Novel approach to synthesis of substituted 3-aminoquinolines from nitroarenes and protected ethyl aminocrotonate

Article abstract of DOI:10.1016/j.tet.2009.11.060

The addition of mono- and dianions of ethyl N-pivaloyl-3-aminocrotonate to substituted nitroarenes, followed by action of silylating or acylating agent, leads to 3-aminoquinoline carboxylic acid derivatives. Hydrolysis and decarboxylation of the latter, carried out efficiently under relatively mild conditions, afford 3-aminoquinolines diversely substituted in the benzo-fused ring.

Full text of DOI:10.1016/j.tet.2009.11.060

Tetrahedron 66 (2010) 698–708
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel approach to synthesis of substituted 3-aminoquinolines
from nitroarenes and protected ethyl aminocrotonate
*
´
Robert Bujok, Andrzej Kwast, Piotr Cmoch, Zbigniew Wrobel
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warszawa, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2009
Received in revised form 29 October 2009
Accepted 12 November 2009
Available online 17 November 2009
The addition of mono- and dianions of ethyl N-pivaloyl-3-aminocrotonate to substituted nitroarenes,
followed by action of silylating or acylating agent, leads to 3-aminoquinoline carboxylic acid derivatives.
Hydrolysis and decarboxylation of the latter, carried out efficiently under relatively mild conditions,
afford 3-aminoquinolines diversely substituted in the benzo-fused ring.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Carbanions
Nitroarenes
Heterocycles
Nitroso group
Cyclisation
1. Introduction
produces variable results. The electrophilic character of the re-
action limits the whole synthesis to anilines bearing electro-
3-Aminoquinolines are frequently employed in synthesis and
modifications of a variety of potentially biologically active com-
pounds.1 In particular, 3-aminoquinoline terminated dipeptides
have been found to exhibit interesting pharmacological proper-
ties.1a–c Taking part in a project directed towards compounds of
similar structure and of potential biological activity, we were re-
quired to synthesize 3-aminoquinolines bearing numerous differ-
ent substituents, such as Cl, Br, F, CF3 and others, in the benzo-fused
ring. Literature reports on synthesis of such derivatives, which have
no additional substituents in the heterocyclic part of the molecule,
or have such substituents, which could be easily removed, are rare.
A majority of them are based upon the reduction of the corre-
sponding 3-nitroquinolines. Preparation of the latter can be ac-
complished by nitration of the quinoline ring, or much more
conveniently and regioselectively, by construction of the hetero-
cyclic ring on substituted aniline derivative.2 The latter approach
involves two pathways (Scheme 1). The first one is based on a two-
step condensation of the appropriate aniline with the sodium salt
of nitromalonaldehyde3dan explosive compound prepared from
mucobromic acid.4 Although the first step, formation of Schiff bases
(anils), is usually efficient, the cyclization step leading to the
bicyclic skeleton requires selected conditions of acidic catalysis and
ndonating substituents.3b This method has been applied to
preparation of 6-methyl- and 6-methoxy- derivatives of 3-
aminoquinolines.3a,b
NO2
OH
OHC
OHC
NH2
N
NO2Na
H+
R
R
acids
reflux
NO2
N
NH2
NO2
NH2
HON
CHO
H+
R
R
+
O
Py
-
EtO2C
Br
N
R
Scheme 1. Common synthetic pathways leading to 3-aminoquinolines.
* Corresponding author. Tel.: þ48 22 6328395; fax: þ48 22 6326681.
´
E-mail address: wrobel@icho.edu.pl (Z. Wrobel).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.060

R. Bujok et al. / Tetrahedron 66 (2010) 698–708
699
Another, more general method, which could be suitable also for
electron deficient systems, is the Friedlander-type condensation,5
which comprises reaction of 2-formylanilines with nitro-
acetaldehyde oxime (metazonic acid)6da product of self-conden-
sation of nitromethane under basic conditions.7 The drawback of
this method is that the desired 2-formylanilines are usually un-
stable and their preparation from easily available substrates is
difficult.8–10 Directed metallation of N-protected anilines8 or bro-
moanilines9 followed by action of dimethylformamide, and re-
duction of ortho-nitro aryl aldehydes10 are employed in this
respect.
The ester group was chosen for stabilization of the allylic anion,
bearing in mind its further removal from the expected cyclization
product. In preliminary experiments, commercial and cheap ethyl-
3-aminocrotonate was employed.
On the basis of our earlier results, two procedures were exam-
ined for the reactiondthe so called ‘one-pot’ procedure12 and the
‘step-by-step’ method.16 The first one consists of mixing the sub-
strates with N,O-bis-trimethylsilylacetamide (BSA) and DBU in DMF
at ambient temperature, for an adequatedusually pro-
longeddtime. In the second procedure, deprotonation of the ami-
nocrotonate with strong base, formation of
s
H-adducts with the
An interesting synthesis of a few substituted 3-aminoquinolines,
omitting preparation of corresponding nitroquinolines, comprises
condensation of substituted 2-formylanilines with 1-(2-ethoxy
carbonyl-2-oxoethyl)pyridinium bromide, which, followed by
aminolysis with pyrrolidine, leads to 3-aminoquinoline-2-carboxy
lates.11 In view of possible further decarboxylation of the latter, it
can be considered as a potential precursor of the target 3-amino-
quinolines. The method, however, also depends on availability of
appropriate 2-formylanilines.
