Amine-mediated synthesis of amides from 1,3-dicarbonyl compounds through a domino diazo transfer/aminolysis process

Article abstract of DOI:10.1016/j.tet.2017.06.013

The dual role of amines as both catalysts and substrates for the synthesis of diazo compounds or carboxamides from 1,3-dicarbonyl compounds is described herein. In the presence of a suitable diazo transfer agent, primary and cyclic secondary amines act as basic catalysts for the diazo transfer reaction to malonates, β-keto esters, and β-diketones. Depending on the structure of the 1,3-dicarbonyl compound and the nucleophilicity of the amine, the resulting α-diazo-β-keto ester undergoes cleavage of the acyl group to give amides. A multifunctionalized γ-azido-α-diazo-β-keto ester was cleanly prepared in good yields by this one-pot protocol under practical and safe conditions, being employed in a Knoevenagel-type condensation with aromatic aldehydes to give densely functionalized diazo azido compounds. Further treatment of these unsaturated γ-azido-α-diazo-β-keto esters with primary amines readily furnished the corresponding α-azidocinnamamides in high yields, which were used in the synthesis of novel indole-2-carboxamides through the rhodium-catalyzed intramolecular C–H insertion.

Full text of DOI:10.1016/j.tet.2017.06.013

Accepted Manuscript
Amine-mediated synthesis of amides from 1,3-dicarbonyl compounds through a
domino diazo transfer/aminolysis process
Taíssa A. Costin, Luiz G. Dutra, Adailton J. Bortoluzzi, Marcus M. Sá
PII:
S0040-4020(17)30632-4
10.1016/j.tet.2017.06.013
TET 28778
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 April 2017
Revised Date: 5 June 2017
Accepted Date: 7 June 2017
Please cite this article as: Costin TaíA, Dutra LG, Bortoluzzi AJ, Sá MM, Amine-mediated synthesis
of amides from 1,3-dicarbonyl compounds through a domino diazo transfer/aminolysis process,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.06.013.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Amine-Mediated Synthesis of Amides from
,3-Dicarbonyl Compounds through a Domino
1
Diazo Transfer/Aminolysis Process
Taíssa A. Costin, Luiz G. Dutra, Adailton J. Bortoluzzi, Marcus M. Sá*
Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil

ACCEPTED MANUSCRIPT
Amine-Mediated Synthesis of Amides from 1,3-Dicarbonyl
Compounds through a Domino Diazo Transfer/Aminolysis Process
Taíssa A. Costin, Luiz G. Dutra, Adailton J. Bortoluzzi, Marcus M. Sá*
Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC
88040-900, Brazil
*
Corresponding Author: Prof. Dr. M. M. Sá
MESOLab (Laboratory of Methodology and Organic Synthesis)
Departamento de Química, Universidade Federal de Santa Catarina
Florianópolis, SC 88040-900, Brazil
Tel.: +55-48-37213642; fax: +55-48-37216850; e-mail: marcus.sa@ufsc.br
Abstract:
The dual role of amines as both catalysts and substrates for the synthesis of diazo
compounds or carboxamides from 1,3-dicarbonyl compounds is described herein. In the
presence of a suitable diazo transfer agent, primary and cyclic secondary amines act as
basic catalysts for the diazo transfer reaction to malonates,
Depending on the structure of the 1,3-dicarbonyl compound and the nucleophilicity of the
amine, the resulting -diazo- -keto ester undergoes cleavage of the acyl group to give
amides. A multifunctionalized -azido- -diazo- -keto ester was cleanly prepared in good
β-keto esters, and β-diketones.
α
β
γ
α
β
yields by this one-pot protocol under practical and safe conditions, being employed in a
Knoevenagel-type condensation with aromatic aldehydes to give densely functionalized
diazo azido compounds. Further treatment of these unsaturated
γ-azido-α-diazo-β-keto
esters with primary amines readily furnished the corresponding -azidocinnamamides in high
α
yields, which were used in the synthesis of novel indole-2-carboxamides through the
rhodium-catalyzed intramolecular C-H insertion.
Keywords:
Diazo transfer
α
-Diazo-
Knoevenagel reaction
-Azidocinnamamides
β-keto esters
α
Indole-2-carboxamides
Intramolecular C-H insertion
1

ACCEPTED MANUSCRIPT
1
. Introduction
Contemporary organic synthesis is founded on the design of chemical processes that are not
only efficient, selective and reliable, but also environmentally friendly. To be both
environmentally and economically acceptable, novel synthetic procedures should eliminate
(
or drastically reduce) the use and generation of hazardous substances, allowing the set-up
1
and work-up steps to be performed under operationally simple conditions.
Synthetic transformations involving
α
-diazo carbonyl compounds, including cyclopropanation,
cycloaddition, and X-H insertion (X = C, N, O), have received considerable attention due to
their versatility, allowing a multitude of carbo- and heterocyclic frameworks of biological and
2
technological importance to be accessed. Reactions involving
α
-diazo carbonyl compounds
include domino processes consisting of sequential arrays of bond-forming and bond-breaking
steps, which are frequently performed under mild conditions and are associated with a high
thermodynamic driving force generating a single product, together with inoffensive
3
byproducts (N or small stable molecules).
2
In spite of their recognized versatility as building blocks for the synthesis of carbo- and
heterocyclic targets, the wider use of
α-diazo carbonyl compounds is, at least in part,
hampered by the limited availability of methods that are truly simple, efficient, inexpensive,
4
and safe. The base-catalyzed diazo transfer reactions from sulfonyl azides to 1,3-dicarbonyl
compounds remain the most studied method for the preparation of
α-diazo carbonyl
5
compounds. Despite its broad applicability, this transformation presents a number of
disadvantages, including the use of large amounts of base, toxic solvents, and shock-
sensitive chemicals, slow conversions to the product, and the generation of large quantities
4,6
of residues.
In the case of para-toluenesulfonyl azide (tosyl azide, TsN ), this diazo transfer reagent is
3
associated with a risk of explosion during manipulation, due to its sensitivity to mechanical
7
shock. Moreover, the generation of one equivalent of tosyl amide (TsNH ) as the byproduct
2
of the diazo transfer reaction using TsN causes serious issues concerning the isolation and
3
purification of the desired diazo product. While several modified diazo transfer reagents have
been designed to avoid the constraints imposed by the use of tosyl azide and its byproduct
tosyl amide, most of them are expensive, commercially unavailable or have limited
8
application. Therefore, the development of greener and more effective synthetic methods for
the preparation of
α-diazo carbonyl compounds is of considerable interest.
During our studies on the preparation and reactivity of functionalized
α
-diazo carbonyl
9,10
compounds 2,
metallocarbenoid originating from the diazo 2a with amines, which would give rise to
we were interested in the metal-catalyzed N-H insertion reaction of the
11
synthetically useful
α
-amino-
γ
-azido-
β
-keto esters A (Scheme 1). Surprisingly, simply mixing
2

ACCEPTED MANUSCRIPT
2
a and n-butylamine in THF for 2 h at r.t. furnished the
product, which was isolated in high yield with no evidence of any product formed by N-H
insertion or other transformation. -Diazo- -keto esters are known to undergo cleavage of
the acyl group in the presence of strong O-nucleophiles (such as the hydroxide ion as well as
α-azido acetamide 3a as the sole
α
β
5b,12
alkoxides) to give acids and esters.
Nonetheless, we envisaged that the use of a
13
nucleophilic amine in this practically unexplored transformation could have synthetic
potential as a route to obtaining amides, due to the chemical and biological importance of
14
this class of nitrogen-containing compounds.
In this paper, we describe an investigation of the dual role of amines as both catalysts and
substrates for the synthesis of diazo compounds or amides, depending on the structure of
the starting amine and the 1,3-dicarbonyl compound employed. In addition, the synthetic
application of this efficient transformation for the synthesis of indole-2-carboxamides is
addressed.
O
O
O
O
N3
N3
OEt
OEt
1
a
NH
A
I)
(
h
I
X
Ref. 9
R
This work
O
O
O
NH2
N3
N3
OEt
N
THF
H
2a
N2
3a
Scheme 1. Unexpected aminolysis of 2a versus N-H insertion.
2
. Results and discussion
In a preliminary approach to evaluate the reactivity of
amines of linear structure, it was shown that n-butylamine and allylamine are potent
nucleophiles for the acyl cleavage of -diazo- -keto esters containing electron-withdrawing
groups at the -position, such as azido (2a) and chloro (2b), leading to the corresponding
α
-diazo-β-keto esters toward primary
α
β
γ
amides 3 and 4 in high yields after 1-2 h at r.t. (Scheme 2). On the other hand, the
unsubstituted analogue 2c was not able to participate in a clean reaction with n-butylamine to
give the elusive amide 3c. Instead, a complex mixture of products was slowly formed after
prolonged periods. Diazo diesters, such as dimethyl and diethyl
even less reactive toward n-butylamine, being recovered intact after exposure for a few days.
These results indicate that the cleavage occurs preferentially with more reactive -keto
esters, where the presence of an electron-withdrawing group at the adjacent -position
α-diazomalonates, were
β
γ
activates the electrophilic carbonyl center for the nucleophilic attack of the amines under
3

