as
carbene sources
Harun M. Mbuvi, Erik R. Klobukowski, Gina M. Roberts and L. Keith Woo*◊
Department of Chemistry, Iowa State University, Ames, IA 50011-3111, USA
Received 26 June 2009
Accepted 16 July 2009
ABSTRACT: Iron(III) tetraphenylporphyrin chloride, Fe(TPP)Cl, efficiently catalyzed the insertion of
carbenes derived from methyl 2-phenyldiazoacetates into O-H bonds of aliphatic and aromatic alcohols,
with yields generally above 80%. Although the analogous N-H insertions are rapid at room temperature,
the O-H insertion reactions are slower and required heating in refluxing methylene chloride for about
8 hours using 1.0 mol.% catalyst. Fe(TPP)Cl was also found to be effective for tandem N-H insertion/
cyclization reactions when 1,2-diamines and 1,2-alcoholamines were treated with diazo reagents to give
piperazinones and morpholinones and related analogs such as quinoxalinones and benzoxazin-2-ones.
This approach provides a new one-pot route for synthesizing these classes of heterocyclic compounds.
KEYWORDS: iron porphyrin, catalysis, insertion, carbene, cyclization.
addition to aromatic rings, and ylide formation [3]. Con-
sequently, synthetic uses of diazocarbonyl compounds
have increased dramatically.
INTRODUCTION
The synthesis of α-hydroxy and α-alkoxy carboxy-
lic acid derivatives is of considerable importance since
Our recent interest in iron porphyrin reactions with diazo
these compounds are useful synthetic intermediates for
reagents centers on C-H and N-H insertion reactions [4],
the construction of natural products and biologically
which despite their potential in synthesis, have not been
active molecules. Diazocarbonyl compounds are useful
widely utilized [5]. Earlier work done by our group estab-
reagents for the synthesis of these types of derivatives
lished that iron tetraphenylporphyrin chloride, Fe(TPP)Cl,
due to their ready availability, relative kinetic stability,
is one of the most effective catalysts for the insertion of
and facile decomposition under thermal, photochemi-
carbenes from diazo esters into N-H [6] and C-H bonds
cal, and metal-catalyzed conditions. Transition-metal-
[7]. The present study sought to extend the use of iron por-
catalyzedproceduresareoftenthemethodofchoice,taking
phyrins to O-H insertion reactions and also determine if
place under relatively mild conditions. The original cata-
the highly efficient N-H insertion process could be cou-
lytic reactions with diazo reagents were based on copper
pled with subsequent cyclization reactions to give prod-
metal or simple copper(II) salts [1]. Rhodium(II) carbox-
ucts that contain piperazinone or morpholinone moieties.
ylates were introduced later by Teyssie and co-workers in
A typical multi-step synthesis of piperazinone is shown in
the early 1970s [2]. In recent years, new transition-metal
Scheme 1 [8]. Improved synthetic methods for 2-piperazi-
catalysts have been developed that are now widely used
none intermediates could lead to important applications,
since they mediate a broad range of carbenoid trans-
such as the production and use of peptide nucleic acids
formations such as cyclopropanation, C-H insertion,
(PNAs) [9]. This has the potential for rapid identification
of PNA oligomers for use in therapeutics, diagnostics and
gene characterization tools. Derivatives of 2-piperazinones
š
SPP full member in good standing
are known to have therapeutic properties and generally act
by controlling or inhibiting cell-adhesion [10].
*Correspondence to: L. Keith Woo, email: kwoo@iastate.edu,
tel: +1 515-294-5854, fax: +1 515-294-9623
Copyright © 2010 World Scientific Publishing Company

O-H INSERTION AND TANDEM N-H INSERTION/CYCLIZATION REACTIONS
285
H
N
acetate, resulting in an isolated yield of 74%. The product
exhibited a 1H NMR singlet for the new methine proton
at 4.84 ppm while the two α-methylene hydrogens gave
diastereotropic multiplets at 3.53 ppm.
1. H2NCH2CH2NH2,
EtOH, 3.5 h, 22 ˚C
O
O
C
EtO
CH2Cl
N
H
2. NaOEt, EtOH, 2 h
3. DMF, 24 h, 65 ˚C
82%
O
O
O
O
1 mol.%
Scheme 1.
O
N2
RO-H +
Fe(TPP)Cl
R
(1)
CH2Cl2
40 ˚C
RESULTS AND DISCUSSION
X
X
R = Ph (1), cyclohexyl (2),
Et (3), n-Pr (4), i-Pr (5)
X = Me (a), OMe (b)
O-H insertion reactions
Substituted methyl 2-phenyldiazoacetates (MPDAs)
were found to be useful carbene sources for O-H inser-
tion reactions with alcohols when Fe(TPP)Cl was used
as the catalyst (Equation 1). However, when ethyl diazo-
acetate (EDA) was tried as the carbene source for O-H
insertion reactions using Fe(TPP)Cl as a catalyst, only
maleates and fumarates were formed. This is in contrast
to analogous N-H insertions reactions where EDA was
shown to be an excellent carbene source [6]. Treating an
alcohol with 1–2 equiv. of substituted methyl 2-phenyl-
diazoacetate in refluxing methylene chloride using
1.0 mol.% catalyst efficiently produced O-H inser-
tion products. The yields obtained were as high as 88%
(Table 1). No aromatic C-H insertion products [7] were
detected by GC when phenol was used as the substrate.
These products were readily characterized by mass spec-
Isopropanol was found to react with p-MeO-MPDA to
give a mixture of O-H insertion product 5b and C-H inser-
tion product 6b in a ratio of 6:1, respectively (Equation 2).
1 mol.%
O
O
O
O
O
O
O
OH
Fe(TPP)Cl
+
+
Aryl
Aryl
CH2Cl2
(2)
N2
Aryl
20 °C
OH
5
6
Aryl = -C6H4-p-X; X = H, Cl, Me, OMe
The O-H insertion product 5b exhibited characteristic
NMR signals for the two types of methine protons. The
isopropyl methine hydrogen appeared at 3.67 (1H, m) and
a singlet at 4.95 ppm was assigned to the methine hydro-
gen alpha to the ester group. The diastereotropic nature
of the isopropyl methyl groups is manifested by distinct
doublets at 1.24 and 1.19 ppm, each integrating as three
protons. Although it was not possible to isolate a pure
sample of the C-H insertion product, the presence of dou-
blets for the terminal CH3 proton signal at 0.96 ppm (3H)
and multiplets at 3.65 (2H) and 4.03 ppm (1H) for the
methylene and methine protons, respectively, suggested
that an insertion into the terminal C-H group occurred
to give 6b. These results illustrate that Fe(TPP)Cl is an
effective catalyst for O-H insertion reactions and is more
efficient than typical rhodium catalysts that produce lower
O-H insertion yields under similar conditions [12].