The considerations presented above and also attempted prepa-
rations of selected target 3-aminoquinolines, carried out according
to known schemes, led us to the conclusion, that synthesis of 3-
aminoquinolines in general, and particularly those bearing electro-
nwithdrawing groups, is a really demanding task and made us think
about an alternative, shorter and/or more effective way of their
preparation.
Working for the last decade on synthesis of polycyclic nitrogen
compounds we have found that the combination of a base and
a Lewis acid promoted multistep reactions of nitroarenes with
properly functionalized precursors of allylic anions, leading to var-
ious substituted quinolines and other bicyclic heterocycles with
a fused pyridine ring.12 Similar approach was successful also in
transformations of nitroarenesddepending on the structure of the
nucleophilic agentdinto 1-hydroxyindole,13 2,1-benzisoxazole14,15b
or acridine15,16 systems. The role of the Lewis acid could be played
efficiently also by silylating12a–c,15,16 or acylating agents.16 Thus we
decided to adopt this methodology for synthesis of the title
compounds.
nitroarene, its transformation into nitroso compound promoted by
pivaloyl chloride and final cyclizationdalthough carried out in the
same potdwere time-separated. The process was carried out at
ꢀ78 ꢁC in order to attain possibly high stability of the intermediate
s
H-adduct.
Unfortunately, for ethyl 3-aminocrotonate treated with nitro-
arenes such as 4-chloro- and 2,4-dichloronitrobenzene, neither of
the above methods led to the desired products. Hence, one can
suppose, that protection of the amino function to avoid its depro-
tonation is necessary to generate the allylic anion. However,
attempted reactions of an N,N-disubstituted derivative, namely
ethyl-3-phthalimidocrotonate, were also unsuccessful. On the
other hand, N-benzoyl and N-pivaloyl aminocrotonates gave posi-
tive preliminary results, and the latterdmore promisingdwas
subjected to the further inspection.
Thus, when ethyl 3-(N-pivaloylamino)crotonate17 2 was reacted
with substituted nitrobenzenes and selected heterocyclic nitro-
arenes (1) under ‘one-pot’ conditions, the slow reactions led to the
3-aminoquinoline derivatives, but the yields were generally low.
Only the more electrophilic 6-nitroquinoline (1a) gave the cycli-
zation product in moderate 30% yield, while substituted nitroben-
zenes (1e,f) reacted very poorly (Scheme 3, Table 1).
CO2Et
NHCOt-Bu
NO2
O
N
R1
BSA
DBU
R1
NH
CO2Et
+
R3
R3
DMF
R2
R2
1
2
3a R1 = H, R2 - R3 = -N(CH)3-
3e R1 = H, R2 = CF3, R3 = H
3f R1 = R2 = Cl, R3 = H
2. Results and discussion
As we have found earlier, the reaction of nitroarenes with allylic
carbanions leads to a new fused pyridine ring via addition of the
more nucleophilic centre of the ambident anion at the ortho posi-
NHCOt-Bu
CO2Et
CO2Et
CO2Et
NHCOt-Bu
H
NHCOt-Bu
tion with formation of s
H-adducts, followed by transformation of
H
N
N
N
the nitro group into a nitroso groupdpromoted by base and Lewis
acid, silyl or acyl halidedthen completed by condensation of the
nitroso function with a side-chain allylic anion. Accordingly, the
assumed course of the reaction leading to 3-aminoquinoline de-
rivatives, is depicted on Scheme 2.
S
N
3b
3d
3c
Scheme 3. One-pot synthesis of precursors of 3-aminoquinolines.
_
Table 1
One-pot condensation of nitroarenes 1 with 2
NO2
NO2
NR2
H
_
+
NR2
EWG
Entry
Nitroarene
R1
3
Yield a/%
EWG
R
R
R2
R3
1
2
3
4
5
6
H
H
–N(CH)3–
a
b
c
d
e
f
30
20
18
11
6
–(CH)4–
O
b
NR2
EWG
NR2
N
c
N
_
H
Cl
CF3
Cl
H
H
EWG
2
a
R
Isolated.
2-Nitrothiophen.
4-Nitropyridine.
R
b
c
Scheme 2. Projected synthesis of substituted 3-aminoquinoline precursors.

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R. Bujok et al. / Tetrahedron 66 (2010) 698–708
Surprisingly, the isolated cyclization product 3 did not have the
in Table 3) show that also some side reactions can be responsible for
observed requirement of the excess of the nitroarene. In the re-
actions finished at room temperature a difficult to separate product
of pivaloylation of 22ꢀ was formed in substantial amounts.19 Its
formation was, however, suppressed by quenching the reaction
mixture at ꢀ78 ꢁC.
expected structure, with the ethoxycarbonyl group at position 2 of
the quinoline system. The substitution pattern was unambiguously
determined by means of 1D NOESY experiments applied to 3b, in
which protons at positions 1 (singlet, 10.5 ppm) and 10 (multiplet,
around 8.7 ppm) demonstrated a strong NOE effect. In this case
numbering of the ring positions obeys the rules for benzoquinoline
systems (corresponding protons are indicated on Scheme 3).
Formation of 3 implies that addition of 2 to the nitroaromatic
ring occurred with its terminal carbon atom 4. It is obvious that
action of the base (DBU) on 2 should preferentially lead to the
abstraction of the amide proton with formation of the most stable,
strongly delocalised allylic anion 2ꢀN (Fig. 1). Apparently, its nu-
Table 2
Step-by-step synthesis of 3f from 1f and 2 carried out under various reaction
conditions
Entry
Base/equiv
HMPA/equiv.
