Exploring the synthetic versatility of the lewis acid induced decomposition reaction of α-diazo-β-hydroxy esters. the case of ethyl diazo(3-hydroxy-2-oxo-2,3-dihydro-1 H-indol-3-yl)acetate

Article abstract of DOI:10.1021/jo201205u

Ethyl diazo(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate was prepared by aldol-type condensation of ethyl diazoacetate with isatin. A systematic and mechanistic study on the Lewis acid induced decomposition reaction of this valuable diazo precursor w

Full text of DOI:10.1021/jo201205u

ARTICLE
pubs.acs.org/joc
Exploring the Synthetic Versatility of the Lewis Acid Induced
Decomposition Reaction of r-Diazo-β-hydroxy Esters. The Case of
Ethyl Diazo(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate
Antimo Gioiello, Francesco Venturoni, Maura Marinozzi, Benedetto Natalini, and Roberto Pellicciari*
Dipartimento di Chimica e Tecnologia del Farmaco, Universitꢀa di Perugia, Via del Liceo 1, 06123 Perugia, Italy
S Supporting Information
b
ABSTRACT:
Ethyl diazo(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate was prepared by aldol-type condensation of ethyl diazoacetate with
isatin. A systematic and mechanistic study on the Lewis acid induced decomposition reaction of this valuable diazo precursor was
carried out with the aim to gain new insights into the mechanistic aspects of the reaction as well as to further understand the factors
and experimental conditions which affect the relative product distribution. The reaction, which may proceed via cationic and
noncationic mechanisms, was found to be significantly influenced by the reaction environment determined by the characteristics of
the Lewis acid employed, by the ability of the Lewis acid to form a complex with the alcohol functionality of the R-diazo-β-hydroxy
ester, and by the polarity and nucleophilicity of the solvent used.
Scheme 1. General Scheme for BF3 OEt2-Induced Decom-
position of r-Diazo-β-hydroxy Esters 3a,b
’ INTRODUCTION
3
One of the main challenges for synthetic chemists is related to
the development and implementation of efficient methodologies
for the preparation of complex scaffolds and intermediates of
biologically relevant compounds. Among the chemical transfor-
mations that exemplify innovative and flexible methods, the
Lewis acid promoted reaction of R-diazo esters has attracted
great attention because of their wide range of synthetic applica-
tions in both organic and medicinal chemistry.1
corresponding acylacetylene derivatives 4 in good yield.3
This procedure, which proceeds by the extrusion of molecular
nitrogen, was successfully applied to the synthesis of biologically
active terpenes.3
In this framework, we have investigated the potentiality
associated with the use of R-diazo-β-hydroxy esters as synthetic
precursors and defined the structural and experimental para-
meters which influence product types and ratios.2 An important
contribution to the development of synthetically useful reactions
came from the employment of boron trifluoride etherate
Notably, exposure to BF3 OEt2 of R-diazo-β-hydroxycarbo-
3
nyl compounds derived from ketones 3b was shown to afford
an array of diverse products (Scheme 1). In particular, using
acetonitrile as the solvent of the reaction, R- and β-enamino
esters were obtained as the final compounds with diverse
(BF3 OEt2) as the Lewis acid. We have shown, in particular,
3
that the reaction of BF3 OEt2 with R-diazo-β-hydroxy esters 3a,
3
b generated a variety of products as the result of carbenium
ion rearrangement and solvent trapping (Scheme 1).2b,c Thus,
the reaction of acyclic compounds of type 3a (R2 = H) with
Received: June 10, 2011
Published: July 29, 2011
BF3 OEt2 in a polar solvent such as acetonitrile furnished the
3
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
ARTICLE
Scheme 2. BF3 OEt2-Induced Decomposition of r-Diazo-β-
Scheme 4. Reactions of Isatin Derivatives with Diazo-
methane and Ethyl Diazoacetate
3
hydroxy Esters 5, 8, and 10 in Acetonitrile
Scheme 3. Synthesis of Ethyl Diazo(3-hydroxy-2-oxo-2,3-
dihydro-1H-indol-3-yl)acetate (14)
and diazoarylalkanes,6 furnished 2-quinolinones by ring expan-
sion of the diazo carbinol intermediate 16 (Scheme 4a). In a later
study, Kennewell and co-workers observed different results using
2-alkyloxyindol-3-ones as starting materials.7 In particular, they
found that N-methylisatin (18) reacted with a slight excess
(1.07 equiv) of diazomethane to produce hydroxyquinoline 19
in 74% yield. On the other hand, when an excess of diazomethane
was used, the epoxide 21 was isolated along with 2-quinolinones
19 and 20 (Scheme 4b). Rather less investigated are the C-3
additions of diazo carbonyl compounds. The few examples
reported by Eistert concerned the reaction of ethyl diazo(3-
hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate (14) with hy-
drochloric acid (or a catalytic amount of zinc chloride) to afford
ethyl 3-hydroxy-2-oxo-1,2-dihydroquinoline-4-carboxylate (22),
in 86% yield (Scheme 4c).8
Despite the great potential of this approach in the preparation
of 2-quinolinone derivatives, to date its employment is quite
limited and has been scarcely explored. Since the mechanism
proposed for this process involves a vinyl cation intermediate,
we decided to extend the understanding of the decomposition
pathways of ethyl diazo(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-
3-yl)acetate (14) as well as to further demonstrate its synthetic
versatility. The effects of both Lewis acid and solvent in the
product distribution, as well as the mechanistic aspects of the
reactions, are herein described.