The mechanism for catalytic O-H insertion is likely to
be similar to that proposed for the analogous N-H process
[6]. This involves reaction of the iron porphyrin with the
diazo reagent to form a transient carbene complex. Sub-
sequent attack of the alcohol oxygen at the electrophilic
carbene-carbene ligand produces the insertion product. The
need to heat the O-H insertion reactions is consistent with
the lower nucleophilicity of alcohols relative to amines. In
contrast, N-H insertion reactions catalyzed by Fe(TPP)Cl
typically occurred within minutes at ambient temperature.
1
trometry and H and 13C NMR spectroscopy. For exam-
ple, methyl 2-phenoxy-2-(p-tolyl)acetate, 1a, produced
from phenol and methyl 2-(p-tolyl)-diazoacetate, gave
a characteristic methine singlet H NMR signal at 5.63
1
ppm while the methine carbon exhibited a 13C NMR sig-
nal at 78.5 ppm. Both the 1H and 13C NMR spectra were
found to match literature values [11]. This reaction was
extended to aliphatic alcohols. Treatment of ethanol with
p-MeO-MPDA in refluxing methylene chloride and 1.0
mol.% Fe(TPP)Cl produced methyl 2-ethoxy-2-(p-meth-
oxy-phenyl)acetate, 3b. This product was purified by elu-
tion through a silica gel column using 20:1 hexanes/ethyl
Table 1. Summary of catalytic reactions of para-substi-
tuted methyl 2-phenyldiazoacetate compounds with various
alcoholsa
Alcohol
MPDA p-X
Product
% yieldb
phenol
CH3-
1a
1b
2a
2b
3b
4a
5b
80
83
86
88
74
71
56c
phenol
CH3O-
CH3-
cyclohexanol
cyclohexanol
ethanol
CH3O-
CH3O-
CH3-
n-propanol
2-propanol
CH3O-
Tandem insertion/cyclization reactions
a
Conditions: CH2Cl2 used as solvent, 40 °C for 8 hours,
alcohol:diazo reagent ratio of 2:1, 1.0 mol.% Fe(TPP)
Cl catalyst. bIsolated yield. cMethyl C-H insertion product
also detected by NMR.
Ethylenediamine reacted rapidly with ethyl diazoac-
etate in the presence of 1.0 mol.% catalyst at ambient
temperature to give 2-piperazinone in yields above 80%
Copyright © 2010 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2010; 14: 285–292

286
H.M. MBUVI ET AL.
(Equation 3, Table 2). This was confirmed by the absence
of the H NMR methine signal for EDA that appears at
4.72 ppm.
in water and insoluble in organic solvents and could not
therefore be purified by silica gel chromatography. How-
ever, it was extracted from methylene chloride with a 1:1
mixture of methanol and water to give a 90% pure prod-
uct. This product exhibited a proton NMR singlet at 3.53
ppm for the two hydrogens at C3, a triplet of doublets at
3.38 ppm for the two protons at C6, and a triplet at 3.04
for the two hydrogens at C5. The amide N-H proton was
detected as a broad peak at 6.47 ppm while the amine
proton was not observed. These NMR data compare well
with spectra of other 2-piperazinone nucleoside analogs
substituted at the amine nitrogen [13].
1
1 mol.%
O
OEt
Fe(TPP)Cl
EtO
H2N
NH2
+
H
H2N
O
O
CH2Cl2
-N2
N2
+ EtOH
NH
(3)
H
N
20 °C
86%
N
H
The absence of 1H NMR signals around 4.2 (q) and 1.2 (t)
indicated that the ethyl group of the ester had been lost.
The highly polar 2-piperazinone was found to be soluble
In contrast, ethanolamine reacted with one equiv. of
EDA to give a single product, 7, that resulted from an
insertion at the amino group. Unlike
Table 2. Summary of products from 1,2-disubsituted substrates
the reaction of ethylenediamine with
EDA, this product did not undergo an
ensuing cyclization, even after reaction
times greater than one day and elevated
temperature or with added acid. This
linear product was purified by flash
column chromatography using 10:1
methylene chloride/methanol as the
eluent. No product derived from O-H
insertion was observed. This is consis-
tent with earlier observations that have
clearly shown that N-H insertion reac-
tions are more facile than O-H inser-
tions [6]. Slow addition of 2 equiv. of
EDA to ethanolamine resulted only in
maleates and fumarates as determined
by GC-MS analysis.
Substrate
Eq. EDA
Product
% yielda
86
NH2
O
H2N
HO
1
HN
NH
NH2
O
7
H
N
1
1
62
HO
OEt
OH
OH
NH
O
O
+
NH2
N
H
71 (8)
OEt
8
9
O
OH
O
O
NH2
2
42
N
OEt
Geometrically constrained 1,2-
aminoalcohols and phenylene diamines
were found to undergo partial cycliza-
tion after N-H insertion with 1 equiv.
EDA (Table 2). For example, the reac-
tion of 2-aminophenol with one equiv.
of EDA afforded a mixture of products.
The major species was a N-H insertion
product 8 which exhibited a character-
istic glycyl methylene proton singlet
at 3.91 ppm [6a]. GC-MS analysis
revealed the formation of about 10%
of another minor product. Although the
minor product could not be isolated, its
molecular ion peak of 150 m/z reflected
loss of an ethoxy group and was con-
sistent with the cyclization product 9.
When 2 equiv. of EDA were added
slowly to 2-aminophenol, three differ-
ent insertion products were detected
by GC-MS along with maleates and
fumarates. However, when the mixture
was separated by SiO2 chromatogra-
phy, cyclized product 10 was obtained
in 42% yield. Two isomers are possible
10
O
NH2
NH2
H
NH2
N
O
1
2
40 (12)
OEt
N
H
N
H
11
12
O
O
NH2
NH2
H
N
OEt
OEt
68
N
H
13
HN
O
O
H
O
OEt
N
OEt
OEt
N
0
2
88b
44c
N
14
O
H
O
Cl
Cl
NH2
N
O
Cl
N
OEt
NH2
16
Cl
O
a Typical conditions: 0.500 mmol substrate, 1.0 mol.% Fe(TPP)Cl, 5.0 mL CH2Cl2,
22 °C, stirring for 10–30 min. b Heating substrate neat for 12 h at 60 °C under N2.
c See experimental section for details.