1f:2 ratio
Procedurea
Yieldb/%
NaH
n-BuLi
cleophilicity is too low to produce
s
H-adducts with nitroarenes.
1
2
3
4
5
6
7
8
9
1.3
1.3
1.4
1.1
1.3
1.3
d
1.2
1.2
2
d
2
2
2
4
2
2
2
2
1
1
0.9
0.9
1.4
3
3
2
1
A
A
A
A
A
B
B
B
B
23
34
45
30
31
54
49
57
41
Instead, less stable allylic anion 2ꢀC or, maybe, dianion 22ꢀ, al-
though formed in very low concentrations, are reactive enough to
react with the nitroarene, leading to the cyclization products 3.
2c
2
2
3
2.2
2.2
d
_
_
N
O
CO2Et
HN
O
CO2Et
O
CO2Et
N
d
_
_
a
Procedure A: dianion of 2 was treated with 1f for 10 min at ꢀ78ꢁC then 4 equiv
of Et3N and 4 equiv of pivaloyl chloride were added. The mixture was heated to
room temperature, stirred for 2 h and quenched. B: as procedure A, but after ad-
dition of pivaloyl chloride the mixture was stirred at ꢀ78ꢁC for 2 h, then quenched
at that temperature.
2- N
22-
2- C
Figure 1. Possible anions generated from 2.
b
Isolated by column chromatography. Based on 2.
LDA instead of n-BuLi was used.
c
In the light of these results, we decided to produce a more re-
active nucleophile from 2, by generating its dianion 22ꢀ in higher
concentration. This process required stronger base for the second
deprotonation, therefore we applied the ‘step-by-step’ procedure
(Scheme 4).
Table 3
Step-by-step condensation of substituted nitroarenes 1 with dianion of 2
Entry R1
R2
R3
3
Yielda/%
Based on 2 On consumed 1
_
NO2
1
2
3
4
5
6
7
8
H
Cl
F
CF3
Cl
H
H
H
H
H
Cl
H
H
H
H
e
f
g
h
i
j
k
l
m
n
o
p
q
r
24
18
O
NO2
57
41
R1
N
_
R1
2 eq BuLi
44
40
t-BuCOCl
NEt3
H
+
2
Cl
Br
Cl
Cl
Br
Cl
Cl
CN
47
52
R3
34 (9)b
47
35 (9)b
78
R3
CO2Et
H
R2
R2
CH2OCOt-Bu
CF3
H
H
Cl
H
H
H
H
H
47
34
H
1
- adduct
48
32
9
CO2t-Bu
H
Cl
40
31
10
11
12
13
14
15
16
17
18
31
52
23
26
CO2t-Bu Cl
Cl
CO2t-Bu
CN
H
20 (7)b
13 (13)b
20
26 (9)b
25 (25)b
20
_
O
OMe
H
H
CN
F
t-BuCOO
R1
O
O
NO
dc
N
R1
N
_
s
t
u
v
16
N
_
H
H
H
16
23
28
25
3
H
H
17d
5
R3
R2
CO2Et
R3
CO2Et
Cl
R2
a
Isolated yields.
Yield of 6 in parentheses.
Not estimated.
5
b
c
4
Scheme 4. Reaction pathway of the step-by-step synthesis of 3.
d
Prior to the quench the reaction mixture was warmed to room temperature and
stirred overnight.
Preliminary attempts at generation of dianion 22ꢀ were done by
means of NaH and n-BuLi added consecutively as in the usual
methodology used for generation of dianions from b-dicarbonyl
It is worth mentioning, that the product obtained in the model
reaction of 1f with the dianion 22ꢀ was identical with that isolated
from the ‘one-pot’ reaction of 1f, and this result was actually
a reason to disprove the initially assumed structure of the latter
product, shown in Scheme 2.
On the basis of the results of introductory experiments, condi-
tions presented in Table 2, entry 8, and procedure B were chosen,
and applied in the step-by-step reactions of 2 with numerous dif-
ferently substituted nitroarenes (Scheme 5, Table 3). Intentionally,
most of the substituents are of electronwithdrawing character,
since such electron deficient aromatic substrates were difficult to
transform into corresponding aminoquinolines following known
methods (see above).
compounds.18 Optimization of selected reaction conditions of the
model reaction of 2 with 1f (Table 2) revealed that this procedure
could be simplified by use of n-BuLi alone as a base in the presence
of 2.2 equiv of HMPA. It was found that the yield of products 3 was
somewhat improved by use of a twofold excess of nitroarene 1, the
unreacted part of which could be easily recovered. This observation
may indicate the importance of the s
H-adduct formation step, as
the excess of 1 shifts its equilibrium. On the other hand, conversion
of 1, which, in many cases, is much higher than the yield of the
product, and sometimes exceeds stoichiometric amount (the cases
when the yield based on consumed 1 is lower than that, based on 2

R. Bujok et al. / Tetrahedron 66 (2010) 698–708
701
temperature prior to the quench. From the reaction performed in
the usual way i.e., when quenched at ꢀ78 ꢁC, the only defined
product isolated was nitroso compound 5uH (Scheme 4, H refers to
the protonated form). It was unstable, but could be isolated, puri-
fied and fully characterized including the 15N NMR spectrum,
confirming the nitroso form against the tautomeric oxime struc-
ture. Nitroso derivatives were often postulated as intermediates in
reactions of nitroarenes with nucleophiles leading to various ni-
trogen heterocycles, but to our knowledge, they have never been
isolated from such reactions.20
Compound 5uH could be transformed to quinoline 3u either
under the previous reaction conditions or under improved condi-
tions, consisting of trimethylsilyl chloride and Et3N in DMF at room
temperature. In both cases the reactions were not very efficient (11
and 24% yield, respectively), which may explain the low yield of 3u
obtained in the reaction of 2 with 1u (Table 3, entry 17). The ex-
ceptional behaviour of 4-fluoronitrobenzene can be rationalized by
strong conjugation of the lone pair of para-fluorine with the nitroso
group, which could stabilize and decrease the reactivity of the
latter.