ACCEPTED MANUSCRIPT
study. The proposed intermediate B would undergo intramolecular proton transfer and
eventually expels ethyl diazoacetate (EDA), which can be detected by NMR analysis of the
crude reaction but is ultimately destroyed in the work-up and purification stages (Scheme 2).
Besides the simplicity, this transformation is carried out under mild conditions to give amides
in high chemical yields.
O
O
1
O
R NH , THF
2
X
X
R1
o
OEt
25 C, 1-2 h
N
H
8
0-90%
3, 4
2
a-c N2
O
O
X
OEt
H
CO Et
2
H N
2
N2
-
R1
B
N2 EDA
X = N (a); Cl (b); H (c)
3
1
R = CH (CH ) (3); CH CHCH (4)
3
2 3
2
2
Scheme 2. Aminolysis of diazo esters 2.
The aminolysis of α-diazo-β-keto esters 2 was highly efficient in terms of producing amides 3
and 4. However, it would be more synthetically attractive if the diazo function could be
generated in situ from the 1,3-dicarbonyl compounds 1 in a one-pot process, instead of first
preparing the
α
-diazo-
β
-keto esters 2 and then transforming them to the desired amides 3
-diazo carbonyl compounds
and 4. We recently developed a mild method to prepare
α
through the diazo transfer reaction starting from 1,3-dicarbonyl compounds 1. This procedure
involves the use of a diazo transfer agent (such as TsN ) and a heterogeneous base (such
3
9
as molecular sieves - MS) in THF as the solvent. Because the heterogeneous conditions
were compatible with the aminolysis reaction, we tested the MS-catalyzed diazo transfer
reaction in the presence of n-butylamine to verify whether the preformed diazo product 2a
participates in subsequent amine-mediated transformations (Scheme 3).
O
O
NH2
O
N3
N3
OEt TsN
, THF, 30 min
N
3
H
(
with or without
1a
3a (95%)
MS 4A)
O
O
N3
OEt
2a
N2
Scheme 3. Domino diazo transfer/aminolysis of keto ester 1a.
4

ACCEPTED MANUSCRIPT
Indeed, the expected amide 3a was obtained in high yield, but the time required to achieve
this transformation was exceedingly low (30 min) compared to the MS-catalyzed diazo
9
transfer (26 h). Clearly, the presence of the added amine was crucial not only as a
nucleophile for the aminolysis of the diazo intermediate 2a in the second step, but also as a
basic catalyst for the initial formation of 2a through the diazo transfer reaction from 1a. This
hypothesis was confirmed by running a similar reaction, but in the absence of MS, wherein
the expected amide 3 was obtained in comparable yield and time (Scheme 3).
This domino diazo transfer/aminolysis process was extended to other substrates, including
keto esters and primary as well as cyclic secondary amines (Table 1). The results for the
primary amines tested (n-butyl and allyl) were similar and led to the corresponding -azido
β-
α
acetamides 3a and 4a in excellent yields (Table 1, entries 1 and 2) after a simple work-up
consisting of triturating the crude product with a combination of ethyl ether and hexane to
separate the solid tosylamide that is formed as a byproduct.
Table 1
Amine-mediated diazo transfer reaction versus domino diazo transfer/aminolysis.
O
O
O
O
O
1
2
R R NH
R1
X
X
X
OEt
OEt
N
R2
TsN , THF
3
1
2
N2
3-6
1
2
a
#
1
X
R R NH
Time (h) Product Yield (%)
1
a
a
N3
0.5
0.5
3a
4a
95
94
NH2
NH2
NH
2
3
N3
N3
a
a
a
c
c
c
29
26
24
3
5a
6a
2a
5c
2c
2c
95
87
80
85
89
91
4
5
6
7
8
N3
N3
H
NH
NH
NH
NH
NH
O
H
13
16
H
O
a
Isolated yields.
5

ACCEPTED MANUSCRIPT
On the other hand, the outcome of the reaction involving cyclic secondary amines and β-keto
esters was not as predictable and was dependent on the structure of the reactants involved,
providing either the expected amides 5 and 6, through the domino diazo transfer/aminolysis
process, or the diazo intermediate 2 (Table 1, entries 3-8). For instance, pyrrolidine was
sufficiently basic and nucleophilic to give the corresponding tertiary amides 5a and 5c, even
in the case of the less reactive γ-unsubstituted β-keto ester 1c (Table 1, entries 3 and 6).
Likewise, piperidine was able to participate as a nucleophile in the domino sequence to give
amide 6a when the azido-substituted 1,3-dicarbonyl compound 1a was used as the precursor
(
entry 4). However, when the
unsubstituted -diazo- -keto ester 2c was isolated as the sole product, with no trace of the
elusive amide 6c (entry 7). Moreover, morpholine was not sufficiently nucleophilic under the
conditions tested and only the corresponding -diazo- -keto esters 2a and 2c were isolated
from the starting -keto esters 1a and 1c (respectively, entries 5 and 8).
In the case of the -chloro- -keto ester 1b, the reactions with a variety of amines led to
interesting results due to the presence of an additional electrophilic center at the -position,
which allowed further in situ transformations through chlorine displacement by the amine,
besides the diazo transfer and aminolysis (Scheme 4). Therefore, the treatment of the
chloro- -keto ester 1b with TsN and 2 equiv of pyrrolidine furnished the bis-adduct 8, which
β-keto ester 1c was employed as the starting material, the γ-
α
β
α
β
β
γ
β
γ
γ-
β
3
might come from a domino process starting with the diazo transfer reaction generating 2b
followed by chloro displacement and aminolysis (not necessarily in this order). On the other
hand, the α-chloro acetamides 3b and 4b were the exclusive products originating from the
primary linear amines tested (n-butylamine and allylamine), in which the diazo
transfer/aminolysis sequence occurred while the halogen group remained intact. The less
reactive amines, namely, N-methylpiperazine and morpholine, were also able to catalyze the
diazo transfer reaction, although the subsequent aminolysis of the diazo intermediate 2b was
not observed. Instead, the amines were incorporated in the final product through the
displacement of the
diazo- -keto esters 2k and 2l from a multicomponent-type transformation. For these
particular transformations, the best results were observed by replacing TsN with 4-
γ-chloro group, which ultimately furnished the corresponding γ-amino-α-
β
3
7a
acetamidobenzenesulfonyl azide [ABSN ], which is considered a safer diazo transfer agent.
3
A distinct behavior was observed for the weakly nucleophilic t-BuNH , which was able to
2
cleanly catalyze the diazo transfer reaction to
TsN to give the -chloro- -diazo- -keto ester 2b as the only product detected, with no
further transformation (e.g., aminolysis or chloro displacement). The preparation of -halo-
diazo- -keto esters, such as 2b, is of particular interest due to their importance as building
blocks for the synthesis of a variety of multifunctionalized compounds.
γ-chloro-β-keto ester 1b in the presence of
γ
α
β
3
γ
α-
β
10a,15
6

ACCEPTED MANUSCRIPT
O
O
O
N
Cl
N
OEt
8
(82%)
2b (85%) N2
NH2
TsN3
TsN3
2 h
N
23 h
O
O
H
Cl
OEt
1
TsN3
ABSN3
1b
R NH
W
NH
2
0.5-1 h
24 h
O
W
O
O
Cl
R1
N
N
OEt
H
N2
1
3
4
b: R = CH (CH ) (99%)
2k: W = CH N (35%)
2l: W = O (72%)
3
2 3
3
1
b: R = CH CHCH (98%)
2
2
Scheme 4. Amine-mediated diazo transfer reaction to
γ-chloro-β-keto ester 1b versus
domino diazo transfer/aminolysis with or without nucleophilic displacement.
Because the use of t-BuNH under mild conditions allowed simple access to the
α-diazo
2
carbonyl compound 2b in high yield, it appeared that this simple protocol might be suitable
for the synthesis of diverse -diazo carbonyl compounds. Therefore, representative 1,3-
dicarbonyl compounds 1 ( -keto esters, malonates, 1,3-diketones) were screened in the t-
BuNH -catalyzed diazo transfer reaction using TsN as the diazo transfer reagent (Table 2,
α
β
2
3
method A). Good yields and short reaction times were obtained in most cases. The exception
was malonate 1f, for which the conversion to the corresponding diazo diester 2f was slower
than in the case of the 1,3-dicarbonyl compounds 1 tested, although the yield was similar.
Remarkably, the presence of reactive functional groups, including azido, chloro, and nitro
groups is well tolerated (Table 2, products 2a, 2b, 2e). The catalytic nature of t-BuNH was
2
attested by running a reaction with 0.25 equiv of t-BuNH under identical conditions to give
2
the expected diazo compound 2b, although the reaction rate was considerably diminished
(
with a conversion of 55% after 2 h) compared to the conditions generally applied (i.e., 1.0-
.1 equiv base).
It is also possible to replace the diazo transfer reagent (TsN with ABSN ; product 2b) and
1
3
3
the amine catalyst (t-BuNH with i-Pr NH; product 2c) without a significant reduction in the
2
2
reaction rate or yield. In all cases, the fast and high-yield preparation of
α-diazo carbonyl
compounds 2a-h using tert-butylamine was found to be much more efficient than the method
9
employing molecular sieves previously described by our group.
Motivated by these results, we envisioned that the procedure for the diazo transfer reaction
using t-BuNH as the catalyst could be adapted to a more environmentally benign protocol if
2
the potentially explosive TsN and the harmful THF were replaced by a safer diazo transfer
3
7