Copyright © 2010 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2010; 14: 286–292

O-H INSERTION AND TANDEM N-H INSERTION/CYCLIZATION REACTIONS
287
O
N
O
O
The observed product 10 is most likely formed through
a double insertion at the amine nitrogen, followed by an
ensuing cyclization (Scheme 2).
O
- EtOH
a
OEt
OEt
O
O
N
H
Treatment of 1,2-phenylenediamine with one equiv.
of EDA in methylene chloride and 1.0 mol.% catalyst
afforded three products as detected by GC-MS. The two
major products had molecular ion peaks of 191 m/z, 11,
and 148 m/z, 12, in about a 3:1 ratio. The third product
was a bisinsertion product, 13, observed in small amounts.
The main product exhibited a molecular ion peak at 191
m/z, suggesting that it was a product in which one of its
amino groups has undergone a single insertion of EDA.
However, separation by silica gel chromatography using
hexane/ethyl acetate (1:1) as the eluent resulted in the
A
OEt
OH
N
O
N
O
- EtOH
b
OEt
O
O
OEt
B
OEt
O
Scheme 2.
1
for the benzomorpholinone product as shown in Scheme 2.
Pathway (a) involves a double OH/NH insertion interme-
diate and produces 3-keto product A via amine attack at
the O-bound ester. Given the lower propensity for carbene
insertion at the OH position, this is the less likely path-
way. Alternatively, 2-keto isomer B arises from phenol
attack (pathway b) at one of the N-bound diesters.
isolation of only product 12. The H NMR spectrum of
the product showed no 1H NMR peaks around 4.2 (q) or
1.2 (t), indicating that the ethyl unit of the ester group
had been lost, most likely following a cyclization path-
way similar to that involved in the reaction of ethyl-
enediamine and EDA (Equation 3). This suggested that
subsequent cyclization occurred on the column.
The structure of compound 10 was initially assigned
by a comparison of its 13C NMR spectrum with those
of two similar compounds, 2H-1,4-benzoxazin-3(4H)-
one (benzomorpholin-3-one) [14], and 3,4-dihydro-1,
4-benzoxazin-2-one (benzomorpholin-2-one) [15]. The
methylene carbon (C2) on the aliphatic ring appears at
67 ppm for the 3-keto isomer, while the methylene car-
bon (C3) on the aliphatic ring appears at 45 ppm for the
2-keto analog. In compound 10, the methylene carbon on
the aliphatic ring appears at 51 ppm. This value is more
consistent with a 2-keto product, B. The structure of
10 was confirmed spectroscopically through 2D 13C-1H
HSQC, 13C-1H HMBC, and 15N-1H HMBC experiments.
The 13C-1H HSQC showed no direct C-H couplings to
the two carbonyl peaks (169.2 and 164.3 ppm) nor to
the two aromatic carbons (141.7 and 133.4 ppm). The
13C-1H HMBC spectrum exhibited cross peaks between
the carbonyl signal at 169.2 ppm and the methylene reso-
nances at 4.01 (s, 2H) and 4.24 (q, 2H) ppm. These 2-
and 3-bond couplings definitively allow the assignment
of these signals to the carbonyl and methylene units of
the ester side chain. In addition, an HMBC cross peak
between the ring carbonyl (164.3 ppm) and the CH2 sig-
nal at 4.13 ppm (s, 2H) definitively assigned this proton
resonance to the methylene unit in the morpholinone
ring. Both methylene singlets (4.01 and 4.13 ppm) also
showed cross peaks with the quarternary aromatic carbon
at 133.4 ppm. These 3-bond correlations can only occur
with the ring junction carbon at C5 in the 2-keto structure.
It is not possible for both methylene singlets to correlate
to the same quarternary aromatic carbon in the 3-keto
isomer. Further support for the 2-keto isomer was derived
from the 15N-1H HMBC data in which the 15N resonance
(243 ppm) showed 2-bond correlations to both methylene
singlets at 4.13 and 4.01 ppm. This correlation is only
possible if both these units are adjacent to the nitrogen.
Treatment of 1,2-phenylenediamine with 2 equiv. of
EDA resulted in clean formation of product 13 in which
both the amine groups had undergone N-H insertions.
1
This double insertion product gave a four-proton H
NMR doublet at 3.90 ppm for the new methylene hydro-
gens of the two N-acetate groups. Heating solid 13 under
nitrogen at 60 °C for 12 h produced bicyclic compound
14 in an 88% isolated yield in analytically pure form. The
1
increased complexity in the H NMR spectrum relative
to that of the diester 13 indicated a reduction of symme-
try in the product. Moreover, the loss of an ethoxy group
indicated that the molecule had undergone a cyclization.
Over time, compound 14 converted to a new product
15 in solution (Equation 4). The new aromatic protons of
15 shifted strongly downfield relative to 14 by an average
of 0.7 ppm to 7.93 (1H, dd), 7.58 (1H, td), 7.39 (1H, td),
and 7.12 (1H, d). Proton signals at 4.26 (2H, q) and 1.28
(3H, t) indicated that the ethyl ester group was retained.
New downfield signals at 8.36 (1H, s) and 5.03 (2H, s)
were observed. These NMR data are consistent with qui-
noxalin-3-one structure 15, in which the imine proton is
assigned to the downfield resonance at 8.36 ppm and the
methylene protons are assigned to the 5.03 ppm singlet.
The quinoxalinone product was prepared independently
by treatment of 14 with DDQ. Heating this mixture in
benzene for 30 minutes at 60 °C resulted in clean oxida-
tion to produce 15 in a 79% isolated yield.
H
N
N
N
N
[ox]
(4)
O
O
O
O
14
15
OEt
OEt
In general, the addition of one equiv. of EDA to a
1,2-diamine or aminoalcohol substrate led to mixtures
Copyright © 2010 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2010; 14: 287–292

288
H.M. MBUVI ET AL.
that typically contained an N-H insertion product and a
subsequent partial cyclization to a piperazinone or mor-
pholinone structure. Under various conditions, it was not
possible to cleanly cyclize all of the initial N-H insertion
product. However, using 2 equiv. of EDA allowed the
isolation of a clean product as illustrated by the prepara-
tion of compounds 10 and 14. As further demonstration
of the utility of this approach, 1,2-diamino-4,5-dichlo-
robenzene was treated with 2 equiv. of EDA and 1 mol.%
Fe(TPP)Cl. The intermediate N,N′ bisinsertion product
was subsequently heated under N2 at 60 °C for 12 h to
produce cyclized, dehyrogenated imine compound 16 in
44% yield.
reagent was then added over a period of 40 minutes by
syringe pump. The mixture was then stirred until the
diazo reagent was consumed, as monitored by TLC or
GC. The products were purified using a flash column
as above.