Transformation of the protected ethoxycarbonyl aminoquino-
lines 3 into desired aminoquinolines 7 was accomplished by pro-
longed heating with concentrated hydrochloric acid (Scheme 6,
Table 4). Since the hydrolyses of both the ester and the amide
groups were relatively fast, which was observed by monitoring the
reaction, the rate of the whole process depended on de-
carboxylation of the intermediate carboxylic acids. Under the
conditions applied, hydrolysis of all ester functions as well as the
ArOMe group took place, which resulted in formation of the cor-
responding carboxylic acids (7m, p), hydroxymethyl (7j) and hy-
droxy (7q) quinolines.
O
R3
O
R3
R1
R2
R2
NH
NH
i, ii, iii, iv
2
N
CO2Et
N
O
CO2Et
R1
3
6
Scheme 5. Reagents and conditions: (i) 2.2 equiv of HMPA, 2.2 equiv of BuLi/THF
ꢀ78 ꢁC (ii) 2 equiv of 1 (iii) 4 equiv of NEt3, 4 equiv of t-BuCOCl (iv) H2O ꢀ78 ꢁC.
All products of the ‘step-by-step’ reactions were assumed to
have a structure of 3, i.e., ethoxycarbonyl substituent in vicinity of
the ring nitrogen, on the basis of the expected reactivity of the
dianion 22ꢀ. This assumption was confirmed by 1H NMR selective
NOESY 1D spectra of 3h in which protons at positions 4 (s,
9.07 ppm) and 5 (dd, 8.01 ppm) showed evident NOE effect.
The results indicate that although electronegative groups facil-
itate formation of
s
H-adductsdan inevitable intermediate in the
synthesisdactivation of the aromatic ring is not the most impor-
tant factor governing the entire, multistep process. The best results
were obtained from nitroarenes with the ortho-position occupied
by a halogen atom (Table 3, entries 2–10), and the effect of addi-
tional activation of the ring by strong EWG (CF3, CO2t-Bu) at the
meta or para positions was not observed (entries 7 and 9). More-
over, replacing the ortho-halogen atom in 1 with CO2t-Bu and CN
groups led to significantly worse results (entries 14 and 15). Ap-
parently, the helpful role of the ortho-halogens is an effect of
a combination of their electronegativity, activating the ring for
nucleophilic addition at the other ortho position, and adequate
steric hindrance, which may facilitate formation of the nitroso in-
termediates (4 / 5, Scheme 4) and also increases resistance of the
latter against possible side reactions. 2-Iodonitrobenzene did not
enter the reaction; it seems that steric effect of the exceptionally
bulk ortho-halogen significantly reduces electrophilic reactivity of
the nitroaromatic ring.
R3
R2
NH2
20 % HCl
In a few cases (entries 5, 12 and 13), along with formation of 3,
noticeable amounts of their N-oxides (6) are produced (Scheme 5).
Their origin is unknown yet. Possibly, they come from the oxidation
3
N
reflux
R1
of s
H-adducts (e.g., by the excess of the nitroarene) and subsequent
7
intramolecular condensation of the nitro, instead of the nitroso,
group.
Scheme 6. Hydrolysis and decarboxylation of 3.
Table 4
Hydrolysis of 3 to substituted 3-aminoquinolines 7
Entry
3
Time/days
7
R1
R2
R3
Yielda/%
Total yield 1->7 based on 2/%
1
2
3
4
5
6
7
8
a
b
e
f
g
h
j
k
l
m
n
p
q
6
10
2
2
2
2
2
3
2
2
3
2
2
a
b
e
f
g
h
j
k
l
m
n
p
q
H
H
H
Cl
F
Cl
Cl
Cl
Br
Cl
Cl
COOH
Cl
–N(CH)3–
–(CH)4–
CF3
Cl
H
H
H
H
Cl
72
56
22
11
22
38
44
47
27
40
39
40
25
19
11
H
H
H
H
91b
67
w100b
w100b
57
CH2OH
CF3
H
H
Cl
H
84b
9
81b
10
11
12
13
COOH
H
Cl
w100b
81b
93b
86
OH
H
a
Isolated yield.
Isolated and characterized as hydrochloride.
b
In the reactions of para-substituted nitroarenes, in which the
Besides the total hydrolysis/decarboxylation described above,
the amide function of 3 can be cleaved selectively. Heating 3f with
trimethylsilyl chloride in ethanol gave 8 in 67% yield (Scheme 7).
The reaction was used to provide additional confirmation of the
structure of 3. Hydrogenolysis of 8 led to dechlorinated ethyl-3-
aminoquinoline-2-carboxylate 9, a compound described in the
ortho-substituent is absent (entries 1, 16–18) the yields of the
products were rather low and the consumption of 2 comparatively
high. Among them, 4-fluoronitrobenzene turned out to be an ex-
ceptional case. The expected aminoquinoline derivative 3u was
obtained, in low yield, when the reaction was warmed to room

702
R. Bujok et al. / Tetrahedron 66 (2010) 698–708
NH2
extracted with AcOEt (3ꢂ50 mL), the combined extracts were
NH2
Cl
H2 Pd/C
EtOH
3f
washed with water, dried and evaporated. The products were pu-
rified by short column chromatography (SiO2/hexane, then hexane/
AcOEt, 13:1).