ACCEPTED MANUSCRIPT
reagent and less toxic aqueous solvent. In this regard, the in situ generation of the diazo
transfer reagent in an aqueous environment seemed not only promising but also feasible.
Table 2
Yields for the t-BuNH -catalyzed diazo transfer reaction with TsN or ABSCl/NaN .
2
3
3
O
O
O
O
t-BuNH or i-Pr NH
2
2
R
R'
TsN or ABSCl/NaN
R
R'
3
3
o
1
25 C
2
N2
a
a
Method A
[Time (h)]
88 [1]
Method B
Product
R
R’
[Time (h)]
b
2
a
N CH
EtO
EtO
3
2
2b
ClCH2
85 [2]
78 [2]
65 [4]
c
75 [3]
2c
CH3
EtO
90 [1]
d
86 [2]
2
d
CH3
MeO
EtO
92 [1]
85 [0.5]
87 [16]
-
-
2
e
4-NO C H
4
2
6
2
f
MeO
MeO
57 [24]
e
72 [24]
2g
BnO
BnO
-
77 [24]
f
92 [24]
2
h
OC(CH ) O
-
40 [2]
76 [3]
3
2
2
i
CH C(CH ) CH
75 [1]
2
3 2
2
f
70 [2]
2j
CH3
CH3
82 [0.5]
61 [2]
a
b
Method A: TsN /t-BuNH /THF; Method B: ABSCl/NaN /t-BuNH /BTEAC/acetone/H O.
3
2
3
2
2
Azido-substituted diazo ester 2a was prepared directly from chloro-substituted keto ester 1b
by adapting method B to a one-pot procedure (see Scheme 6).
c
TsN was replaced with ABSN (4-acetamidobenzenesulfonyl azide) as the diazo transfer
3
3
reagent.
d
t-BuNH was replaced with i-Pr NH as the base.
2
2
e
f
Reaction was carried out without BTEAC.
t-BuNH /BTEAC was replaced with i-Pr NH/β-CD as the base/additive combination.
2
2
Treating representative 1,3-dicarbonyl compounds
acetamidobenzenesulfonyl chloride [ABSCl], NaN3 and
benzyltriethylammonium chloride [BTEAC]) in aqueous acetone led to the expected
1
with
a
combination of 4-
a
phase transfer agent
(
α
-diazo
8

ACCEPTED MANUSCRIPT
carbonyl product in good-to-high yields, usually after a few hours (Table 2, method B). As in
the case of method A, slower reaction rates were observed for the malonate derivatives
(
products 2f, 2g). In one particular case (product 2f), the presence of BTEAC had a negative
effect on the reaction rate and better results were obtained without this additive. In a few
instances, another combination of catalyst (i-Pr NH) and additive ( -cyclodextrin [ -CD]) was
found to be more efficient than or at least of similar applicability as t-BuNH /BTEAC (products
β
β
2
2
2g, 2i).
As an additional feature of this straightforward method for the diazo transfer reaction, it was
16
possible to prepare the donor-acceptor
α
-diazo ester 9 through the acyl cleavage of the α-
substituted
β
-keto ester 10 (Scheme 5).
O
O
O
ABSN3
t-BuNH , THF
OEt
2
OEt
o
2
5 C, 16 h
69%
N2
10
9
Scheme 5. Synthesis of donor-acceptor α-diazo ester 9.
Besides being applicable to a variety of 1,3-dicarbonyl compounds 1, this simple method for
the preparation of -diazo carbonyl compounds in aqueous medium was also practical in
α
terms of work-up. This consisted of evaporating the volatiles and triturating the crude product
with a combination of ethyl ether and hexane followed by separating out the solid
sulfonamide byproduct, which provides high-quality
α-diazo carbonyl compounds with no
additional purification stages. It is also worth noting that despite the higher yields and shorter
reaction times observed for method A, the one-pot condition described in method B is not
only greener but also more practical due to the use of an aqueous medium and the in situ
generation of the diazo transfer reagent (dispensing with the need for its previous
preparation), thus reducing the amount of waste generated.
We have previously demonstrated the versatility of
γ-azido-
α-diazo-β-keto ester 2a as a
10
synthetic building block. However, its preparation involves either a three-step procedure
10d
with the intermediacy of a potentially toxic diazo mercurial or an interchangeable two-step
protocol starting with 1b, consisting of an MS-catalyzed diazo transfer reaction and S 2-type
N
9
displacement. In order to combine the practicability of generating the diazo transfer reagent
7b,12b
in situ
anion, we designed a one-pot process to prepare the
the -chloro- -keto ester 1b using commercially available reagents and without the isolation
with the introduction of the azido group through chloro displacement by the azide
γ
-azido- -diazo- -keto ester 2a from
α
β
γ
β
of intermediates (Scheme 6). It is worth mentioning the dual role of NaN , which acts as the
3
9

ACCEPTED MANUSCRIPT
source of the diazo transfer reagent (through the in situ formation of ABSN from ABSCl) and
3
also as the nucleophile that displaces the chlorine ion at the
amines, additives, and solvents in a variety of stoichiometric amounts of reagents were fine-
tuned to find the best conditions to prepare the -azido- -diazo- -keto ester 2a on a
γ-position. Thus, different
γ
α
β
preparative scale. For the 1-mmol scale, the use of t-BuNH combined with BTEAC was
2
effective as expected, but the yield dropped considerably when the reaction was scaled up to
3
mmol. After extensive evaluation, the most reliable protocol for the 3-mmol scale was found
to be a combination of i-Pr NH and -CD in aqueous acetone. With a slight excess of ABSCl
β
2
as the precursor of the diazo transfer reagent, high-quality 2a was obtained in reproducible
yields (up to 80%) without the need for a chromatography stage (Scheme 6).
O
O
NaN
3
(2.5 equiv), ABSCl (1.3 equiv)
O
O
Cl
i-Pr NH (1.0 equiv),
2
β
-CD (0.05 equiv)
N3
OEt
OEt
o
Acetone:H O (2:1), 25 C, 16 h
2
1b
2a
N2
Scheme 6. One-pot preparation of azido diazo ester 2a.
The safe and practical one-pot synthesis of the
γ-azido-α-diazo-β-keto ester 2a from γ-chloro-
β
-keto ester 1b allowed the full exploitation of its reactivity through the Knoevenagel-Knittel
17
10a
condensation toward aldehydes. The original reaction of 2a with benzaldehyde
using
piperidinium acetate as the promoter was modified in order to improve the reaction yield and
selectivity. Thus, a variety of carboxylic acids and amines were tested as the acid-base
promoters of the condensation in a number of solvents. After some experimentation, the best
conditions were found to be the combination of 3-chloropropionic acid and pyrrolidine (1.5
equiv each) in isopropanol as the solvent. The use of the more nucleophilic ethanol as the
10a
solvent was deleterious due to the observed formation of ethyl α-azidocinnamate through
the acyl cleavage of the preformed condensation product 11. With this mild condition in hand,
a series of representative Knoevenagel-Knittel adducts was prepared in good to high yields
(
Table 3).
This late functionalization of the
resulting unsaturated -azido- -diazo-
reaction in the presence of a suitable amine. Accordingly, treating 11a with n-butylamine
cleanly furnished the corresponding -azidocinnamamide 12a in excellent yields (Table 4).
Due to the importance of -azidocinnamamides 12 as starting materials for imidazole-based
γ
-azido-
α-diazo-β-keto ester 2a was useful since the
γ
α
β
-keto esters 11 also participated in the aminolysis
α
α
18
fluorophores used in RNA imaging, this transformation was further extended to other
substrates and found to be wide in scope (Table 4, 12b-j).
10

ACCEPTED MANUSCRIPT
Table 3
Preparation of unsaturated
condensation.
γ-azido-
α
-diazo-
β
-keto esters 11 through Knoevenagel-Knittel
O
O
3
O
O
R C H CHO
6
4
R3
N3
Catalyst
OEt
OEt
o
i-PrOH, 25 C
N2
N3
N2
11
2
a
O
H N
2
Catalyst =
O-
Cl
3
a
Product
R
Time (h) Yield (%)
11a
11b
11c
11d
11e
H
14
26
22
19
26
65
90
75
76
67
4-CH3
4-CH O
3
3-CH O
3
4-Br
a
Isolated yields.
Table 4
Preparation of
α-azidocinnamamides 12 through the aminolysis reaction of unsaturated γ-
azido-
α
-diazo-
β
-keto esters 11.
O
O
O
R3
1
R3
R NH
R1
2
OEt
N
H
THF
25 C
N3 N2
o
N3
11
12
1
3
a
Product
R
R
H
H
Time (h) Yield (%)
12a
12b
12c
12d
12e
CH CH CH CH
26
30
22
2
88
65
90
76
94
85
66
87
92
91
3
2
2
2
2
2
C H CH
6 2
5
CH CH CH CH
4-CH3
4-CH3
3
2
2
CH =CHCH
2
2
CH CH CH CH
4-CH O
9
3
2
2
3
12f
CH =CHCH
4-CH O
2
2
2
3
1
2g
2h
C H CH
6
4-CH O
50
1
5
2
3
1
CH =CHCH
3-CH O
2
2
3
12i
CH CH CH CH
4-Br
4-Br
2
3
2
2
2
12j
C H CH
6 2
35
5
a
Isolated yields.
α
-Azidocinnamic esters are well-known precursors for indole-2-carboxylates. These can be
obtained either by thermally-induced cyclization with the intermediacy of vinyl nitrene-azirine
11