regioselectivity. For instance, the treatment of ethyl 2-diazo-2-
(1-hydroxycyclopentyl)acetate (5) with freshly distilled BF3 OEt2
3
in acetonitrile gave the R-acetylamino-cyclopentylidenyl carbox-
ylate 6 and β-acetylamino-cyclohexenyl carboxylate 7 in 55%
and 6% yields, respectively.2b Moreover, the reaction of acyclic
R-diazo-β-hydroxyacyl methanes 8 and 10 with BF3 OEt2 in
3
acetonitrile afforded β-enamine derivatives 9, 11, and 12 as the
major products in good yields (Scheme 2).2b,c
These results have not only been instrumental for the devel-
opment of new synthetic methodologies but have also provided
new insights into the mechanistic aspects of the reaction as well
as a further understanding of the factors and experimental
conditions which govern the product formation and their relative
distribution. As an expansion of the aim and applications of this
reaction, herein we report a detailed investigation on experi-
mental parameters along with a survey of the reaction scope
with respect to ethyl diazo(3-hydroxy-2-oxo-2,3-dihydro-1H-
indol-3-yl)acetate (14), prepared from the reaction of isatin
(13) with ethyl diazoacetate (EDA, 15) in the presence of
Et2NH (Scheme 3).8b
’ RESULTS AND DISCUSSION
Ethyl diazo(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate
(14) was prepared as previously described (Scheme 3).8b Initially,
we examined the BF3 Et2O-promoted decomposition reaction
3
of 14 in acetonitrile. Thus, a solution of 14 (3.7 ꢀ 10ꢁ2 M in
’ BACKGROUND
Isatin (13) and its derivatives are synthetically useful sub-
strates for the preparation of several heterocyclic compounds
endowed with biological and pharmacological interest.4 The
presence of several reaction centers makes them suitable for
various types of reactions, including reduction and oxidation of
the heterocyclic ring, nucleophilic addition at the C-3 position,
nucleophilic substitution at the C-2 position, and N-alkylation
and -acylation, as well as Mannich and Michael reactions and
benzene electrophilic substitutions.
acetonitrile) was added by syringe pump (0.02 mmol/min) to an
acetonitrile solution of BF3 Et2O (1.5 equiv), at room tempera-
3
ture, to furnish three compounds in a 4:40:56 ratio, as evidenced by
HPLC analysis of the crude reaction mixture (Table 1, entry a).
The products were purified by silica gel flash chromatography and
characterized by mono- and bidimensional NMR spectroscopy. In
addition to ethyl 3-hydroxy-2-oxo-1,2-dihydroquinoline-4-carbox-
ylate (22) and ethyl 3-acetylamino-2-oxo-1,2-dihydroquinoline-4-
carboxylate (23a), obtained in 2% and 40% yields, respectively, the
unexpected ethyl (2-aminophenyl)propynoate (24)9 was formed
as the major product of the reaction in 51% yield.
Among C-3 nucleophilic additions, it was shown that the
reaction of isatin (13) with diazoalkanes, such as diazomethane5
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Table 1. Decomposition of Ethyl Diazo(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate (14) with Different Lewis Acidsa
ARTICLE
entry
Lewis acid
product ratio (%)b 22:23a:24
a
b
c
d
e
f
BF3 Et2O
4:40:56
100:0:0
100:0:0
100:0:0
100:0:0
100:0:0
99:0.5:0.5
95:3:2
3
SnCl2
Mg(ClO4)2
Zn(OTf)2
ZnCl2
ZnBr2
g
h
i
InBr3
InCl3
In(OTf)3
Yt(OTf)3
Al(OTf)3
Sc(OTf)3
SnCl4
82:9:9
l
65:17:18
43:26:31
39:28:33
0:40:60
m
n
o
a Conditions: solvent CH3CN, addition rate 0.02 mmol/min. b Ratios determined by HPLC analysis of the crude reaction mixture.
Table 2. BF3 Et2O-Promoted Decomposition of Ethyl Diazo(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate (14) in
3
Various Solventsa
entry
solvent
products (amt (%))b
isolated products (amt (%))c
a
b
c
d
e
f
CH3CN
CH3CH2CN
ClCH2CN
CH2Cl2
CH2Br2
C6H6
22 (4), 23a (40), 24 (56)
22 (5), 23b (37), 24 (58)
22 (4), 23c + 23d (44), 24 (52)
22 (34), 23d (24), 24 (52)
22 (52), 23e (14), 24 (33)
22 (58), 23f (10), 24 (23), 25 (9)
22 (100)
23a (40), 24 (51)
23b (38), 24 (39)
23c (34), 23d (9), 24 (42)
23d (15), 24 (40)
23e (12), 24 (20)
23f (8), 24 (26), 25 (3)
g
MeOH
a Conditions: 1.5 equiv of BF3 Et2O, addition rate 0.02 mmol/min. b Determined by RP-HPLC analysis of the crude reaction mixture. c Isolated yield
3
after flash chromatography; 22 was not isolated.