N
CO2Et
N
CO2Et
Me3SiCl
Cl
8 67%
9
88%
4.2.2. tert-Butyl 3-chloro-4-nitrobenzoate (1m). Yield 10.5 g, 82%.
Yellowish solid; mp 51–53 ꢁC. Rf (hexane/AcOEt 8:1) 0.50; IR (KBr,
Scheme 7.
cmꢀ1
(400 MHz, DMSO-d6)
J¼2.3 Hz, H-6), 7.92 (1H, d, J¼2.3 Hz, H-2), 8.09 (1H, d, J¼8.7 Hz, H-
)
nmax: 3103, 2987, 1713, 1584, 1530, 1293, 1136; 1H NMR
literature.11a While the melting point of not crystallized material
was unreliable, 1H NMR spectra taken in the same solvent matched
very well reported chemical shifts. However, coupling constants
reported in the literature, J¼5 Hz for all vicinal protons, including
those of the ethyl group, seem to be erroneous.
d
1.51 (9H, s, t-Bu), 7.88 (1H, dd, J¼8.7 Hz,
5); 13C NMR (100 MHz, CDCl3)
d
28.0, 83.1, 125.2, 116.9, 128.5, 132.8,
136.3, 150.1, 162.6; MS (EI, 70 eV, m/z (%)): 257 (1, Mþ), 186 (13), 185
(13),184 (47), 57 (100), 56 (40), 41 (15). Anal. Calcd for C11H12ClNO4:
C, 51.27; H, 4.69; N, 5.44. Found: C, 51.29; H, 4.89; N, 5.40.
3. Conclusions
4.2.3. tert-Butyl 5-chloro-2-nitrobenzoate (1p). Yield 8.8 g, 69%.
Yellow-orange oil. Rf (hexane/AcOEt 5:1) 0.46; IR (KBr, cmꢀ1
)
nmax
:
Searching for a general and possibly short method for the syn-
thesis of substituted 3-aminoquinoline building blocks, a novel ap-
proach was demonstrated. Starting from substituted nitrobenzenes,
step-by-step reaction with the dianion of protected 3-amino-
crotonate ester, promoted by Et3N/pivaloyl chloride, leads to N-ac-
ylated 3-aminoquinoline-2-carboxylates. For more electrophilic
nitroarenes the simplified ‘one-pot’ procedure for the reaction can be
used. Efficient hydrolysis/decarboxylation of the products yields the
desired 3-aminoquinolines. The method, although not general, en-
ables the preparation of certain 3-aminoquinolines substituted with
halogens and some other electronwithdrawing groups in the benzo-
fused ring in synthetically acceptable yields, offering a useful alter-
native to the known methods. Intermediate 2-ethoxycarbonyl
derivatives of 3-aminoquinoline can also be considered as a starting
point to build additional condensed rings.10b,21
3111, 2988, 1725, 1543, 1338, 1292, 1137; 1H NMR (400 MHz, DMSO-
d6)
d
1.57 (9H, s, t-Bu), 8.05 (1H, dd, J¼8.3 Hz, J¼1.7 Hz, H-4), 8.13
(1H, d, J¼1.7 Hz, H-6), 8.19 (1H, d, J¼8.3 Hz, H-3); 13C NMR
(125 MHz, CDCl3) d 27.2, 83.8, 126.0, 129.3, 129.7, 132.0, 138.3, 146.0,
162.4; MS (EI, 70 eV, m/z (%)): 257 (1, Mþ), 184 (22), 57 (100), 56
(41), 41 (18); HRMS (ESI, MeOH): (MþNa)þ found 280.0353.
C11H1235ClNO4Na requires 280.0347.
4.2.4. tert-Butyl 2-nitrobenzoate (1r). Yield 8.7 g, 78%. Yellow oil.
1H NMR (400 MHz, DMSO-d6)
d 1.51 (9H, s, t-Bu), 7.77–7.80 (1H, m,
Ar-H), 7.81–7.83 (2H, m, Ar-H), 8.00–8.03 (1H, m, Ar-H); MS (EI,
70 eV, m/z (%)): 223 (1, Mþ), 168 (15), 151 (21), 150 (72), 76 (13), 57
(100), 56 (36), 51 (10), 41 (22); HRMS (ESI, MeOH): (MþNa)þ, found
246.0745. C11H13NO4Na requires 246.0737.
4. Experimental
4.1. General
4.3. 4-Chloro-3-nitrobenzyl pivalate (1j)
To a solution of 4-chloro-3-nitrobenzyl alcohol (1.5 g, 8.0 mmol)
in pyridine (20 mL), pivaloyl chloride (1.2 mL, 1.18 g, 9.8 mmol) was
added and the solution was stirred at room temperature for 3 days.
Pyridine was evaporated under high vacuum at room temperature
and water (20 mL) was added to the residue. The mixture was
extracted with AcOEt (2ꢂ25 mL), the combined extracts were
washed with 2 M HCl (10 mL), water (2ꢂ10 mL), dried and evapo-
rated to obtain 2.15 g (99%) of the pure product.