Synthesis
Methyl 2-(p-tolyl)diazoacetate insertion with phe-
nol. The general procedure was used with methyl 2-(p-
tolyl)diazoacetate (60.8 mg, 0.320 mmol), (TPP)FeCl
(2.20 mg, 1.0 mol.%), phenol (30.0 mg, 0.320 mmol)
and 5.0 mL of methylene chloride. The mixture was
heated at reflux for 8 h. The product was purified by elut-
ing through a silica gel column using a 20:1 hexane/ethyl
acetate mixture. The product methyl 2-phenoxy-2-(4-
methylphenyl)acetate, 1a, (66.2 mg, 0.257 mmol, 80%
yield) was obtained. The proton NMR and 13C NMR
EXPERIMENTAL
Fe(TPP)Cl was obtained from Aldrich and used with-
out further purification. Substituted methyl 2-phenyl-
diazoacetates were prepared as outlined in the literature
[11]. All reactions were performed under an atmosphere
of nitrogen. Proton NMR and 13C NMR spectra were
run in CDCl3 and recorded on a Varian VXR 300 or a
Bruker DRX400 spectrometer. Two dimensional NMR
experiments were run on a Bruker 700 MHz Avance II
700 spectrometer with a Bruker Z-gradient inverse TXI
1
spectra matched literature values [11]. H NMR (400
MHz, CDCl3): δ, ppm 7.47 (d, 2H, JH = 7.9, aryl-H), 7.29
(d, 2H, JH = 7.9, aryl-H), 7.22 (d, 2H, JH = 7.9, aryl-H),
6.97 (m, 3H, aryl-H), 5.63 (s, 1H, methine C-H), 3.75
(s, 3H, OCH3), 2.37 (s, 3H, Ar-CH3). 13C NMR (100.5
MHz, CDCl3): δ, ppm 170.6, 157.4, 139.0, 132.5, 129.6,
129.5, 127.1, 121.8, 115.5, 78.5, 52.6, 21.3. MS (EI):
m/z 258 [M]+.
1
1H/13C/15N 5 mm cryoprobe at 25 °C. H NMR peak
Methyl 2-(p-methoxyphenyl)diazoacetate inser-
tion with phenol. The general procedure was used with
methyl 2-(p-methoxyphenyl)diazoacetate (65.9 mg,
0.320 mmol), (TPP)FeCl (2.20 mg, 1.0 mol.%), phenol
(30.0 mg, 0.320 mmol) and 5.0 mL of methylene chlo-
ride. The mixture was heated at reflux for 8 h. The prod-
uct was purified by eluting through a silica gel column
using a 20:1 hexane/ethyl acetate mixture. The product
methyl 2-phenoxy-2-(4-methoxyphenyl)acetate, 1b,
(72.2 mg, 0.265 mmol, 83% yield) was obtained. The
proton NMR and 13C NMR spectra matched literature
positions were referenced against residual proton reso-
nances of CDCl3 (δ, 7.27). Gas chromatographic analy-
ses were performed on a HP 5890 series II or a Finnigan
GC-MS instrument. IR data was collected on a Bruker
IFS-66V FT-IR using samples that were prepared as a
thin film on NaCl plates. Elemental analyses were per-
formed on a PerkinElmer Model 2400 CHN/S elemental
analyzer by Iowa State University Chemical Instrument
Services.
General procedure
1
values [11]. H NMR (400 MHz, CDCl3): δ, ppm 7.50
O-H insertion reactions. The alcohol (0.32–0.64
mmol) was accurately weighed, placed in a 50 mL round
bottom flask containing a stir bar and dissolved in 5.0 mL
of methylene chloride. A condenser, fitted with a rubber
septum, was attached to the flask and the contents thor-
oughly flushed with nitrogen. The catalyst (1.0 mol.%)
and 1.0 equiv. diazo reagent were added and the contents
bubbled with dry nitrogen for 5 min. The mixture was
then heated for 8 h at reflux while being stirred. The
products were purified by eluting on a flash silica gel col-
umn (4 cm diameter, 30 cm height, hexane/ethyl acetate;
20:1).
N-H insertion reactions. About 0.500 mmol of the
amine were accurately weighed, placed in a 50 mL
round bottom flask containing a stir bar and dissolved in
5.0 mL of methylene chloride. A condenser, fitted with
a rubber septum, was attached to the round bottom flask
and the contents thoroughly flushed with nitrogen. The
catalyst (1.0 mol.%) and the desired amount of the diazo
(d, 2H, JH = 8.4, aryl-H), 7.36 (d, 2H, JH = 8.4, aryl-H),
6.95 (m, 5H, aryl-H), 5.61 (s, 1H, methine C-H), 3.82
(s, 3H, ArOCH3), 3.75 (s, 3H, OCH3). 13C NMR (100.5
MHz, CDCl3): δ, ppm 170.7, 160.2, 157.3, 129.6, 128.6,
127.5, 121.8, 115.5, 114.3, 78.2, 55.4, 52.6. MS (EI): m/z
272 [M]+.