It should be noted, in this regard, that the product ratio was
strongly dependent on the experimental protocol used. As an
the β-enol ester 22 (Table 1, entries bꢁf), which was the main
product of the reaction also with InBr3, InCl3, In(OTf)3, and
Yt(OTf)3 (Table 1, entries gꢁl). In the case of Al(OTf)3 and
Sc(OTf)3 catalysis (Table 1, entries m and n), although 22 was
still the main product, 23a and 24 notably increased, while with
the use of SnCl4, 22 was absent and only the two products 23a
and 24 were formed (Table 1, entry o).
example, when BF3 Et2O was added to an acetonitrile solution
3
of 14, the reaction afforded the quinolinone derivative 22 as the
sole product of decomposition (97% HPLC yield), following a
mechanism similar to the Lewis acid (catalytic) induced decom-
position reaction.8
The reaction was then repeated in the presence of different
Lewis acids (Table 1). Various trends could be discerned
according to the Lewis acid employed. In particular, in the
presence of stoichiometric amounts of SnCl2, Mg(ClO4)2, Zn-
(OTf)2, ZnCl2, and ZnBr2, the reaction furnished quantitatively
Subsequently, BF3 Et2O was selected to investigate the effect
3
of different reaction solvents (Table 2). As previously observed in
the case of acetonitrile (Table 2, entry a), the reaction of 14 in
polar solvents, such as propionitrile and chloroacetonitrile,
results in the formation of the acetylene derivative 24 as the
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ARTICLE
Scheme 5. Proposed Mechanism for Ethyl Diazo(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate (14) Decomposition
Reactions
major product together with the corresponding solvent-addition
products 23b,c and minor amounts of 22 (Table 2, entries b
and c). Unexpectedly, by using chloroacetonitrile, ethyl 3-chloro-
2-oxo-1,2-dihydroquinoline-4-carboxylate 23d was also obtained
in 9% yield after silica gel flash chromatography.10 Likewise, 23d
was obtained along with the acetylene 24 and the β-enol ester 22,
when the reaction was performed in dichloromethane (Table 2,
entry d). However, with a variation in product ratio, a mixture
of three compounds was obtained by using dibromomethane as
solvent (Table 2, entry e). In this case, the compound derived
from bromine addition, 23e, was isolated in 12% yield. Exposure
In particular, analogously to our previous reports,2b,c in
the case of “hard” Lewis acids such as BF3 Et2O and SnCl4
3
(Table 1, entries a and o), a cationic cascade mechanism which
nicely accommodates the products formed can be proposed
(Scheme 5). The first step of the reaction consists of the
complexation of the hydroxy group of the R-diazo-β-hydroxy
ester 14 with the Lewis acid, followed by the generation of the
diazonium salt 27a (Scheme 5, path a). The loss of nitrogen
produces the highly destabilized linear vinyl cation 29, which
apparently was not trapped by the solvent. Instead, ring expan-
sion of the cation 29 via a 1,2-aryl shift is a fast process and the
resulting vinyl cation 30 is trapped by the solvent to afford pro-
ducts 23aꢁg or, to a lesser extent, by the Lewis acid coordinated
hydroxyl group to give the β-enol ester 22 (Scheme 5).
of 14 to BF3 Et2O in benzene afforded a mixture of four
3
components, including the β-enol ester 22 and the propynoate
24 as the main products (Table 2, entry f). The two new minor
compounds were characterized, after isolation by flash chroma-
tography, as the expected ethyl 3-phenyl-2-oxo-1,2-dihydroqui-
noline-4-carboxylate (23f, 8% yield) and the unexpected
symmetric urea derivative 25 (Scheme 5), whose structure
was unambiguously determined by HRMS and NMR analysis.
Finally, the decomposition reaction of 14 in methanol gave ethyl
3-hydroxy-2-oxo-1,2-dihydroquinoline-4-carboxylate (22) as the
single product (Table 2, entry g).
The formation of the acetylene 24 is consistent with path b
depicted in Scheme 5. In accord with a recent work,11 we
hypothesize that, as dinitrogen leaves, lone pair donation from
the γ-nitrogen atom of 27a or from the γ-oxygen of 27b would
lead to CβꢁCγ bond cleavage, resulting in the highly reactive
isocyanate 28, which finally affords the propynoate 24 by
water addition/decarboxylation (Scheme 5, path b). To validate
this hypothesis, the BF3 Et2O-induced decomposition of 14 was
3
quenched with diverse alcohols, including methanol, ethanol,
and tert-buttl alcohol (Scheme 5). The isolation of ethyl
(2-methoxycarbonylaminophenyl)propynoate (31a, 46%), ethyl
(2-ethoxycarbonylaminophenyl)propynoate (31b, 46%), and
ethyl (2-tert-butoxycarbonylaminophenyl)propynoate (31c,12
36%) clearly supported the synthetic pathway for 24 formation.