Melting points are uncorrected. 1H and 13C NMR spectra were
recorded on a Bruker (500 MHz) (500 MHz for 1H and 125 MHz for
13C spectra), Varian-NMR-vnmrs600 (600 MHz for 1H spectra) and
a Varian Mercury 400 (400 MHz for 1H and 100 MHz for 13C spec-
tra) instruments. Chemical shifts d are expressed in ppm referred to
TMS, coupling constants in Hertz. Mass spectra (EI, 70 eV) were
obtained on an AMD-604 spectrometer. Silica gel Merck 60 (230–
400 mesh) was used for flash column chromatography. THF was
distilled from sodium/benzophenone ketyl prior to use. HMPA was
dried over CaH2, distilled and stored over molecular sieves. 2-
Nitronaphtalene was obtained according to the literature
method.22 All other reagents and starting nitroarenes, except 1j, m,
p, r were commercially available.
1j: Yellow-orange oil. Rf (hexane/AcOEt 5:1) 0.32; IR (KBr, cmꢀ1
)
nmax: 3082, 2935, 1732, 1542, 1358,1151; 1H NMR (500 MHz, DMSO-
d6)
d
1.19 (9H, s, t-Bu), 5.17 (2H, s, CH2), 7.69 (1H, dd, J¼8.3, 2.0 Hz,
H-6), 7.80 (1H, d, J¼8.3 Hz, H-5), 8.06 (1H, d, J¼2.0 Hz, H-2); 13C
NMR (125 MHz, CDCl3)
d 27.1, 38.8, 63.9, 124.5, 126.5, 132.0, 132.1,
137.0, 147.9, 177.9; MS (EI, 70 eV, m/z (%)): 271 (1, Mþ), 170 (25), 169
(17), 124 (11), 89 (16), 57 (100), 41 (12); (ESI, MeOH): 294 (MþNa)þ.
HRMS (ESI): (MþNa)þ, found 294.0516. C12H1435ClNO4Na requires
294.0504.
4.2. Synthesis of tert-butyl esters 1m, p, r
4.2.1. General procedure. To a suspension of the corresponding
nitrobenzoic acid (50 mmol) in CH2Cl2 (100 mL), DMF (0.2 mL,
2.6 mmol, 5% mol) was added. The mixture was cooled to w10 ꢁC
and oxalyl chloride (6.5 mL, 9.6 g, 75 mmol) was added in portions
over 30 min. The mixture was stirred for 30 min, then the cooling
bath was removed and the mixture was stirred overnight at room
temperature (clear orange-brown solution was formed). The sol-
vent was evaporated under vacuum. The obtained benzoyl chloride
was used in the next step without purification. A solution of cor-
responding acid chloride (w50 mmol) in dry THF (80 mL) was
cooled to 0 ꢁC and a solution of t-BuOK (6.8 g, 60 mmol) in THF
(90 mL) was added dropwise (w20 min). The cooling bath was
removed and the mixture was stirred overnight at room tempera-
ture. Water (80 mL) was added. The mixture was concentrated,
4.4. One-pot synthesis of 2-ethoxycarbonyl-3-
(N-pivaloylamino)quinolines 3
4.4.1. General procedure. To a solution of nitroarene 1 (5 mmol) and
ethyl [N-(2,2-dimethylpropanoyl)amino]but-2-enoate (2, 1066 mg,
5 mmol) in dry DMF (10 mL) was added N,O-bis(trimethylsilyl)-
acetamide (5.1 g, 6.1 mL, 25 mmol) and DBU (3.8 g, 3.7 mL,
25 mmol) and the reaction mixture was stirred at room temperature
for 3–10 days while monitored by TLC. The mixture was then poured
into saturated NH4Cl and 3–4 times extracted with AcOEt. The
extract was dried with Na2SO4 and the solvent was evaporated.

R. Bujok et al. / Tetrahedron 66 (2010) 698–708
703
The residue was chromatographed to obtain pure products. The
yields are given in Table 1.
DMSO-d6)23
d
14.5, 27.4, 62.5, 124.4 (q, JC–F¼273 Hz, CF3), 124.7 (q,
JC–F¼3 Hz),126.4 (q, JC–F¼4 Hz),128.6,128.7,129.1 (q, JC–F¼32 Hz, C–
CF3), 131.4, 133.4, 143.3, 144.1, 166.1, 177.5; MS (EI, 70 eV, m/z (%)):
368 (23, Mþ), 311 (33), 295 (11), 237 (11), 212 (39), 210 (10), 209
(10), 57 (100), 41 (15). Anal. Calcd for C18H19F3N2O3: C, 58.69; H,
5.20; N, 7.60. Found: C, 58.44; H, 5.29; N, 7.54.