ACCEPTED MANUSCRIPT
19
species (the Hemetsberger indole synthesis), or through the milder rhodium-catalyzed
generation of a metallo-nitrenoid intermediate and subsequent intramolecular C-H insertion
20
followed by rearomatization. While the importance of the related indole-2-carboxamides 13
21
has been widely recognized in the medicinal area (Figure 1), the synthesis of indole-2-
carboxamides 13 through the cyclization of the corresponding -azidocinnamamides, such
α
22
as 12, has not been well documented, possibly due to the absence of truly general
methods for the synthesis of this class of compounds.
CN
H
Me
N
O
N
S
N
O O
O
N
N
O
H
O
N
F
N
F
N
H
H
N
N
H
H
HN
Rescriptor
Androgen receptor inhibitor
β-Amyloid inhibitor
(Delarvidine)
Figure 1. Selected examples for bioactive indole-2-carboxamides.
To further demonstrate the synthetic potential of
blocks, we pursued a straightforward route to indole-2-carboxamides 13 employing the
known metal-catalyzed intramolecular C-H nitrene insertion of related -azidocinnamic
In this regard, we initially based our studies on the use of rhodium(II)
α-azidocinnamamides 12 as useful building
α
20
esters.
perfluorobutyrate [Rh (pfb) ] in toluene at 40 °C , as described by Driver and c ols.
20a
2
4
However, the treatment of cinnamamide 12e with Rh (pfb) in toluene (or dichloromethane)
2
4
20a
under Driver’s conditions provides only a slow conversion to the expected indoles (less
than 40% after 30 h). Gratifyingly, replacing the catalyst (Rh (pfb) with Rh (AcO) ) cleanly
2
4
2
4
23
gave indole 13b in excellent yield (Table 5).
Therefore, a representative group of -azidocinnamamides 12 was treated with Rh (AcO) (5
mol%) in CH Cl to give the corresponding indole-2-carboxamides 13 in 93-98% yield. The
α
2
4
2
2
reaction is very slow at room temperature, but can be dramatically improved at 40 °C (Table
). It is worth noting the relevant differences between the two rhodium(II) catalysts: the use of
Rh (AcO) for the previous intramolecular C-H nitrene insertion of -azidocinnamic esters did
5
α
2
4
20
not give satisfactory results compared to the more electrophilic Rh (pfb) , while the reverse
2
4
situation was observed for the
α-azidocinnamamides 12 presented herein. These results
highlight the ability of each ligand to determine the course of the catalytic process involved in
the generation of nitrenoid species from azides, as observed before for the intermediacy of
24
carbenoids originated from the related diazo compounds.
12

ACCEPTED MANUSCRIPT
Table 5
Synthesis of indole-2-carboxamides 13 from
α
-azidocinnamamides 12 through rhodium-
catalyzed intramolecular C-H nitrene insertion.
1
3
a
Product
3a
3b
3c
3d
3e
Isolated yields.
R
R
Time (h) Yield (%)
1
CH CH CH CH
CH3
27
13
20
26
20
98
93
96
93
94
3
2
2
2
1
CH CH CH CH
CH O
3
2
2
2
3
1
CH =CHCH
CH O
2
2
3
1
CH CH CH CH
Br
Br
3
2
2
2
1
C H CH
6 5 2
a
Since the reaction rate for the rhodium-catalyzed synthesis of indole-2-carboxamides 13 from
-azidocinnamamides 12 is strongly dependent on the temperature, attempts were made to
adapt the Hemetsberger indole synthesis to a method using microwave irradiation in the
α
19d
absence of a catalyst, as reported earlier for
α-azidocinnamic esters. The irradiation of 12b
in toluene at 120-130 °C for 5 min led to complete consumption of the starting
α
-
azidocinnamamide 12b, but the resulting indole-2-carboxamide 13b was accompanied by
small amounts of non-identifiable byproducts. Changing the solvent (toluene with ethanol) or
running the reaction under solvent-free conditions was detrimental to the process due to the
formation of complex mixtures of products. Despite the limitations observed for the
microwave-assisted Hemetsberger synthesis of indoles, the very fast conversion of
α-
azidocinnamamides 12 to indole-2-carboxamides 13 in toluene (5 min) compared to the
rhodium-catalyzed process (13 to 27 h) is encouraging and suggests that the reaction time
could be considerably reduced through a fine-tuning of the reaction parameters to achieve
yields and selectivity similar to those obtained under rhodium catalysis.
3
. Conclusions
We have presented a general and benign approach for the preparation of
compounds 2 through the diazo transfer reaction to 1,3-dicarbonyl compounds catalyzed by
primary or secondary amines. The resulting -diazo- -keto esters undergo cleavage of the
α
-diazo carbonyl
α
β
acyl group to give amides depending on the reaction conditions and the substrates
employed. This domino diazo transfer/aminolysis process occurs under mild conditions and
13

ACCEPTED MANUSCRIPT
the resulting amides were isolated in high yields. The use of a γ-chloro-β-keto ester allowed
further in situ transformations through chlorine displacement by cyclic amines.
Due to their poorer nucleophilicity, the use of tert-butylamine and diisopropylamine did not
lead to aminolysis products and thus they were successfully employed as basic catalysts for
the diazo transfer reaction to give a representative group of diazo compounds. The
involvement of readily available reagents, the in situ generation of the diazo transfer reagent
in an aqueous environment, and the tolerance to a variety of functional groups, together with
the simple work-up and good-to-high yields of the diazo compounds, were the main
advantages of this diazo transfer reaction over the existing methods. This simple protocol
allowed the development of a one-pot process for the synthesis of the multifunctionalized
azido- -diazo- -keto ester 2a under more practical and safer conditions compared with
previously reported procedures.
Subsequent organocatalyzed Knoevenagel-type condensation of 2a with aldehydes followed
by aminolysis of the resulting unsaturated -azido- -diazo- -keto esters 11 under mild
conditions and in short reaction times led to a novel protocol to access the important class of
-azidocinnamamides 12 in excellent yields. Finally, the synthetic application of amides 12
γ-
α
β
γ
α
β
α
as suitable precursors of indole-2-carboxamides 13 was firmly established through rhodium-
catalyzed intramolecular C-H insertion, but the fast microwave-assisted cyclization in the
absence of a catalyst shows potential for additional investigations to achieve improved
selectivity. Due to the recognized importance of amides and diazo compounds, further
studies are in progress to apply the methods developed herein for the synthesis of
biologically relevant targets.
4
. Experimental section
4.1. General Experimental Methods
All chemicals were of reagent grade and were used as received. Melting points were
determined using a hot plate apparatus and are uncorrected. Infrared spectra were acquired
-1
with a FT-IR spectrometer (range 4000-400 cm ) using KBr or ZnSe for solids and film for
1
13
1
liquid samples. H NMR spectra were recorded at 400 MHz or at 200 MHz and C { H} NMR
spectra (fully decoupled) were recorded at 100 MHz or at 50 MHz. Splitting patterns are
designated as s (singlet), brs (broad singlet), d (doublet), dd (doublet of doublet), ddt (doublet
of doublet of triplet), t (triplet), tt (triplet of triplet), q (quartet), qt (quintet), st (sextet), m
(
multiplet). Coupling constants (J) are measured in Hertz (Hz). Chemical shifts were
recorded in parts per million (ppm, δ) relative to solvent (CDCl at 7.26 ppm or DMSO-d at
3 6
1
13
2
.48 ppm for H NMR, and CDCl at 77.16 ppm or DMSO-d at 39.52 ppm for C NMR) as
3
6
the internal standard. Column chromatography was performed using silica gel (70-230 mesh)
14