Reaction Mechanism and Possible Role of Lewis Acid
and Solvent. The results reported in Table 1 suggest that
the decomposition reaction of ethyl diazo(3-hydroxy-2-oxo-
2,3-dihydro-1H-indol-3-yl)acetate (14) can follow both cationic
and noncationic mechanisms according to the Lewis acid
employed.
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ARTICLE
Table 3. Relation between SdP Values and Solvent Adduct
Yields18
Scheme 6. Proposed Mechanism for the Formation of the
Solvent Trapping Products
solvent adduct
yield (%)a
solvent
SdP17
23c + 23d
23a
44
40
37
24
10
ClCH2CN
CH3CN
CH3CH2CN
CH2Cl2
1.024
0.974
0.888
0.769
0.270
23b
23d
23f
C6H6
a Determined by RP-HPLC analysis of the crude mixture.
In the case of weaker Lewis acid media (Table 1, entries bꢁi),
the reaction may not go through a cationic process and instead
undergoes via concerted 1,2-aryl migration followed by dinitro-
gen release compound 22 as the only or major product of
the reaction (Scheme 5, path c). Thus, when the Lewis acid is
moderately strong or the reaction conditions provide a moder-
ately strong Lewis acid environment, the decomposition reac-
tion of 14 furnishes a mixture of 22, 23a, and 24 (Table 1,
entries lꢁn).
In addition, although there is no clear logical connection
between Lewis acid parameters and the results summarized in
Table 1, it can be then assumed that the percentage of the β-enol
ester 22 formed in the course of the reaction is inversely
proportional to the ability of the Lewis acid to form a stable
complex with the hydroxy group of the R-diazo-β-hydroxy ester
14.13 Indeed, according to the proposed mechanism depicted in
The double site of addition of chloroacetonitrile furnishes the
two products of solvent addition 23c,d, with the percentage
probably dependent on the diverse nucleophilic properties of
the nitrile group and chlorine atom (Scheme 6). Methanol is
not considered here because it follows a different reaction
mechanism. Indeed, in the case of methanol, the addition of
BF3 Et2O leads first to the formation of [BF3 OMe]ꢁH+, which
represents the effective reactant that promotes the decomposi-
tion of 14. Thus, as in the proton-induced decomposition, the
reaction in methanol affords the β-enol ester 22 as the exclusive
product.8
Scheme 5 (path a), BF3 Et2O and SnCl4, which are considered
3
“hard” Lewis acids,14 are able to remove the hydroxy group
from the R-diazo-β-hydroxy ester 14, resulting in the relatively
stable [LAꢁOH]ꢁ. The stability of the complexes, which may
correlate with the HSAB principle,14 favors path b, namely
solvent addition and CβꢁCγ bond cleavage, and hampers the
formation of 22.
3
3
In addition to the role played by the Lewis acid, an analysis of
the results obtained in Table 2 clearly indicates that the product
type and ratio are greatly influenced also by the solvent employed
in the decomposition reaction. Several studies have already
refined the physical role played by the solvent in the transition-
state stabilization of solvolysis reactions.15 It has been proposed,
in particular, that the mechanism for solvolysis of tertiary carbon
centers depends on two physically diverse interactions of nu-
cleophilic solvents with the developing carbocation in the
transition state: nucleophilic solvent participation (NSP), repre-
senting a reaction without a carbocation intermediate, and
nucleophilic solvation (NS), which represents transition state
stabilization for stepwise solvolysis through carbocation or ion
pair intermediates by chargeꢁdipole interactions.16 According to
these considerations, it can be supposed that the solvent para-
meters which could influence the ratio of the products should be
related to the solvent (di)polarity and to the stabilizing interac-
tions between the dipole of the solvent and the vinyl cation 30.
As shown in Table 3, the formation of the solvent adducts 23aꢁf
is favored with higher solvent dipolarity parameter (SdP)
values,17 suggesting that the relative product ratio can be affected
by dipolar interactions between 30 and the solvent.
’ CONCLUSIONS
In conclusion, we have reported a systematic study of the
Lewis acid mediated decomposition reaction of ethyl diazo-
(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate (14) in differ-
ent solvents. The reaction, which proceeds via cationic and
noncationic pathways, leads to a diversity of products according
to the Lewis acid and the solvent used. The products and the
related mechanism by which they are formed are indeed sig-
nificantly influenced by several factors: (a) the reaction environ-
ment (strong Lewis acid median favors the cationic process),
(b) the Lewis acid's ability to form a stable complex with the
hydroxy group of 14 (a strong interaction enables the rearrange-
ment of the vinyl cation and the trapping of the solvent), (c) the
polarity of the solvent (polar solvents stabilize the rearranged
vinyl cation), and (d) the nucleophilicity of the solvent
(nucleophilic solvents favor the solvent adduct formation). We
think that the decomposition reaction of ethyl diazo(3-hydroxy-
2-oxo-2,3-dihydro-1H-indol-3-yl)acetate (14) represents a rich
source of useful intermediates and gives easy access to privileged
structures, such as 3-substituted ethyl 2-oxo-1,2-dihydroquino-
line-4-carboxylates, structural frameworks of many natural
compounds and drugs, as well as ynoate isocyanate, a crucial
precursor of o-aminophenylpropynoic acid derivatives.