Methyl 2-(p-tolyl)diazoacetate insertion with cyclo-
hexanol. The general procedure was used with methyl
2-(p-tolyl)diazoacetate (60.8 mg, 0.320 mmol), (TPP)
FeCl (2.20 mg, 1.0 mol.%), cyclohexanol (48.0 mg, 0.480
mmol) and 5.0 mL of methylene chloride. The mixture was
heated at reflux for 8 h. The product was purified by elut-
ing through a silica gel column using a 20:1 hexane/ethyl
acetate mixture. The product methyl 2-cyclohexanoxy-2-
(4-methylphenyl)acetate, 2a, (72.2 mg, 0.276 mmol, 86%
yield) was obtained. 1H NMR (400 MHz, CDCl3): δ, ppm
7.36 (d, 2H, JH = 8.0, aryl-H), 7.17 (d, 2H, JH = 8.0, aryl-H),
5.03 (s, 1H, methine C-H), 3.71 (s, 3H, OCH3), 3.34
(m, 1H, cyclo-methine C-H), 2.35 (s, 3H, ArCH3), 1.99
Copyright © 2010 World Scientific Publishing Company
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O-H INSERTION AND TANDEM N-H INSERTION/CYCLIZATION REACTIONS
289
(m, 1H), 1.88 (m, 1H), 1.74 (m, 2H), 1.53 (m, 1H)
Methyl 2-(p-methoxyphenyl)diazoacetate inser-
tion with isopropanol. The general procedure was used
with methyl 2-(p-methoxyphenyl)diazoacetate (65.9 mg,
0.320 mmol), (TPP)FeCl (2.2 mg, 1.0 mol.%), isopro-
panol (39.4 mg, 0.640 mmol) and 5.0 mL of methylene
chloride. The mixture was heated at reflux for 8 h. The
product was purified by eluting through a silica gel col-
umn using a 20:1 hexane/ethyl acetate mixture. The prod-
uct methyl 2-isopropanoxy-2-(4-methoxyphenyl)acetate,
5b, (42.6 mg, 0.179 mmol, 56% yield) was obtained.
1H NMR (400 MHz, CDCl3): δ, ppm 7.39 (d, 2H, JH =
8.6, aryl-H), 6.89 (d, 2H, JH = 8.6, aryl-H), 4.95 (s, 1H,
methine C-H), 3.81 (s, 3H, ArOCH3), 3.71 (s, 3H, OCH3),
3.65 (m, 1H, OCH), 1.24 (d, 3H, JH = 6.2, RCH3), 1.19 (d,
3H, JH = 6.2, RCH3). 13C NMR (100.5 MHz, CDCl3): δ,
ppm 171.3, 159.4, 128.7, 115.6, 114.4, 78.2, 70.8, 55.5,
52.4, 22.4, 22.1. MS (EI): m/z 238 [M]+.
1.41 (m, 2H), 1.23 (m, 3H). 13C NMR (100.5 MHz,
CDCl3): δ, ppm 172.3, 138.3, 134.4, 129.3, 127.1, 78.0,
52.2, 32.3, 32.2, 25.7, 24.2, 21.2. MS (EI): m/z 262 [M]+.
Methyl 2-(p-methoxyphenyl)diazoacetate inser-
tion with cyclohexanol. The general procedure was used
with methyl 2-(p-methoxyphenyl)diazoacetate (65.9 mg,
0.320 mmol), (TPP)FeCl (2.20 mg, 1.0 mol.%), cyclo-
hexanol (48.0 mg, 0.480 mmol) and 5.0 mL of meth-
ylene chloride. The mixture was heated at reflux for
8 h. The product was purified by eluting through a silica
gel column using a 20:1 hexane/ethyl acetate mixture.
The product methyl 2-cyclohexanoxy-2-(4-methoxy-
phenyl)acetate, 2b, (78.3 mg, 0.282 mmol, 88% yield)
was obtained. 1H NMR (400 MHz, CDCl3): δ, ppm 7.38
(d, 2H, JH = 8.4, aryl-H), 6.89 (d, 2H, JH = 8.4, aryl-H),
5.00 (s, 1H, methine C-H), 3.81 (s, 3H, ArOCH3), 3.71
(s, 3H, OCH3), 3.32 (m, 1H, cyclo-methine C-H), 1.99
(m, 1H), 1.87 (m, 1H), 1.73 (m, 2H), 1.53 (m, 1H)
1.39 (m, 2H), 1.22 (m, 3H). 13C NMR (100.5, CDCl3):
δ, ppm 172.3, 159.7, 129.5, 128.5, 114.0, 77.6,
55.3, 52.2, 32.3, 32.2, 25.7, 24.2. MS (EI): m/z 278 [M]+.
Anal. calcd. for C16H22O4: C, 69.04; H, 7.97. Found: C,
69.70; H, 7.40.
EDA insertion with ethylenediamine. Ethylenedi-
amine (30.0 mg, 0.500 mmol) and (TPP)FeCl (3.50 mg,
1.0 mol.%) were placed in a 50 mL round bottom flask
and dissolved in 5.0 mL of methylene chloride. The mix-
ture was flushed with nitrogen and ethyl diazoacetate
(57.0 mg, 0.500 mmol), dissolved in 3.0 mL of methyl-
ene chloride, added dropwise using a syringe pump while
continuously stirring the flask contents. The reaction was
complete within 10 min. The product was extracted using
distilled water and dried under reduced pressure to obtain
Methyl 2-(p-methoxyphenyl)diazoacetate inser-
tion with ethanol. The general procedure was used with
methyl 2-(p-methoxyphenyl) diazoacetate (65.9 mg,
0.320 mmol), (TPP)FeCl (2.20 mg, 1.0 mol.%), ethanol
(29.4 mg, 0.640 mmol) and 5.0 mL of methylene chlo-
ride. The mixture was heated at reflux for 8 h. The prod-
uct was purified by eluting through a silica gel column
using a 20:1 hexane/ethyl acetate mixture. The product
methyl 2-ethoxy-2-(4-methoxyphenyl)acetate, 3b, (53.0
1
2-piperazinone (43.1 mg, 0.431 mmol, 86% yield). H
NMR (300 MHz, CDCl3): δ, ppm 6.47 (bs, 1H, NH), 3.53
(s, 2H, CH2), 3.38 (td, 2H, JH = 5.4, JH = 2.4, CH2), 3.01
(t, 2H, JH = 5.4, CH2). 13C NMR (100.5 MHz, CDCl3):
δ, ppm 170.1, 49.9, 43.0, 42.3. MS (EI): m/z 100 [M]+.
Spectral results match reported values [16].
1
mg, 0.237 mmol, 74% yield) was obtained. H NMR
EDA insertion with ethanolamine. Ethanolamine
(30.0 mg, 0.500 mmol) and (TPP)FeCl (3.50 mg, 1.0
mol.%) were placed in a 50 mL round bottom flask and
dissolved in 5.0 mL of methylene chloride. The mixture
was flushed with nitrogen, after which ethyl diazoacetate
(57.0 mg, 0.500 mmol) dissolved in 3.0 mL of methylene
chloride was added dropwise using a syringe pump while
continuously stirring the flask contents. The reaction was
done within 15 min. The product was purified by eluting
through a silica gel column using a 10:1 methylene chlo-
ride/methanol mixture. The product N-(2-hydroxyethyl)
glycine ethyl ester, 7, (45.6 mg, 0.310 mmol, 62% yield)
was obtained. 1H NMR (300 MHz, CDCl3): δ, ppm 4.21
(q, 2H, JH = 7.2, CH2), 3.63 (t, JH = 5.1, 2H, CH2), 3.44
(s, 2H, CH2), 2.82 (t, JH = 5.1, 2H, CH2), 2.14 (bs, 2H,
OH, NH), 1.29 (t, JH = 7.2, 3H, CH2). 13C NMR (100.5
MHz, CDCl3): δ, ppm 172.5, 60.8, 60.7, 51.0, 50.3, 14.1.