ACCEPTED MANUSCRIPT
and hexane/ethyl acetate as the eluent. TLC analysis was performed in silica gel plates. The
ESI-QTOF mass spectrometer was operated in the positive ion mode at 4.5 kV and at a
desolvation temperature of 180 °C . The standard ele ctrospray ion (ESI) source was used to
generate the ions. The instrument was calibrated in the range m/z 50-3000 using a
calibration standard (low concentration tuning mix solution) and data were processed with
the aid of computer software.
Caution: Organic azides are potentially explosive substances that can decompose with the
input of energy from external sources (light, heat, pressure etc).
4.2. Typical procedure for the amine-mediated domino diazo transfer/aminolysis
To a solution of the corresponding β-keto ester 1 (1.0 mmol) and TsN (197 mg, 1.0 mmol) in
3
THF (2.0 mL) under stirring at 25 °C was added the amine (1.1 mmol). Then the reaction
mixture was stirred at room temperature until consumption of the starting material (monitored
by TLC: 30 min to 29 h, see Table 1 and Scheme 4). Next, the mixture was diluted in 5 mL of
CH Cl and concentrated under reduced pressure. After complete removal of the solvent, the
2
2
residue was triturated in ethyl ether and the resulting mixture was again concentrated under
reduced pressure. The final solid residue was repeatedly triturated with hexane (for amides 3
and 4) or a 9:1 hexane/CH Cl mixture (for amides 5 and 6) to separate out the insoluble
2
2
TsNH by decantation. The resulting supernatants were filtered and concentrated under
2
25
reduced pressure to give the known amides 3-6 as oils with high degree of purity.
Alternatively, further purification through column chromatography on silica gel using gradient
mixtures of hexane/EtOAc as eluent was employed to furnish pure products in 80-99% yield.
4.3. Preparation of 1-(2-pyrrolidinoacetyl)pyrrolidine (8) from the pyrrolidine-mediated domino
diazo transfer/chloro displacement/aminolysis
To a solution of 4-chloroacetoacetate (1b, 164 mg, 1.0 mmol) and TsN (197 mg, 1.0 mmol)
3
in THF (2.0 mL) under stirring at 25 °C was added p yrrolidine (150 mg, 2.1 mmol). Then the
reaction mixture was stirred at room temperature for 23 h. The final mixture was diluted with
CH Cl and the organic extract was washed with 0.5 M NaOH and brine, dried over Na SO ,
2
2
2
4
filtered and concentrated under reduced pressure. The resulting residue was purified through
column chromatography on silica gel (8:2 hexane/EtOAc) to give the corresponding product
-
1
8
1
1
(149 mg, 82%) as an oil; IR (neat) νmax/cm : 3468, 2967, 2873, 2792, 1643, 1453, 1192,
1
159; H NMR (400 MHz, CDCl ):
δ 3.40 (q, J = 6.5 Hz, 4H), 3.24 (s, 2H), 2.62-2.60 (m, 4H),
3
13
.92-1.85 (m, 2H), 1.82-1.72 (m, 6H); C NMR (100 MHz, CDCl ):
δ 168.2, 58.2, 54.1 (2 ×
3
+
+
CH ), 45.9, 45.6, 26.0, 24.0, 23.6 (2 × CH ); HRMS (ESI+) calcd for C H N O [M+H] :
2
2
10 19
2
183.1492, found: 183.1492.
15

ACCEPTED MANUSCRIPT
4.4. Procedure for the amine-catalyzed domino diazo transfer/chloro displacement
To a solution of 4-chloroacetoacetate (1b, 164 mg, 1.0 mmol) and ABSN (240 mg, 1.0
3
mmol) in THF (3.0 mL) under stirring at 25 °C was a dded the cyclic amine (2.5 mmol), then
the reaction mixture was stirred at room temperature for 24 h. Next, the mixture was diluted
in 5 mL of EtOAc and the organic extract was washed with brine, dried over Na SO , filtered
2
4
and concentrated under reduced pressure. After complete removal of the solvent, the residue
was triturated in ethyl ether and the resulting mixture was again concentrated under reduced
pressure. The final solid residue was repeatedly triturated with 9:1 hexane/CH Cl mixture to
2
2
separate out the insoluble ABSNH by decantation. The resulting supernatants were filtered
2
and concentrated under reduced pressure and the final residue was purified through column
chromatography on alumina (8:2 hexane/EtOAc) for 2k and silica gel (8:2 hexane/EtOAc) for
2
l to give the corresponding diazo compounds 2k (89 mg, 35%) and 2l (173 mg, 72%) as
oils.
.4.1. Ethyl 2-diazo-4-(4-methylpiperazin-1-yl)-3-oxobutanoate (2k)
4
-1
IR (neat) νmax/cm : 2978, 2939, 2800, 2136, 1715, 1666, 1456, 1373, 1305, 1222, 1012, 744;
1
H NMR (200 MHz, CDCl ):
δ 4.26 (q, J = 7.0 Hz, 2H), 3.63 (s, 2H), 2.60-2.55 (m, 4H), 2.48-
3
13
2
.42 (m, 4H), 2.24 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H); C NMR (100 MHz, CDCl ):
δ
188.9,
3
1
61.1, 64.4, 61.4, 54.7 (2 × CH ), 53.0 (2 × CH ), 45.7, 14.2 (C=N is absent); HRMS (ESI+)
2
2
2
+
3
+
calcd for C H N O [M+H] : 255.1452, found: 255.1451.
11
18
4
4.4.2. Ethyl 2-diazo-4-(4-morpholinyl)-3-oxobutanoate (2l)
-1
1
IR (neat) νmax/cm : 2961, 2910, 2853, 2134, 1714, 1665, 1305, 1220, 1116, 866, 745; H
NMR (400 MHz, CDCl ): 4.28 (q, J = 7.2 Hz, 2H) 3.74 (t, J = 4.5 Hz, 4H), 3.66 (s, 2H), 2.59
δ
3
1
3
(
(
t, J = 4.5 Hz, 4H), 1.32 (t, J = 7.2 Hz, 3H); C NMR (50 MHz, CDCl ):
δ
188.8, 161.0, 66.8
3
2 × CH ), 64.8, 61.4, 53.6 (2 × CH ), 14.2 (C=N is absent); HRMS (ESI+) calcd for
2
2
2
+
4
+
C H N O [M+H] : 242.1135, found: 242.1137.
10
15
3
4
.5. Typical procedure for the t-BuNH -catalyzed diazo transfer reaction with TsN (Method
2
3
A)
To a solution of the corresponding 1,3-dicarbonyl compound 1 (1.0 mmol) and TsN (197 mg,
3
1
.0 mmol) in THF (2.0 mL) under stirring at 25 °C w as added t-BuNH (80 mg, 1.1 mmol).
2
Then the reaction mixture was stirred at room temperature until consumption of the starting
material (monitored by TLC: 30 min to 16 h, see Table 2). Next, the mixture was diluted in 5
mL of CH Cl and concentrated under reduced pressure. After complete removal of the
2
2
solvent, the residue was triturated in ethyl ether and the resulting mixture was again
16

ACCEPTED MANUSCRIPT
concentrated under reduced pressure. The final solid residue was repeatedly triturated with
hexane to separate out the insoluble TsNH by decantation. The resulting supernatants were
2
9,10d,26
filtered and concentrated under reduced pressure to give diazo compounds
with high degree of purity in 75-92% yield.
2 as oils
4.6. Typical procedure for the amine-catalyzed diazo transfer reaction under aqueous
medium through the in situ generation of ABSN (Method B)
3
To a solution of the corresponding 1,3-dicarbonyl compound 1 (1.0 mmol) and ABSCl (304
mg, 1.3 mmol) in acetone (2.0 mL) under stirring at 0-5 °C was added a cold solution of NaN 3
(
71 mg, 1.1 mmol) in H O (1.0 mL) followed by BTEAC (45 mg, 0.20 mmol) and t-BuNH (73
2 2
mg, 1.0 mmol) [or β-CD (57 mg, 0.05 mmol and i-Pr NH (101 mg, 1.0 mmol); see Table 2].
2
Then the reaction mixture was stirred at room temperature until consumption of the starting
material (monitored by TLC: 2 to 24 h, see Table 2). Next, the mixture was diluted in 5 mL of
EtOAc and the organic extract was washed with brine, dried over Na SO , filtered and
2
4
concentrated under reduced pressure. After complete removal of the solvent, the residue
was triturated in ethyl ether and the resulting mixture was again concentrated under reduced
pressure. The final solid residue was repeatedly triturated with hexane to separate out the
insoluble ABSNH by decantation. The resulting supernatants were filtered and concentrated
2
9,10d,26
under reduced pressure to give diazo compounds
2 as oils with high degree of purity in
40-92% yield.
4
.7. Preparation of ethyl 2-diazohydrocinnamate (9) through the t-BuNH -catalyzed diazo
2
transfer reaction with ABSN3
To a solution of -benzyl- -keto ester 10 (220 mg, 1.0 mmol) and ABSN (240 mg, 1.0 mmol)
α
β
3
in THF (2.0 mL) under stirring at 25 °C was added t-BuNH (73 mg, 1.0 mmol). After 1 h,
2
another portion of ABSN (120 mg, 0.5 mmol) and t-BuNH (36 mg, 0.5 mmol) was added to
3
2
the reaction mixture and the stirring was continued at room temperature until consumption of
the starting material (monitored by TLC: 16 h). Next, the mixture was diluted in 5 mL of
EtOAc and the organic extract was washed with 1 M NaOH, dried over Na SO , filtered and
2
4
concentrated under reduced pressure. The resulting residue was purified through column
27
chromatography on silica gel (8:2 hexane/EtOAc) to give ethyl 2-diazohydrocinnamate (9)
-1
as an oil (140 mg, 69%) with high degree of purity. IR (neat) νmax/cm : 3064, 3031, 2982,
1
2
935, 2085, 1742, 1693, 1263, 1105, 738, 702; H NMR (400 MHz, CDCl ):
δ
7.35-7.21 (m,
3
13
5
H), 4.24 (q, J = 7.1 Hz, 2H), 3.62 (s, 2H), 1.27 (t, J = 7.1 Hz, 3H); C NMR (100 MHz,
167.1, 137.2, 128.7 (2 × CH), 128.3 (2 × CH), 127.0, 60.8, 29.3, 14.4 (C=N is
CDCl ):
δ
3
2
+
2
+
absent); HRMS (ESI+) calcd for C H N O [M+Na] : 227.0791, found: 227.0790.
11
12
2
17