Thus, polar and nucleophilic solvents, such as nitriles, result in
a strong stabilization of the vinyl cation 30 and afford 23 as the
main product of the reaction, while in contrast, the relatively
lower polarity of dichloromethane, dibromomethane, benzene,
and anisole favors the reaction of 30 with [BF3 OH]ꢁ.
3
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ARTICLE
’ EXPERIMENTAL SECTION
Ethyl 3-Hydroxy-2-oxo-1,2-dihydro-quinoline-4-carboxy-
late (22):8 obtained as a pure white solid. Data were consistent with
previous literature data.
General Methods. 1H NMR spectra were recorded at 200 and 400
MHz, and 13C NMR spectra were recorded at 100.6 and 50.3 MHz using
the solvents indicated below. Chemical shifts are reported in ppm.
The abbreviations used are as follows: s, singlet; d, doublet; dd, doublet
of doublets; ddd, doublet of doublets of doublets, dddd, doublet of
doublets of doublets of doublets, t, triplet, dt, doublet of triplets, qt,
quartet of triplets, bs, broad signal. The final products were purified by
flash chromatography on silica gel (0.040ꢁ0.063 mm). TLC was
performed on aluminum-backed silica plates (silica gel 60 F254). All
the reactions were performed under a nitrogen atmosphere using
distilled solvent. The HPLC analytical-scale experiments were carried
out on a LC-Workstation Class LC-10 equipped with a SCL-10 A VP
system controller, a LC-10AT VP high-pressure binary gradient delivery
system, an SPD-10A VP variable-wavelength UVꢁvis detector, and
a Rheodyne 7725i injector with a 20 μL stainless steel loop. The
chromatographic profile was obtained with EZ Start software. All
analytical runs were performed by employing a H2O/MeCN/H3PO4
(50/50/0.025 v/v/v) solution as the mobile phase. HPLC-grade water
was obtained from a tandem Milli-Ro/Milli-Q apparatus. An Ultra
Aqueous C18 250 ꢀ 4.6 mm i.d. 5 μm 100 Å analytical column was
used after previous conditioning by passing through the column the
selected mobile phase for at least 30 min. The UV detection wavelengths
were set at 254 and 268 nm. Samples for the analytical-scale analyses
were preparedin approximate concentrations between0.1and 0.5 mg/mL
in filtered mobile phase components and sonicated until completely
dissolved. The method EVAL (furnished with the software Enhanced
ChemStation Agilent Technology) was used to generate the gradient
temperature in the GC-MS analysis.
Ethyl Diazo(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-
acetate (14).8. Ethyl diazoacetate (15; 42 mL, 360 mmol) and
diethylamine (3 mL) were added to a stirred solution of isatin (3;
15 g, 120 mmol) in absolute ethanol (400 mL). After 3 days the solvent
was evaporated and the crude product was triturated with benzene and
filtered to give pure ethyl diazo(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-
3-yl)acetate (14) in 80% yield (25 g; 96 mmol). Compound 14 was
obtained as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 1.19 (t, 3H,
J = 7.4 Hz), 4.15 (m, 2H), 4.75 (brs, 1H), 6.86 (d, 1H, J = 7.8 Hz), 7.01
(t, 1H, J = 7.8 Hz), 7.25 (t, 1H, J = 7.8 Hz), 7.43 (d, 1H, J = 7.8 Hz), 8.39
(br, 1H); 13C NMR 14.1, 61.2, 71.6, 110.9, 123.4, 124.8, 128.6, 130.7,
140.8, 165.3, 177.5.
Ethyl 3-(Acetylamino)-2-oxo-1,2-dihydroquinoline-4-car-
boxylate (23a): obtained in 40% yield (121 mg, 0.44 mmol) as yellow
pure solid; mp 204ꢁ206 °C; 1H NMR (400 MHz, CDCl3, CD3OD) δ
1.36 (t, 3H, J = 4.6 Hz), 1.39 (t, 3H, J = 7.1 Hz), 4.48 (q, 2H, J = 7.2 Hz),
6.86 (d, 1H, J = 7.8 Hz), 6.94 (dt, 1H, Jd = 0.9 Hz, Jt = 7.7 Hz), 7.16 (m,
2H); 13C NMR (100 MHz, CDCl3, CD3OD) δ 13.7, 23.4, 62.8, 106.0,
110.3, 120.3, 120.8, 122.3, 128.3, 137.0, 138.9, 163.2, 168.4, 170.8;
GC-MS Rt = 25.784 min, m/z 103 (28), 132 (25), 133 (13), 158 (72),
159 (48), 160 (33), 232 (100), 233 (14), 274 (26); HRMS (+ES) m/z
calcd for C14H15N2O4 275.1032, found 275.1035.