MS (EI): m/z 148 [M + 1]+. Spectral data matched litera-
ture values [17].
(400 MHz, CDCl3): δ, ppm 7.38 (d, 2H, JH = 8.8, aryl-H),
6.90 (d, 2H, JH = 8.8, aryl-H), 4.84 (s, 1H, methine C-H),
3.81 (s, 3H, ArOCH3), 3.72 (s, 3H, OCH3), 3.53 (m, 2H,
OCH2), 1.27 (t, 3H, JH = 8.8, CH3). 13C NMR (100.5
MHz, CDCl3): δ, ppm 170.3, 159.2, 128.8, 128.6, 114.1,
80.5, 65.1, 55.3, 52.3, 15.2. MS (EI): m/z 224 [M]+.
Methyl 2-(p-tolyl)diazoacetate insertion with
n-propanol. The general procedure was used with methyl
2-(p-tolyl)diazoacetate (60.8 mg, 0.320 mmol), (TPP)
FeCl (2.20 mg, 1.0 mol.%), n-propanol (39.7 mg, 0.640
mmol) and 5.0 mL of methylene chloride. The mixture
was heated at reflux for 8 h. The product was purified by
eluting through a silica gel column using a 20:1 hexane/
ethyl acetate mixture. The product methyl 2-propanoxy-
2-(4-methoxyphenyl)acetate, 4a, (50.4 mg, 0.227 mmol,
71% yield) was obtained. 1H NMR (400 MHz, CDCl3): δ,
ppm 7.35 (d, 2H, JH = 8.0, aryl-H), 7.18 (d, 2H, JH = 8.0,
aryl-H), 4.85 (s, 1H, methine C-H), 3.71 (s, 3H, OCH3),
3.48 (m, 1H, OCH2), 3.40 (m, 1H, OCH2), 2.35 (s, 3H,
ArCH3), 1.67 (m, 2H, CH2), 0.94 (t, 3H, JH = 7.6, CH3).
13C NMR (100.5 MHz, CDCl3): δ, ppm 171.7, 138.5,
133.8, 129.3, 127.2, 80.9, 71.5, 52.2, 22.8, 21.2, 10.5.
MS (EI): m/z 222 [M]+.
EDA reaction with 2-aminophenol (1:1). 2-amino-
phenol (54.2 mg, 0.500 mmol) and (TPP)FeCl (3.5 mg,
1.0 mol.%) were placed in a 50 mL round bottom flask and
dissolved in 5.0 mL of methylene chloride. The mixture
was flushed with nitrogen, after which ethyl diazoacetate
Copyright © 2010 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2010; 14: 289–292

290
H.M. MBUVI ET AL.
(57.0 mg, 0.500 mmol) dissolved in 3.0 mL of methylene
chloride was added dropwise using a syringe pump while
continuously stirring the flask contents. The reaction was
complete within 20 min. The products were purified by
eluting through a silica gel column using a 1:1 hexane/
ethyl acetate mixture. The product N-(2-hydroxyphenyl)
glycine ethyl ester, 8, (69.3 mg, 0.355 mmol, 71% yield)
was obtained. 1H NMR (300 MHz, CDCl3): δ, ppm 6.57–
6.86 (m, 4H, aryl-H), 4.27 (q, JH = 7.2, 2H, CH2), 3.95 (s,
2H, CH2), 1.31 (t, JH = 7.2, 3H, CH3). 13C NMR (100.5
MHz, CDCl3): δ, ppm 172.4, 153.6, 127.9, 126.4, 120.4,
116.0, 61.7, 56.4, 14.5. MS (EI): m/z 195 [M]+. Anal.
calcd. for C10H13NO3: C, 61.53; H, 6.71; N, 7.18. Found:
C, 61.02; H, 6.60; N, 6.96.
(3.50 mg, 1.0 mol.%) were placed in a 50 mL round bot-
tom flask and dissolved in 5.0 mL of methylene chloride.
The mixture was flushed with nitrogen, after which ethyl
diazoacetate (114 mg, 1.00 mmol) dissolved in 3.0 mL of
methylene chloride was added dropwise using a syringe
pump while continuously stirring the flask contents. The
reaction was finished within 20 min. The product was
purified by eluting through a silica gel column using a
1:1 hexane/ethyl acetate mixture. The product N,N-bis(2-
aminophenyl)glycine ethyl ester, 13, (95.2 mg, 0.340
1
mmol, 68% yield) was obtained. H NMR (300 MHz,
CDCl3): δ, ppm 6.82 (m, 2H, aryl-H), 6.60 (m, 2H, aryl-H),
4.26 (q, JH = 7.2, 4H, CH2), 4.09 (bt, 2H, JH = 6.0, NH),
3.90 (d, 4H, JH = 6.0, CH2), 1.31 (t, 6H, JH = 7.2, CH3). 13C
NMR (100.5 MHz, CDCl3): δ, ppm 171.3, 136.5, 120.0,
112.6, 61.2, 46.5, 14.2. MS (EI): m/z 280 [M]+. IR (NaCl):
EDA reaction with 2-aminophenol (2:1). 2-amino-
phenol (54.2 mg, 0.500 mmol) and (TPP)FeCl (3.50 mg,
1.0 mol.%) were placed in a 50 mL round bottom flask and
dissolved in 5.0 mL of methylene chloride. The mixture
was flushed with nitrogen, after which ethyl diazoacetate
(114 mg, 1.00 mmol) dissolved in 3.0 mL of methylene
chloride was added dropwise using a syringe pump while
continuously stirring the flask contents. The reaction
was finished within 30 min. The product was purified by
eluting through a silica gel column using a 1:1 hexane/
ethyl acetate mixture. The product, 10, ethyl (2-oxo-2-
,3-dihydro-4H-1,4-benzoxazin-4-yl) acetate (49.4 mg,
ν
C=O, cm-1 1741. Anal. calcd. for C14H20N2O4: C, 59.99; H,
7.19; N, 9.99. Found: C, 60.04; H, 6.91; N, 9.98.