ACCEPTED MANUSCRIPT
4
.8. i-Pr NH-mediated one-pot preparation of ethyl 4-azido-2-diazo-3-oxobutanoate (2a) from
2
ethyl 4-chloroacetoacetate (1b) under aqueous medium
To a solution of ethyl 4-chloroacetoacetate (1b, 494 mg, 3.0 mmol) and ABSCl (911 mg, 3.9
mmol) in acetone (6.0 mL) under stirring at 0-5 °C was added a cold solution of NaN (487
3
mg, 7.5 mmol) in H O (3.0 mL) followed by β-CD (170 mg, 0.15 mmol) and i-Pr NH (303 mg,
2
2
3.0 mmol). Then the reaction mixture was stirred at room temperature for 16 h. Next, the
mixture was diluted in 15 mL of EtOAc and the organic extract was washed with brine, dried
over Na SO , filtered and concentrated under reduced pressure. After complete removal of
2
4
the solvent, the residue was triturated in ethyl ether and the resulting mixture was again
concentrated under reduced pressure. The final solid residue was repeatedly triturated with
hexane to separate out the insoluble ABSNH by decantation. The resulting supernatants
2
were filtered and concentrated under reduced pressure to give 4-azido-2-diazo-3-
oxobutanoate (2a) as an oil (464 mg, 78%) with high degree of purity.
4.9. Typical procedure for the Knoevenagel-Knittel condensation
To a mixture of pyrrolidine (212 mg, 3.0 mmol) and 3-chloropropionic acid (325 mg, 3.0
mmol) in isopropanol (4.0 mL) under stirring at 25 °C was added ethyl 4-azido-2-
diazoacetoacetate (2a, 394 mg, 2.0 mmol) followed by the aromatic aldehyde (2.5 mmol).
Then the reaction mixture was stirred at room temperature until consumption of the starting
material (monitored by TLC: 14 to 26 h, see Table 3). The final mixture was diluted with
CH Cl and the organic extract was washed with 0.1 M HCl, satd NaHCO and brine, dried
2
2
3
over Na SO , filtered and concentrated under reduced pressure. The resulting residue was
2
4
purified through column chromatography on silica gel using gradient mixtures of
hexane/EtOAc as eluent to give the corresponding condensation products 11 as oils.
10a
4.9.1. Ethyl (Z)-4-azido-2-diazo-3-oxo-5-phenylpent-4-enoate (11a)
1
Yield 65% (371 mg); H NMR (400 MHz, CDCl ):
δ 7.77 (d, 2H, J = 7.6 Hz), 7.42-7.32 (m,
3
3H), 6.45 (s, 1H), 4.31 (q, 2H, J = 7.2 Hz), 1.31 (t, 3H, J = 7.2 Hz).
4.9.2. Ethyl (Z)-4-azido-2-diazo-5-(4-methylphenyl)-3-oxopent-4-enoate (11b)
-1
Yield 90% (539 mg); IR (neat) νmax/cm : 2980, 2115, 1722, 1620, 1603, 1370, 1325, 1300,
1
1
099, 746; H NMR (400 MHz, CDCl ):
δ
7.68 (d, 2H, J = 8.0 Hz), 7.19 (d, 2H, J = 8.0 Hz),
3
13
6
.45 (s, 1H), 4.31 (q, 2H, J = 7.2 Hz), 2.37 (s, 3H), 1.30 (t, 3H, J = 7.2 Hz); C NMR (100
180.8, 160.8, 140.1, 130.6 (2 × CH), 130.2, 130.1, 129.4 (2 × CH), 127.0,
MHz, CDCl ):
δ
3
+
+
6
2.1, 21.6, 14.4 (C=N is absent); HRMS (ESI+) calcd for C H N O Na [M+Na] : 322.0911,
2 14 13 5 3
found: 322.0909.
.9.3. Ethyl (Z)-4-azido-2-diazo-5-(4-methoxyphenyl)-3-oxopent-4-enoate (11c)
4
18

ACCEPTED MANUSCRIPT
-1
Yield 75% (473 mg); IR (neat) νmax/cm : 2980, 2838, 2134, 2115, 1722, 1597, 1509, 1304,
1
1
257, 1177, 831; H NMR (400 MHz, CDCl ):
δ
7.76 (d, 2H, J = 8.8 Hz), 6.91 (d, 2H, J = 8.8
3
13
Hz), 6.46 (s, 1H), 4.30 (q, 2H, J = 7.0 Hz), 3.84 (s, 3H), 1.30 (t, 3H, J = 7.0 Hz); C NMR
100 MHz, CDCl ): 180.4, 160.6 (2 × C), 132.3 (2 × CH), 128.7, 127.0, 125.6, 113.8 (2 ×
(
δ
3
+
+
CH), 61.8, 55.1, 14.1 (C=N is absent); HRMS (ESI+) calcd for C H N O Na [M+Na] :
2
14 13
5
4
338.08598, found: 338.08596.
4.9.4. Ethyl (Z)-4-azido-2-diazo-5-(3-methoxyphenyl)-3-oxopent-4-enoate (11d)
-1
Yield 76% (478 mg); IR (neat) νmax/cm : 2982, 2836, 2138, 2116, 1726, 1620, 1370, 1304,
1
1
105, 741, 688; H NMR (400 MHz, CDCl ):
δ
7.38 (d, 1H, J = 1.6 Hz), 7.30-7.26 (m, 2H),
3
6.90-6.86 (m, 1H), 6.39 (s, 1H), 4.29 (q, 2H, J = 7.2 Hz), 3.81 (s, 3H), 1.28 (t, 3H, J = 7.2
13
Hz); C NMR (100 MHz, CDCl ):
δ
180.8, 160.5, 159.5, 134.1, 131.0, 129.4, 126.2, 123.3,
3
+
1
15.4, 115.3, 62.1, 55.3, 14.3 (C=N is absent); HRMS (ESI+) calcd for C H N O Na
2 14 13 5 4
+
[
M+Na] : 338.0860, found: 338.0858.
4.9.5. Ethyl (Z)-4-azido-5-(4-bromophenyl)-2-diazo-3-oxopent-4-enoate (11e)
-1
Yield 67% (488 mg); IR (neat) νmax/cm : 2980, 2118, 1724, 1616, 1582, 1484, 1370, 1300,
1
1
6
1
096, 1010; H NMR (400 MHz, CDCl ):
δ
7.64 (d, 2H, J = 8.5 Hz), 7.50 (d, 2H, J = 8.5 Hz),
3
13
.35 (s, 1H), 4.31 (q, 2H, J = 7.2 Hz), 1.30 (t, 3H, J = 7.2 Hz); C NMR (100 MHz, CDCl ):
δ
3
80.8, 160.5, 132.0 (2 × CH), 131.9, 131.8 (2 × CH), 131.5, 124.9, 123.8, 62.2, 14.4 (C=N is
2
+
+
absent); HRMS (ESI+) calcd for C H BrN O Na [M+Na] : 385.9859, found: 385.9857.
13
10
5
3
4.10. Typical procedure for the aminolysis of Knoevenagel-Knittel adducts 11
To a solution of the Knoevenagel-Knittel adduct 11 (1.0 mmol) in THF (2.0 mL) under stirring
at 25 °C was added the corresponding amine (1.2 mmo l). Then the reaction mixture was
stirred at room temperature until consumption of the starting material (monitored by TLC: 1 to
5
0 h, see Table 4). The final mixture was diluted with CH Cl and the organic extract was
2 2
washed with 0.1 M HCl and brine, dried over Na SO , filtered and concentrated under
2
4
reduced pressure. The resulting residue was purified through column chromatography on
silica gel (85:15 hexane/EtOAc) to give the corresponding acrylamides 12 as crystalline
yellow solids.
4.10.1. (Z)-2-Azido-N-butyl-3-phenylacrylamide (12a)
-1
Yield 88% (215 mg); mp 78-79 °C ; IR (neat) νmax/cm : 3319, 2957, 2872, 2114, 1636, 1613,
1
1
537, 1371, 690; H NMR (400 MHz, CDCl ):
δ
7.59 (d, 2H, J = 7.5 Hz), 7.38 (t, 2H, J = 7.5
3
Hz), 7.30 (t, 1H, J = 7.5 Hz), 6.76 (s, 1H), 6.44 (br s, 1H), 3.37 (q, 2H, J = 7.3 Hz), 1.57 (qt,
13
2
H, J = 7.3 Hz), 1.39 (st, 2H, J = 7.3 Hz), 0.95 (t, 3H, J = 7.3 Hz); C NMR (100 MHz,
CDCl ): 163.2, 133.5, 132.9, 129.5 (2 × CH), 128.6, 128.4 (2 × CH), 121.3, 39.8, 31.5, 20.1,
δ
3
+
+
1
3.7; HRMS (ESI+) calcd for C H N ONa [M+Na] : 267.1216, found: 267.1218.
13 16 4
19