Ethyl 2-Oxo-3-(propionyloamino)-1,2-dihydroquinoline-
4-carboxylate (23b): obtained in 38% yield (120 mg, 0.417 mmol)
as yellow pure solid; mp 214ꢁ217 °C; 1H NMR (400 MHz, CDCl3) δ
1.28 (t, 3H, J = 7.5 Hz), 1.45 (t, 3H, J = 7.2 Hz), 2.54 (q, 2H, J = 7.5 Hz),
4.56 (q, 2H, J = 7.2 Hz), 6.92 (d, 1H, J = 7.8 Hz), 7.02 (dt, 1H, Jd = 0.9
Hz, Jt = 7.7 Hz), 7.22 (dt, 1H, Jd = 1.1 Hz, Jt = 7.7 Hz), 7.26 (d, 1H, J = 7.8
Hz), 8.27 (s, 1H), 11.65 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 8.9,
13.9, 29.9, 62.8, 110.1, 120.7, 121.0, 122.6, 128.1, 137.9, 138.1, 163.2,
170.7, 171.9; GC-MS Rt = 26.466 min, m/z 57 (19), 103 (20), 132 (16),
158 (51), 159 (33), 160 (26), 232 (100), 233 (15), 288 (23); HRMS
(+ES) m/z calcd for C15H16N2O4Na 311.1008, found 311.1007.
Ethyl 2-Oxo-3-(chloroacetyl)amino-1,2-dihydroquinoline-
4-carboxylate (23c): obtained in 34% yield (115 mg, 0.373 mmol) as
yellow pure solid; mp 210ꢁ211 °C; 1H NMR (400 MHz, CDCl3) δ 1.44
(t, 3H, J = 7.1 Hz), 4.23 (s, 2H), 4.55 (q, 2H, J = 7.2 Hz), 6.92 (d, 1H, J =
7.8 Hz), 7.04 (dt, 1H, Jd = 1.0 Hz, Jt = 7.7 Hz), 7.24 (dd, 1H, J = 1.1, 7.8
Hz), 7.27 (m, 1H) 7.96 (br s, 1H), 12.48 (br s, 1H); 13C NMR (100 MHz,
CDCl3) δ 13.8, 42.2, 63.0, 107.7, 110.2, 120.2, 121.5, 122.7, 128.9, 136.2,
138.6, 162.7, 164.8, 170.2; GC-MS Rt =27.971min, m/z 77 (17), 103 (44),
132 (29), 158 (93), 159 (60), 160 (34), 207 (73), 232 (100), 308 (43);
HRMS (+ES) m/z calcd for C14H14N2O4Cl 309.0642, found 309.0640.
Ethyl 3-Chloro-2-oxo-1,2-dihydroquinoline-4-carboxylate
(23d): obtained in 15% (42 mg, 0.166 mmol) and 9% yield (25 mg,
0.10 mmol) as yellow pure solid; mp 139ꢁ141 °C; 1H NMR (400 MHz,
CDCl3) δ 1.44 (t, 3H, J = 7.1 Hz), 4.50 (q, 2H, J = 7.1 Hz), 6.91 (d, 1H,
Jd = 7.8 Hz), 7.00 (dt, 1H, Jd = 0.9 Hz, Jt = 6.8 Hz), 7.30 (dt, 1H, Jd = 1.0
Hz, Jt = 7.7Hz), 7.44 (d, 1H, J = 7.8Hz); 13C NMR(100MHz, CDCl3) δ
14.0, 63.3, 110.2, 120.1, 122.4, 123.8, 126.4, 128.8, 131.3, 140.1, 163.2,
166.7; GC-MS Rt = 23.880 min, m/z 89 (20), 114 (31), 116 (24), 125
(10), 144 (99), 150 (69), 152 (22), 170 (59), 172 (19), 179 (57), 181
(17), 188 (21), 206 (37), 251 (100), 253 (35); HRMS (+ES) m/z calcd
for C12H11NO3Cl 252.0427, found 252.0420.
Caution! Diazo compounds may be explosive and should be handled
with care. Storage at ꢁ4 °C under an argon atmosphere is strongly
recommended.
Ethyl 3-Bromo-2-oxo-1,2-dihydroquinoline-4-carboxylate
(23e): obtained in 12% yield (39 mg, 0.133 mmol) as yellow pure solid;
mp 149ꢁ150 °C; 1H NMR (400 MHz, CDCl3) δ 1.44 (t, 3H, J = 7.1
Hz), 4.50 (q, 2H, J = 7.1 Hz), 6.90 (psdt, 1H, Jt = 0.7Hz, Jd = 7.7 Hz), 7.00
(dt, 1H, Jd = 1.0 Hz, Jt = 7.8 Hz), 7.32 (m, 2H), 8.20 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 13.9, 63.2, 110.1, 117.8, 120.8, 122.5, 123.3, 127.5,
131.2, 139.5, 164.2, 166.5; GC-MS Rt = 23.707 min, m/z 62 (22), 88
(42), 116 (64), 144 (82), 170 (91), 172 (100), 194 (41), 196 (38), 223
(23), 225 (22), 250 (28), 252 (28), 295 (85), 297 (87); HRMS (+ES)
m/z calcd for C12H11NO3Br 295.9922, found 295.9929.