4.4.2. Ethyl 3-[(2,2-dimethylpropanoyl)amino]pyrido[2,3-g]quinoline-
2-carboxylate (3a). Yield 0.56 g, 30%. White powder; mp 234–237 ꢁC
(AcOEt). Rf (hexane/AcOEt 1:1) 0.13; IR (KBr, cmꢀ1
)
nmax: 3286, 2959,
1693, 1668, 1580, 1550, 1498, 1317, 1218; 1H NMR (400 MHz, DMSO-
d6)
d
1.33 (9H, s, t-Bu), 1.41 (3H, t, J¼7.2 Hz, OCH2CH3), 4.46 (2H, q,
4.4.7. Ethyl 6,8-dichloro-3-[(2,2-dimethylpropanoyl)amino]quinoline-
J¼7.2 Hz, OCH2CH3), 7.82 (1H, dd, J¼8.4 Hz, J¼4.4 Hz, Ar-H), 8.13–
8.21 (2H, m, Ar-H), 9.08 (1H, dd, J¼4.4 Hz, J¼1.5 Hz, Ar-H), 9.10–9.13
(1H, m, Ar-H), 9.92 (1H, s, Ar-H), 10.78 (1H, s, NH); 13C NMR
2-carboxylate (3f). Yield 38 mg, 2%. Pale-yellꢀo1w solid; mp 155–
159 ꢁC. Rf (hexane/AcOEt 2:1) 0.52; IR (KBr, cm
) nmax: 3292, 2962,
1698, 1556, 1434, 1303, 1194, 1080; 1H NMR (400 MHz, DMSO-d6)
(100 MHz, CDCl3)
d
14.2, 27.5, 40.6, 63.0, 121.3, 121.8, 124.3, 128.0,
d
1.29 (9H, s, t-Bu), 1.38 (3H, t, J¼7.2 Hz, OCH2CH3), 4.43 (2H, q,
131.3, 132.1, 132.3, 134.0, 136.3, 142.2, 148.7, 151.2, 167.5, 178.9; MS (EI,
70 eV, m/z (%)): 352 (14), 351 (59, Mþ), 307 (17), 295 (12), 294 (67),
278 (17), 248 (35), 222 (51), 221 (11), 220 (27), 196 (19), 195 (95), 194
(16), 193 (31), 192 (22), 168 (26), 167 (17), 166 (12), 165 (15), 140 (14),
139 (14), 57 (100), 41 (29). Anal. Calcd for C20H21N3O3: C, 68.36; H,
6.02; N, 11.96. Found: C, 68.04; H, 6.01; N, 11.85.
J¼7.2 Hz, OCH2CH3), 8.05 (1H, d, J¼2.2 Hz, Ar-H), 8.21 (1H, d,
J¼2.2 Hz, Ar-H), 9.05 (1H, s, H-4), 10.64 (1H, s, NH); 13C NMR
(100 MHz, DMSO-d6)23
d 14.0, 27.0, 62.0, 125.7, 126.6, 129.2, 130.8,
132.9, 133.6, 134.2, 137.4, 140.9, 165.6, 177.1; MS (EI, 70 eV, m/z (%)):
370 (9), 368 (13, Mþ), 313 (13), 311 (21), 239 (13), 214 (20), 212 (33),
57 (100), 41 (27). HRMS (EI): calcd for C17H1835Cl2N2O3: 368.0694;
found: 368.0686. Anal. Calcd for C17H18Cl2N2O3: C, 55.30; H, 4.91; N,
7.59. Found: C, 54.94; H, 5.09; N, 7.14.
4.4.3. Ethyl
carboxylate (3b). Yield 0.35 g, 20%. Pale-yellow solid; mp 180–
181 ꢁC. Rf (hexane/AcOEt 2:1) 0.38; IR (KBr, cmꢀ1
nmax: 3295, 2959,
1694, 1667, 1550, 1510, 1305, 1217; 1H NMR (600 MHz, CDCl3)
1.44
2-[(2,2-dimethylpropanoyl)amino]benzo[f]quinoline-3-
)
4.5. Step-by-step synthesis of 2-ethoxycarbonyl-3-
(N-pivaloylamino)-quinolines 3
d
(9H, s, t-Bu), 1.56 (3H, t, J¼7.2 Hz, OCH2CH3), 4.61 (2H, q, J¼7.2 Hz,
OCH2CH3), 7.68–7.70 (2H, m, Ar-H), 8.0 (1H, d, J¼9.5 Hz, Ar-H), 7.89–
7.91 (2H, m, Ar-H), 8.72–8.74 (1H, m, Ar-H), 10.52 (1H, s, Ar-H), 11.46
4.5.1. General procedure. To a solution of ethyl N-pivaloyl-3-ami-
nocrotonate 2 (0.60 g, 2.83 mmol) and HMPA (1.1 mL, 1.12 g,
6.3 mmol) in dry THF (16 mL) at ꢀ78 ꢁC under argon, 1.6 M BuLi in
hexane (3.8 mL, 6.1 mmol) was added in portions in 3 min. After the
addition was complete, the solution was stirred at that temperature
for 30 min (a yellow colour was formed). A solution of the nitro-
arene 1 (5.66 mmol) in THF (2.0 mL) was added (colour changed to
orange-brown immediately) and the resultant mixture was stirred
for 10 min. Et3N (1.8 mL, 1.31 g, 13 mmol) was added and then
pivaloyl chloride (1.6 mL, 1.57 g, 13 mmol) was added in portions
(14 min). After the addition was complete, the solution was stirred
at ꢀ78 ꢁC for 2 h. The cooling bath was removed, water (15 mL) was
added immediately, the mixture was warmed to room temperature
and stirred for 5 min. The layers were separated, the aqueous layer
was extracted with AcOEt (2ꢂ15 mL) and the combined extracts
were dried end evaporated. The products were purified by column
chromatography (SiO2, hexane, then hexane/AcOEt). The yields are
given in Table 3.
(1H, s, NH); 13C NMR (100 MHz, DMSO-d6)23
d 14.1, 27.1, 61.8, 122.5,
123.6, 127.0, 127.3, 127.8, 128.3, 128.8, 128.9, 130.5, 132.2, 133.8, 137.5,
142.4, 166.3, 177.3; MS (EI, 70 eV, m/z (%)): 351 (23), 350 (100, Mþ),
306 (12), 294 (14), 293 (72), 277 (15), 247 (29), 221 (43), 219 (19),194
(42),192 (21),166 (11), 57 (31), 41 (11). Anal. Calcd for C21H22N2O5: C,
71.98; H, 6.33; N, 7.99. Found: C, 71.93; H, 6.51; N, 8.06.