ACCEPTED MANUSCRIPT
4.10.2. (Z)-2-Azido-N-benzyl-3-phenylacrylamide (12b)
-1
Yield 65% (181 mg); mp 101-102 °C ; IR (neat) νmax/cm : 3287, 3031, 2920, 2115, 1636,
1
1
7
1
616, 1534, 1373, 1271, 689; H NMR (400 MHz, CDCl ):
δ
7.59 (d, 2H, J = 8.0 Hz), 7.45-
3
13
.25 (m, 8H), 6.84 (s, 1H), 6.74 (br s, 1H), 4.58-4.52 (m, 2H); C NMR (100 MHz, CDCl );
δ
3
63.2, 137.7, 132.9, 130.0, 129.8 (2 × CH), 129.0 (2 × CH), 128.9, 128.6 (2 × CH), 128.1 (2 ×
+
+
CH), 127.9, 122.2, 44.2; HRMS (ESI+) calcd for C H N O [M+H] : 279.1240, found:
16
15
4
279.1243.
4.10.3. (Z)-2-Azido-N-butyl-3-(4-methylphenyl)acrylamide (12c)
-1
Yield 90% (232 mg); mp 111-112 °C ; IR (neat) νmax/cm : 3312, 2964, 2931, 2868, 2116,
1
1
7
1
634, 1612, 1533, 1323, 876, 814; H NMR (400 MHz, CDCl ):
δ
7.49 (d, 2H, J = 7.8 Hz),
3
.18 (d, 2H, J = 7.8 Hz), 6.73 (s, 1H), 6.45 (br s, 1H), 3.36 (q, 2H, J = 7.4 Hz), 2.36 (s, 3H),
13
.58 (qt, 2H, J = 7.4 Hz), 1.39 (st, 2H, J = 7.4 Hz), 0.95 (t, 3H, J = 7.4 Hz); C NMR (100
163.3, 138.9, 130.1, 129.6 (2 × CH), 129.4, 129.2 (2 × CH), 121.7, 39.8,
MHz, CDCl ):
δ
3
+
+
3
2
4
1.6, 21.4, 20.1, 13.7; HRMS (ESI+) calcd for C H N O [M+H] : 259.1553, found
14 19 4
59.1554.
.10.4. (Z)-N-Allyl-2-azido-3-(4-methylphenyl)acrylamide (12d)
-1
Yield 76% (184 mg); mp 92-93 °C ; IR (neat) νmax/cm : 3426, 3292, 3045, 2920, 2114, 1636,
1
1
2
1
3
614, 1533, 1369, 922, 810; H NMR (400 MHz, CDCl ):
δ
7.50 (d, 2H, J = 7.8 Hz), 7.20 (d,
3
H, J = 7.8 Hz), 6.82 (s, 1H), 6.43 (br s, 1H), 5.90 (ddt, 1H, J = 6.0, 10.0, 17.2 Hz), 5.26 (dd,
H, J = 1.2, 17.2 Hz, 1H), 5.20 (dd, 1H, J = 1.2, 10.0 Hz), 4.01 (t, 2H, J = 6.0 Hz), 2.37 (s,
13
H); C NMR (100 MHz, CDCl ):
δ 168.0, 139.2, 133.7, 130.1, 129.7 (2 × CH), 129.6, 129.3
3
+
+
(
2 × CH), 122.2, 117.2, 42.5, 21.5; HRMS (ESI+) calcd for C H N O [M+H] : 243.1240,
13 15 4
found 243.1241.
4.10.5. (Z)-2-Azido-N-butyl-3-(4-methoxyphenyl)acrylamide (12e)
-1
Yield 94% (258 mg); mp 116-117 °C ; IR (neat) νmax/cm : 3272, 2958, 2932, 2871, 2121,
1
1
636, 1616, 1540, 1509, 1265, 1177, 1032; H NMR (400 MHz, CDCl ):
δ
7.57 (d, 2H, J = 8.5
3
Hz,), 6.91 (d, 2H, J = 8.5 Hz), 6.73 (s, 1H), 6.25 (br s, 1H), 3.84 (s, 3H), 3.38 (q, 2H, J = 7.2
13
Hz), 1.62-1.54 (m, 2H), 1.41 (st, 2H, J = 7.5 Hz), 0.96 (t, 3H, J = 7.5 Hz); C NMR (100 MHz,
CDCl ): 163.4, 159.9, 131.2 (2 × CH), 128.3, 125.7, 121.4, 114.0 (2 × CH), 55.3, 39.8, 31.6,
δ
3
+
+
2
0.1, 13.7; HRMS (ESI+) calcd for C H N O Na [M+Na] :297.1322, found 297.1321.
14 18 4 2
4.10.6. (Z)-N-Allyl-2-azido-3-(4-methoxyphenyl)acrylamide (12f)
-1
Yield 85% (219 mg); mp 97-98 °C ; IR (neat) νmax/cm : 3273, 2930, 2835, 2123, 1636, 1616,
1
1
605, 1509, 1253, 1177, 1030, 830; H NMR (400 MHz, CDCl ):
δ
7.59 (d, 2H, J = 8.6 Hz,
3
2H), 6.92 (d, 2H, J = 8.6 Hz), 6.78 (s, 1H), 6.37 (br s, 1H), 5.91 (ddt, 1H, J = 5.6, 10.0, 17.0
13
Hz), 5.32-5.17 (m, 2H), 4.02 (tt, 2H, J = 1.5, 5.6 Hz), 3.84 (s, 3H); C NMR (100 MHz,
20

ACCEPTED MANUSCRIPT
CDCl ):
δ
160.0, 150.1, 133.8, 131.4 (2 × CH), 128.0, 125.6, 122.0, 117.2, 114.1 (2 × CH),
3
+
+
5
5.4, 42.5; HRMS (ESI+) calcd for C H N O [M+H] : 259.1190, found 259.1186.
13 15 4 2
4.10.7. (Z)-2-Azido-N-benzyl-3-(4-methoxyphenyl)acrylamide (12g)
-1
Yield 66% (203 mg); mp 88-89 °C ; IR (neat) νmax/cm : 3289, 2932, 2118, 1636, 1605, 1535,
1
1
510, 1250, 1180, 1030, 830; H NMR (400 MHz, CDCl ):
δ
7.57 (d, 2H, J = 8.4 Hz), 7.40-
3
7.30 (m, 5H), 6.91 (d, 2H, J = 8.4 Hz), 6.78 (s, 1H), 6.62 (br s, 1H), 4.57-4.55 (m, 2H), 3.83
13
(
s, 3H); C NMR (100 MHz, CDCl ):
δ
163.6, 160.0, 137.8, 131.4 (2 × CH), 128.9 (2 × CH),
3
128.0 (2 × CH), 127.9, 127.8, 125.6, 122.0, 114.0 (2 × CH), 55.4, 44.2; HRMS (ESI+) calcd
+
2
+
for C H N O [M+H] : 309.1346, found 309.1345.
17
17
4
4.10.8. (Z)-N-Allyl-2-azido-3-(3-methoxyphenyl)acrylamide (12h)
-1
Yield 87% (225 mg); mp 106-107 °C ; IR (neat) νmax/cm : 3410, 2955, 2840, 2121, 1654,
1
1
618, 1534, 1258, 1047; H NMR (400 MHz, CDCl ):
δ
7.29 (t, 1H, J = 7.6 Hz), 7.18 (br s,
3
1H), 7.14 (d, 1H, J = 7.6 Hz), 6.88–6.84 (m, 1H), 6.77 (s, 1H), 6.50 (br s, 1H), 5.90 (ddt, 1H,
J = 6.0, 10.0, 17.2 Hz), 5.25 (dd, 1H, J = 1.2, 17.2 Hz), 5.20 (dd, 1H, J = 1.2, 10.0 Hz), 4.02-
13
3
.98 (m, 2H), 3.82 (s, 3H); C NMR (100 MHz, CDCl ):
δ
163.2, 159.5, 134.2, 133.6, 130.2,
3
+
1
29.5, 122.4, 121.7, 117.2, 114.9, 114.6, 55.4, 42.5; HRMS (ESI+) calcd for C H N O
2
13
15
4
+
[
M+H] : 259.1190, found 259.1187.
4.10.9. (Z)-2-Azido-3-(4-bromophenyl)-N-butylacrylamide (12i)
-1
Yield 92% (297 mg); mp 122-124 °C ; IR (neat) νmax/cm : 3432, 3309, 2962, 2931, 2873,
1
2
114, 1632, 1611, 1540, 1534, 1375; H NMR (400 MHz, CDCl ):
δ
7.50-7.48 (m, 4H), 6.56
3
(
s, 1H), 6.31 (br s, 1H), 3.40-3.35 (m, 2H), 1.58 (qt, 2H, J = 7.6 Hz), 1.40 (st, 2H, J = 7.6 Hz),
1
3
0
1
.95 (t, 3H, J = 7.6 Hz); C NMR (100 MHz, CDCl ):
δ
163.1, 131.9, 131.6 (2 × CH), 131.1,
3
+
31.0 (2 × CH), 122.6, 119.3, 39.9, 31.5, 20.1, 13.7; HRMS (ESI+) calcd for C H BrN O
13
16
4
+
[
M+H] : 323.0502, found 323.0501.
4.10.10. (Z)-2-Azido-N-benzyl-3-(4-bromophenyl)acrylamide (12j)
-1
Yield 91% (325 mg); mp 133-134 °C ; IR (neat) νmax/cm : 3428, 3275, 2115, 1653, 1636,
1
1
616, 1540, 1374; H NMR (400 MHz, CDCl ):
δ
7.52-7.45 (m, 4H), 7.40-7.30 (m, 5H), 6.62
163.0, 137.5, 131.9, 131.7 (2 ×
CH), 131.1 (2 × CH), 130.8, 128.9 (2 × CH), 128.0 (2 × CH), 127.9, 122.9, 120.0, 44.2;
3
13
(
s, 1H), 4.56-4.54 (m, 2H); C NMR (100 MHz, CDCl ): δ
3
+
+
HRMS (ESI+) calcd for C H BrN O [M+H] : 357.0346, found 357.0342.
16
14
4
4
.11. Typical procedure for the synthesis of indoles 13
To a solution of the -azidocinnamamide 12 (0.3 mmol) in anhydrous CH Cl (2.0 mL) under
stirring at 25 °C was added Rh (AcO) (7 mg, 0.015 mmol). Then the reaction mixture was
α
2
2
2
4
stirred at 40 °C until consumption of the starting material (monitored by TLC: 13 to 27 h, see
Table 5). The final mixture was diluted with CH Cl and the organic extract was washed with
2
2
21