General Method for Decomposition of 14. Method A. A
solution of ethyl diazo(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate
(14; 1.11 mmol) in 30 mL of freshly distilled solvent was added at room
temperature by syringe pump (0.02 mmol/min) to a magnetically stirred
solution of Lewis acid (1.66 mmol) in 5 mL of freshly distilled solvent.
At the end of the addition, the reaction mixture was stirred for 30 min
at room temperature (quenched with the appropriate alcohol, for the
preparation of derivatives 31aꢁc) and then poured into a saturated
solution of NaHCO3 (75 mL), extracted with EtOAc (Table 2, entries 1,
2, 6, and 7) or DCM (Table 2, entries 3 and 4) (3 ꢀ 25 mL), dried over
Na2SO4, filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography.
Method B. To a magnetically stirred solution of 14 (1.11 mmol) in dry
solvent (5 mL) was added a solution of Lewis acid (1.66 mmol) in
the same solvent (30 mL) at room temperature with a syringe pump
(0.02 mmol/min). After the end of addition the reaction mixture was
stirred for 30 min and analyzed by HPLC. The crude reaction product
was purified by flash chromatography, furnishing 22 as the sole product
of the reaction.
Ethyl 2-Oxo-3-phenyl-1,2-dihydroquinoline-4-carboxylate
(23f): obtained in 8% yield (26 mg, 0.089 mmol) as yellow-orange pure
1
solid; mp 172ꢁ174 °C; H NMR (400 MHz, CDCl3) δ 1.37 (t, 3H,
J = 7.1 Hz), 4.44 (q, 2H, J = 7.2 Hz), 6.79 (d, 1H, J = 7.8 Hz), 7.00 (dt, 1H,
Jd = 0.9 Hz, Jt = 7.7 Hz), 7.25 (dd, 1H, J = 1.0, 7.7 Hz), 7.35 (d, 1H, J = 7.7
Hz), 7.43 (m, 3H), 7.54 (m, 2H), 7.70 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 14.0, 62.2, 109.8, 122.2, 123.1, 124.8, 128.2, 128.7, 129.5, 130.5,
140.9, 167.2, 167.7; GC-MS Rt = 27.247 min, m/z 165 (43), 190 (15),
191 (18), 207 (19), 220 (100), 221 (28), 248 (15), 264 (16), 292 (17),
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dx.doi.org/10.1021/jo201205u |J. Org. Chem. 2011, 76, 7431–7437

The Journal of Organic Chemistry
ARTICLE
293 (81), 294 (19); HRMS (+ES) m/z calcd for C18H16NO3 294.1130,
found 294.1121.
’ REFERENCES
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Ethyl 3-(2-Aminophenyl)-2-propynoate (24):9 obtained as
yellowish pure amorphous solid; see Tables 1 and 2 for the correspond-
1
ing yields; mp 55ꢁ57 °C; H NMR (400 MHz, CDCl3, CD3OD) δ
1.44(t, 3H, J = 7.1 Hz), 4.23 (br s, 1H), 4.55 (q, 2H, J = 7.2 Hz), 6.95 (t,
1H, J = 7.6 Hz), 7.36 (dt, 1H, Jd = 1.4 Hz, Jt = 8.6 Hz), 7.45 (d, 1H, J = 7.7
Hz), 8.14 (d, 1H, J = 8.5 Hz); 13C NMR (100 MHz, CDCl3, CD3OD) δ
13.6, 29.3, 47.9, 48.1, 48.3, 48.5, 48.7, 48.9, 49.1, 63.3, 83.3, 85.7, 108.5,
120.5, 122.5, 131.8, 133.7, 142.0, 152.6, 154.6; GC-MS Rt = 18.950 min,
m/z 63 (22), 89 (53), 90 (21), 115 (56), 116 (25), 117 (100), 143 (30),
144 (50), 189 (64); HRMS (+ES) m/z calcd for C11H11NO2Na
212.0687, found 212.0682.
(3) Pellicciari, R.; Castagnino, E.; Fringuelli, R.; Corsano, S. Tetra-
hedron Lett. 1979, 20, 481–484.