Cyclization of diester compound 13. Upon heating
at 60 °C, under nitrogen for 12 hours, solid compound
13 (70.1 mg, 0.250 mmol) cyclized to product 14, ethyl
(2-oxo-3,4-dihydroquinoxalin-1(2H)-yl) acetate and was
1
obtained in 88% yield (51.4 mg, 0.220 mmol). H NMR
(400 MHz, CDCl3): δ, ppm 6.94 (td, 1H, JH = 8.0, JH = 1.2,
aryl-H), 6.83 (td, 1H, JH = 8.0, JH = 1.2, aryl-H) 6.73 (dd,
1H, JH = 8.0, JH = 1.2, aryl-H), 6.70 (dd, 1H, JH = 8.0, JH =
1.2, aryl-H), 4.66 (s, 2H, CH2), 4.25 (q, 2H, JH = 7.2, CH2),
4.01 (s, 2H, CH2), 3.96 (bs, 1H, N-H), 1.29 (t, 3H, JH =
7.2, CH3). 13C NMR (100.5 MHz, CDCl3): δ, ppm 168.2,
166.1, 135.5, 128.1, 123.9, 119.9, 114.5, 114.4, 61.6, 47.5,
43.7, 14.1. MS (EI): m/z 234 [M]+. IR (NaCl): νC=O, cm-1
1742, 1675. Anal. calcd. for C12H14N2O3: C, 61.53; H,
6.02; N, 11.96. Found: C, 61.50; H, 5.95; N, 11.63.
Oxidation of 14 with DDQ. Ethyl (2-oxo-3,4-di-
hydroquinoxalin-1(2H)-yl)acetate(50.2mg,0.215mmol)
and 2,3-dichloro-5,6-dicyano-p-benzoquinone (50.0 mg,
0.218 mmol) were placed in a 50 mL round bottom flask
and dissolved in 10.0 mL of benzene. The flask was then
stirred and heated at 60 °C. Complete conversion of the
starting material was seen after 30 min. The grayish pre-
cipitate that formed (DDQH2) was removed by vacuum
filtration. The desired product 15, ethyl (2-oxoquinoxal-
in-1(2H)-yl) acetate (39.3 mg, 0.169 mmol) was obtained
in 79% yield. 1H NMR (400 MHz, CDCl3): δ, ppm 8.36
(s, 1H, CH), 7.93 (dd, 1H, JH = 8.0, JH = 1.2, aryl-H),
7.58 (td, 1H, JH = 8.0, JH = 1.2, aryl-H), 7.39 (td, 1H, JH =
8.0, JH = 1.2, aryl-H), 7.12 (d, 1H, JH = 8.0, aryl-H), 5.03
(s, 2H, CH2), 4.26 (q, 2H, JH = 7.2, CH2), 1.28 (t, 3H, JH =
7.2, CH3). 13C NMR (100.5 MHz, CDCl3): δ, ppm 166.8,
154.5, 149.9, 133.4, 132.3, 131.2, 130.8, 124.1, 113.2,
1
0.210 mmol, 42% yield) was obtained. H NMR (300
MHz, CDCl3): δ, ppm 7.07 (m, 2H, aryl-H), 6.89 (td,
1H, JH = 7.8, JH = 1.5, aryl-H), 6.63 (dd, 1H, JH = 7.8,
JH = 1.5, aryl-H), 4.24 (q, 2H, JH = 7.2, CH2), 4.13 (s,
2H, CH2), 4.01 (s, 2H, CH2), 1.59 (bs, 0.4H, H2O), 1.29
(t, 3H, JH = 7.2, CH3). 13C NMR (100.5 MHz, CDCl3):
δ, ppm 169.2, 164.3, 141.7, 133.4, 125.2, 120.5, 117.2,
112.5, 61.4, 51.1, 50.8, 14.2. MS (EI): m/z 236 [M + 1]+.
Anal. calcd. for C12H13NO4·0.2 H2O: C, 60.35; H, 5.66;
N, 5.86. Found: C, 60.56; H, 5.40; N, 6.02.
EDA insertion on 1,2-phenylenediamine (1:1). 1,2-
phenylenediamine (54.4 mg, 0.500 mmol) and (TPP)
FeCl (3.50 mg, 1.0 mol.%) were placed in a 50 mL round
bottom flask and dissolved in 5.0 mL of methylene chlo-
ride. The mixture was flushed with nitrogen, after which
ethyl diazoacetate (57.0 mg, 0.500 mmol) dissolved in 3.0
mL of methylene chloride was added dropwise using a
syringe pump while continuously stirring the flask con-
tents. The reaction was complete within 20 min. The
products were purified by eluting through a silica gel
column using a 1:1 hexane/ethyl acetate mixture. The
product, 3,4-dihydroquinoxalin-2(1H)-one, 12, (29.5 mg,
0.199mmol, 40%yield)wasobtained. 1HNMR(300MHz,
CDCl3): δ, ppm 8.84 (bs, 1H, NH), 6.90 (m, 1H, aryl-H),
6.77 (m, 2H, aryl-H), 6.68 (d, 1H, JH = 7.8, aryl-H), 4.01
(s, 2H, CH2), 3.88 (bs, 1H, NH). 13C NMR (100.5 MHz,
CDCl3): δ, ppm 167.1, 133.6, 125.4, 123.9, 119.5, 115.7,
114.0, 47.1. MS (EI): m/z 148 [M]+. IR (NaCl): νC=O, cm-1
1680. Spectral results match reported values [18].
62.2, 43.1, 14.1. MS (EI): m/z 232 [M]+. IR (NaCl): νC=O
,
cm-1 1737, 1664. Anal. calcd. for C12H12N2O3: C, 62.06;
H, 5.21; N, 12.06. Found: C, 61.68; H, 5.08; N, 11.72.
EDA insertion on 4,5-dichloro-1,2-phenylene-
diamine (2:1) and cyclization. Using Schlenk techniques
under N2, Fe(TPP)Cl (1 mol.%) and 4,5-dichloro-1,2-
phenylenediamine (305 mg, 1.78 mmol) were transferred
EDA insertion on 1,2-phenylenediamine (2:1). 1,2-
phenylenediamine (54.3 mg, 0.500 mmol) and (TPP)FeCl
Copyright © 2010 World Scientific Publishing Company
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O-H INSERTION AND TANDEM N-H INSERTION/CYCLIZATION REACTIONS
291
to a 50 mL flask and 15 mL of dry, deoxygenated CH2Cl2
Tetrahedron Lett. 1974; 607. c) Hubert AJ, Noels
AF, Anciaux AJ and Teyssie P. Synthesis 1976; 600.
d) Noels AF, Demonceau A, Petiniot N, Hubert AJ
and Teyssie P. Tetrahedron 1982; 38: 2733.