ACCEPTED MANUSCRIPT
brine twice, dried over Na SO , filtered and concentrated under reduced pressure. The
2
4
resulting residue was purified through a pad of celite/silica gel (8:2 hexane/EtOAc for indoles
3a,d,e and 7:3 hexane/EtOAc for 13b,c) to give the corresponding indoles as crystalline
1
solids.
N-Butyl-6-methyl-1H-indole-2-carboxamide (13a)
-1
Yield 98% (68 mg); mp 196-197 °C ; IR (neat) νmax/cm : 3254, 2953, 2924, 1633, 1538, 1406,
1
8
6
3
24, 739; H NMR (400 MHz, CDCl ):
δ
9.46 (br s, 1H), 7.51 (d, 1H, J = 8.2 Hz), 7.22 (s, 1H),
3
.97 (d, 1H, J = 8.2 Hz), 6.77 (br s, 1H), 6.19 (br s, 1H), 3.48 (q, 2H, J = 7.2 Hz), 2.46 (s,
13
H), 1.67-1.59 (m, 2H), 1.48-1.39 (m, 2H), 0.97 (t, 3H, J = 7.2 Hz); C NMR (100 MHz,
162.0, 137.0, 134.6, 130.5, 125.7, 122.8, 121.5, 111.9, 101.7, 39.6, 32.0, 22.0,
CDCl ):
δ
3
+
+
2
0.3, 13.9; HRMS (ESI-qTOF) Calcd for C H N O [M+H] : 231.1492, found 231.1495.
14 19 2
N-Butyl-6-methoxy-1H-indole-2-carboxamide (13b)
-1
Yield 93% (69 mg); mp 169-170 °C ; IR (neat) νmax/cm : 3421, 3261, 2958, 2930, 1624, 1545,
1
1
267, 1161, 826; H NMR (200 MHz, CDCl ):
δ
9.40 (br s, 1H), 7.49 (d, 1H, J = 8.5 Hz), 6.86
3
(
br s, 1H), 6.80 (dd, 1H, J = 2.2, 8.5 Hz), 6.76 (br s, 1H), 6.12 (br s, 1H), 3.85 (s, 3H), 3.49 (q,
13
2
H, J = 7.0 Hz), 1.68-1.55 (m, 2H), 1.52-1.33 (m, 2H), 0.97 (t, 3H, J = 7.2 Hz); C NMR (100
MHz, CDCl ):
δ
162.0, 158.3, 137.6, 130.0, 122.7, 122.1, 112.1, 102.0, 94.3, 55.6, 39.6, 32.0,
3
+
+
2
0.3, 13.9; HRMS (ESI+) calcd for C H N O [M+H] : 247.1441, found 247.1440.
14 19 2 2
N-Allyl-6-methoxy-1H-indole-2-carboxamide (13c)
-1
Yield 96% (66 mg); mp 180-181 °C ; IR (neat) νmax/cm : 3412, 3273, 2922, 2830, 1624, 1543,
1
1
272, 1256, 822; H NMR (400 MHz, CDCl ):
δ
9.69 (br s, 1H), 7.50 (d, 1H, J = 8.8 Hz), 6.87
3
(
d, 1H, J = 2.0 Hz), 6.83-6.79 (m, 2H), 6.28 (br s, 1H), 6.01-5.91 (m, 1H), 5.29 (dd, 1H, J =
13
1
.2, 17.2 Hz), 5.20 (dd, 1H, J = 1.2, 10.0 Hz), 4.15-4.11 (m, 2H), 3.84 (s, 3H); C NMR (100
MHz, CDCl ):
δ
161.9, 158.4, 137.7, 134.3, 129.7, 122.8, 122.1, 116.8, 112.2, 102.5, 94.3,
3
+
+
5
5.6, 42.1; HRMS (ESI+) calcd for C H N O [M+H] : 231.1128, found 231.1127.
13 15 2 2
6-Bromo-N-butyl-1H-indole-2-carboxamide (13d)
-1
Yield 93% (82 mg); mp 208-209 °C ; IR (neat) νmax/cm : 3421, 3246, 2959, 2926, 2860, 1633,
1
1
547, 1404, 1246, 824; H NMR (400 MHz, CDCl , DMSO-d as internal standard):
δ
10.49
3
6
(
br s, 1H), 7.13 (br s, 1H), 6.97 (d, 1H, J = 8.5 Hz), 6.65 (dd, 1H, J = 1.3, 8.5 Hz), 6.52 (br s,
13
1H), 2.94-2.89 (m, 2H), 1.14-1.07 (m, 2H), 0.96-0.87 (m, 2H), 0.45 (t, 3H, J = 7.3 Hz);
C
NMR (100 MHz, CDCl , DMSO-d as internal standard):
δ
160.8, 136.8, 131.9, 125.8, 122.8,
3
6
+
1
22.3, 116.5, 114.4, 102.3, 38.7, 31.1, 19.5, 13.2; HRMS (ESI+) calcd for C H BrN O
13 15 2
+
[
M+H] : 295.0441, found 295.0441.
N-Benzyl-6-bromo-1H-indole-2-carboxamide (13e)
-1
Yield 94% (93 mg); mp 205-206 °C ; IR (neat) νmax/cm : 3434, 3259, 2926, 1636, 1542, 1314,
1
1
243, 734; H NMR (200 MHz, CDCl , DMSO-d as internal standard):
δ
10.61 (br s, 1H),
3
6
22

ACCEPTED MANUSCRIPT
7.87 (br s, 1H), 7.08-6.92 (m, 2H), 6.82-6.70 (m, 5H), 6.63-6.58 (m, 2H), 4.09 (d, 2H, J = 6.0
13
Hz); C NMR (100 MHz, CDCl , DMSO-d as internal standard):
δ
160.8, 138.3, 136.9,
3
6
131.7, 127.9 (2 × CH), 127.2 (2 × CH), 126.6, 125.8, 122.7, 122.4, 116.6, 114.4, 103.2, 42.7;
+
+
HRMS (ESI+) calcd for C H BrN O [M+H] : 329.0284, found 329.0286.
16
13
2
Appendix A. Supplementary data
Supplementary data related to this article (NMR spectra for all novel and relevant products,
and selected crystallographic data for indole 13b) can be found at http://
Full crystallographic tables (including structure factors) for compound 13b have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 1540527. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
We thank the Central de Análises (Departamento de Química, Universidade Federal de
Santa Catarina, Florianópolis) for spectroscopic analysis. Special thanks are due to CEBIME
(
Laboratorio Central de Biologia Molecular e Estrutural) for running the mass spectra. T.A.C.
thanks CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) for a
fellowship. M.M.S. is grateful to CNPq (Conselho Nacional de Desenvolvimento Cientifico e
Tecnológico) for a research fellowship. Financial support from INCT-Catalysis (Brazilian
Research Council) is also gratefully acknowledged.
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