Diethyl 3,30-[Carbonylbis(imino-2,1-phenylene)]bis(prop-
2-ynoate) (25): obtained in 3% yield (13 mg, 0.032 mmol) as pure
white solid; mp 159ꢁ160 °C; 1H NMR (400 MHz, CDCl3, CD3OD) δ1.44
(t, 3H, J = 7.1 Hz), 4.23 (br s, 1H), 4.55 (q, 2H, J = 7.2 Hz), 6.95 (t, 1H, J =
7.6 Hz), 7.36 (dt, 1H, Jd = 1.4 Hz, Jt = 8.6 Hz), 7.45 (d, 1H, J = 7.7 Hz), 8.14
(d, 1H, J = 8.5 Hz); 13C NMR (100 MHz, CDCl3, CD3OD) δ 13.6, 29.3,
47.9, 48.1, 48.3, 48.5, 48.7, 48.9, 49.1, 63.3, 83.3, 85.7, 108.5, 120.5, 122.5,
131.8, 133.7, 142.0, 152.6, 154.6; GC-MS Rt = 18.950 min, m/z 63 (22), 89
(53), 90 (21), 115 (56), 116 (25), 117 (100), 143 (30), 144 (50), 189 (64);
HRMS (+ES) m/z calcd for C23H21N2O5 405.1450, found 405.1444.
Ethyl 3-2-{[(Methoxycarbonyl)amino]phenyl}prop-2-yno-
ate (31a): obtained in 46% yield (125 mg, 0.51 mmol) as colorless solid;
mp 71ꢁ73 °C; 1H NMR (200 MHz, CDCl3) δ 1.41 (t, 3H, J = 7.1 Hz),
3.85 (s, 3H) 4.36 (q, 2H, J = 7.4 Hz), 7.07 (dt, 1H, Jd = 1.1 Hz, Jt = 7.6
Hz), 7.37 (s, 1H), 7.53 (m, 2H), 8.23 (d, 1H, J = 9.2 Hz); 13C NMR (50
MHz, CDCl3) δ 14.1, 52.6, 62.3, 81.2, 87.4, 107.6, 118.1, 122.7, 132.3,
133.4, 140.9, 153.5; GC-MS Rt = 21.943 min, m/z 89 (14), 115 (24), 130
(19), 143 (100), 170 (67), 175 (39), 215 (20), 247 (28); HRMS (+ES)
m/z calcd for C13H14NO4 248.0923, found 248.0926.
Ethyl 3-2-{[(Ethoxycarbonyl)amino]phenyl}prop-2-yno-
ate (31b): obtained in 46% yield (109 mg, 0.51 mmol) as colorless
pure oil; 1H NMR (400 MHz, CDCl3) δ 1.35 (t, 3H, J = 7.1 Hz), 1.38 (t,
3H, J = 6.2 Hz), 4.27 (q, 2H, J = 7.2 Hz), 4.33 (q, 2H, J = 7.1 Hz), 7.04 (dt,
1H, Jd = 1.0 Hz, Jt = 7.6 Hz), 7.46 (dt, 1H, Jd = 1.0 Hz, Jt = 7.6 Hz), 7.52
(dd, 1H, J = 1.1, 7.7 Hz), 8.21 (d, 1H, J = 8.4 Hz); 13C NMR (100 MHz,
CDCl3) δ 14.1, 14.5, 61.7, 62.4, 81.4, 87.4, 107.6, 118.2, 122.6, 132.3,
133.5, 141.1, 153.1, 153.7; GC-MS Rt = 21.743 min, m/z 88 (13), 114
(24), 115 (28), 117 (22), 143 (100), 144 (18), 170 (77), 171 (12), 215
(20); HRMS (+ES) calcd for C14H15NO4Na 284.0899, found 284.0911.
Ethyl 3-2-{[(tert-Butoxycarbonyl)amino]phenyl}prop-2-
ynoate (31c):12 obtained in 36% yield (76 mg, 0.40 mmol) as colorless
pure oil; 1H NMR (400 MHz, CDCl3) δ 1.38 (t, 3H, J = 7.1 Hz), 1.55 (s,
9H), 4.33 (q, 2H, J = 7.1 Hz), 7.00 (dt, 1H, Jd = 1.1 Hz, Jt = 7.6 Hz), 7.19
(s, 1H), 7.43 (t, 1H, J = 7.4 Hz), 7.51 (dd, 1H, J = 1.3, 7.8 Hz), 8.20 (d,
1H, J = 8.5 Hz); 13C NMR (100 MHz, CDCl3) δ 16.0, 30.2, 64.3, 83.3,
89.3, 109.3, 120.1, 124.3, 134.2, 135.4, 143.5, 154.2, 155.7; GC-MS Rt =
22.286 min, m/z 57 (86), 59 (54), 88 (15), 89 (22), 114 (25), 115 (37),
117 (65), 143 (100), 144 (28), 170 (76), 189 (46); HRMS (+ES) m/z
calcd for C16H19NO4Na 312.1212, found 312.1222.
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’ ASSOCIATED CONTENT
S
Supporting Information. Figures giving NMR spectra
b
(1H NMR and 13C NMR). This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: +39 075 5855120. Fax: +39 075 5855124. E-mail: rp@
unipg.it.
7437
dx.doi.org/10.1021/jo201205u |J. Org. Chem. 2011, 76, 7431–7437