3. Doyle MP, McKervey MA and Ye T. Modern Cata-
lytic Methods for Organic Synthesis with Diazo
Compounds, Wiley: New York, 1988.
was added via syringe. A 2.09 M solution of EDA (1.79
mL, 427 mg, 3.74 mmol) in dry, air-free CH2Cl2 was
added to the flask dropwise over an hour. Immediate N2
evolution was noticed as EDA was added. The reaction
was stirred for 16 h, producing three products as detected
by GC. The solution was subsequently concentrated
under vacuum and purified on a silica gel column. Unre-
acted EDA was removed with 10:1 hexane/EtOAc, and
the products eluted with 1:1. The solid double-insertion
product was dried in vacuo overnight and and converted
to the pyrazinone form by heating N2 at 60 °C for approx-
imately 12 h. The resulting brown solid was suspended in
CH2Cl2, filtered, and washed with CH2Cl2. Recrystalliza-
tion from ethyl acetate resulting in a white hydrate, 16,
containing one equiv. of water (228 mg, 44.0% yield). 1H
NMR (400 MHz, CDCl3): δ, ppm 8.33 (s, 1H, aryl-H),
8.00 (s, 1H, aryl-H), 7.20 (s, 1H, N=C-H), 4.95 (s, 2H,
N-CH2), 4.29 (q, 2H, JH = 8.0, OCH2CH3), 1.32 (t, 3H, JH
= 8.0, OCH2CH3), 1.58 (s, 2H, H2O). MS (EI): m/z 301
[M]+. Anal. calcd. for C12H10N2O3Cl2·H2O: C, 45.16; H,
3.79; N, 8.78. Found: C, 44.98; H, 2.91; N, 8.59.
4. a) Heslin JC and Moody CJ. J. Chem. Soc., Perkin
Trans. 1 1988; 1417. b) Moody CJ and Taylor RJ.
J. Chem. Soc., Perkin Trans. 1 1989; 721. c) Davies
MJ, Heslin JC and Moody CJ. J. Chem. Soc., Perkin
Trans. 1 1989; 2473. d) Davies MJ, Moody CJ and
Taylor RJ. J. Chem. Soc., Perkin Trans. 1 1991; 1.
e) Davies MJ and Moody CJ. J. Chem. Soc., Per-
kin Trans. 1 1991; 9. e) Moody CJ, Sie E-RHB and
Kulagowski JJ. Tetrahedron 1992; 48: 3991. f) Cox
GG, Kulagowski JJ, Moody CJ and Sie E-RHB.
Synlett 1992; 975. g) Cox GG, Moody CJ, Aus-
tin DJ and Padwa A. Tetrahedron 1993; 49: 5109.
h) Moody CJ, Sie E-RHB and Kulagowski JJ. J.
Chem. Soc., Perkin Trans. 1 1994; 501. i) Cox GG,
Miller DJ, Moody CJ, Sie E-RHB and Kulagowski
JJ. Tetrahedron 1994; 50: 3195. j) Cox GG, Haigh
D, Hindley RM, Miller DJ and Moody CJ. Tetrahe-
dron Lett. 1994; 35: 3139.
CONCLUSION
5. a) Moyer MP, Feldman PL and Rapoport H. J.
Org. Chem. 1986; 50: 5223. b) Brunner H, Wutz
K and Doyle MP. Monatsh. Chem. 1990; 121: 755.
c) Cama LD and Christensen BG. Tetrahedron Lett.
1978; 44: 4233. d) Salzmann, TN, Ratcliffe RW,
Christensen BG and Bouffard FA. J. Am. Chem.
Soc. 1980; 102: 6161. e) Mastalerz H and Menard
M. J. Org. Chem. 1994; 59: 3223. f) Bouthillier
G, Mastalerz H and Menard M. Tetrahedron Lett.
1994; 35: 4689.
6. a) Baumann LK. M.S. Thesis, Iowa State
University, Ames, IA, 2005. b) Baumann LK,
Mbuvi HM, Du G and Woo LK. Organometallics
2007; 26: 3995. c) Aviv I and Gross Z. Synlett 2006;
951.
Fe(TPP)Cl is an effective catalyst for the O-H inser-
tion reactions of alcohols when substituted MPDAs are
used as carbene sources. Aromatic and normal aliphatic
alcohols gave O-H insertion as the only product. Treat-
ment of isopropanol with p-MeO-MPDA and Fe(TPP)Cl
yielded O-H insertion as the major product and a minor
C-H insertion at the terminal position. This catalyst was
also found to be very efficient in the syntheses of 2-pip-
erazinone and 2-morpholinone through a tandem N-H
insertion/cyclization process using EDA as the carbene
source. The tandem N-H insertion/cyclization process
provides an easy one-pot procedure for the syntheses of
novel piperazinones and their substituted analogs.
Acknowledgements
7. Mbuvi HM and Woo LK. Organometallics 2008;
27: 637.
8. Elmaleh DR, Songwoon C and Fischman AJ. U.S.
Patent 7 381 822, 2008.
9. DeFrees S, Zopf D, Bayer R, Bowe C, Hakes D and
Chen X. U.S. Patent Appl. Publ., 2005.
10. a) Zagnoni G, Andrews SM, Lazzari D, Rossi M,
Zedda A and Borzatta V. U.S. Patent 6 596 461,
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H. U.S. Patent 5550131, 1996. c) Tamura N and
Terashita Z. U.S. Patent 6242600, 2001.
11. Maier TC and Fu GC. J. Am. Chem. Soc. 2006; 128:
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12. a) Aller E, Cox GG, Miller DJ and Moody CJ. Tet-
rahedron Lett. 1994; 35: 5949. b) Aller E, Brown
DS, Cox GG, Miller DJ and Moody CJ. J. Org.
Chem. 1995; 60: 4449.
We thank the National Science Foundation for partial
support of this work.
Supporting information
Supplementary NMR data (Figs S1–S15) are given
in the supplementary material. This material is available
free of charge via the Internet at http://www.worldscinet.
com/jpp/jpp.shtml.
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