4.4.4. Ethyl 5-[(2,2-dimethylpropanoyl)amino]thieno[2,3-b]pyridine-
2-carboxylate (3c). Yield 0.28 g, 18%. Pale-brown solid; mp 140–
144 ꢁC. Rf (hexane/AcOEt 2:1) 0.41; IR (KBr, cmꢀ1
)
nmax: 3295, 2959,
1694, 1667, 1550, 1510, 1305, 1217; 1H NMR (400 MHz, DMSO-d6)
d
1.26 (9H, s, t-Bu), 1.35 (3H, t, J¼7.1 Hz, OCH2CH3), 4.38 (2H, q,
J¼7.1 Hz, OCH2CH3), 7.63 (1H, d, J¼6.1 Hz, Ar-H), 8.05 (1H, d,
J¼6.1 Hz, Ar-H), 8.89 (1H, s, Ar-H), 10.03 (1H, s, Ar-H); 13C NMR
(100 MHz, DMSO-d6)23
d 14.0, 27.0, 61.7, 121.8, 125.0, 129.3, 130.0,
130.6,143.6,157.3,165.1,176.8; MS (EI, 70 eV, m/z (%)): 306 (39, Mþ),
249 (11), 222 (19), 203 (12), 176 (27), 57 (100), 41 (17). Anal. Calcd
for C15H18N2O3S: C, 58.80; H, 5.92; N, 9.14. Found: C, 58.83; H, 5.96;
N, 9.12.
In some cases (3m, p, r, u) products after column chromatog-
raphy contained t-BuCO2H. To remove the acid, the products were
dissolved in AcOEt (30 mL), washed with 10% K2CO3 (15 mL), water
(2ꢂ10 mL), dried and evaporated to dryness.
4.4.5. Ethyl 3-[(2,2-dimethylpropanoyl)amino]-1,6-naphthyridine-2-
carboxylate (3d). Yield 0.17 g, 11%.ꢀO1 range-brown solid; mp 120–
4.5.2. Ethyl 8-fluoro-3-[(2,2-dimethylpropanoyl)amino]quinoline-2-
131 ꢁC. Rf (AcOEt) 0.32; IR (KBr, cm
)
nmax: 3293, 2966, 1697, 1684,
carboxylate (3g). Yield 397 mg, 44%. Yellow-brown solid; mp 128–
1535, 1523, 1293, 1206; 1H NMR (400 MHz, DMSO-d6)
d
1.29 (9H, s,
131 ꢁC. Rf (hexane/AcOEt 2:1) 0.44; IR (KBr, cmꢀ1
)
nmax: 3303, 2968,
t-Bu), 1.38 (3H, t, J¼7.2 Hz, OCH2CH3), 4.42 (2H, q, J¼7.2 Hz,
OCH2CH3), 7.95–8.01 (1H, m, Ar-H), 8.74 (1H, d, J¼5.9 Hz, Ar-H), 9.11
(1H, d, J¼0.7 Hz, Ar-H), 9.48 (1H, d, J¼0.7 Hz, Ar-H), 10.52 (1H, s,
1689, 1543, 1464, 1291, 1216, 1108; 1H NMR (400 MHz, DMSO-d6)
d
1.29 (9H, s, t-Bu), 1.39 (3H, t, J¼7.2 Hz, OCH2CH3), 4.43 (2H, q,
J¼7.2 Hz, OCH2CH3), 7.55–7.60 (1H, m, Ar-H), 7.66–7.71 (1H, m, Ar-
H), 7.84–7.87 (1H, m, Ar-H), 9.09 (1H, d, J¼1.6 Hz, H-4), 10.60 (1H, s,
NH); 13C NMR (100 MHz, DMSO-d6)23
d 14.0, 27.0, 39.3, 62.1, 121.3,
123.9, 127.4, 132.8, 144.7, 145.4, 146.0, 153.1, 165.4, 177.1; MS (EI,
70 eV, m/z (%)): 301 (35, Mþ), 244 (12), 145 (24), 57 (100), 41 (10);
HRMS (EI): Mþ, found 301.1415. C16H19N3O3 requires 301.1426.
NH); 13C NMR (100 MHz, DMSO-d6)23
d 14.7, 27.7, 62.6, 113.7 (d,
JC–F¼18 Hz), 124.1 (d, JC–F¼4 Hz), 127.4 (d, JC–F¼2 Hz), 130.0 (d,
JC–F¼9 Hz), 131.5, 133.5 (d, JC–F¼13 Hz), 133.7, 140.9, 158.0
(d, JC–F¼257 Hz), 166.5, 177.8; MS (EI, 70 eV, m/z (%)): 319 (21), 318
(100, Mþ), 274 (23), 262 (12), 261 (77), 245 (20), 215 (16), 189 (17),
162 (54), 160 (12), 57 (35), 41 (11); HRMS (EI): Mþ, found 318.1369.
C17H19FN2O3 requires 318.1380.
4.4.6. Ethyl 3-[(2,2-dimethylpropanoyl)amino]-6-(trifluoromethyl)-
quinoline-2-carboxylate (3e). Yield 0.11 g, 6%. White crystals; mp
139–143 ꢁC (hexane). Rf (hexane/AcOEt 5:1) 0.24; IR (KBr, cmꢀ1
)
nmax: 3316, 2959, 1698, 1684, 1542, 1290, 1121, 1059; 1H NMR
(400 MHz, DMSO-d6)
d
1.29 (9H, s, t-Bu), 1.39 (3H, t, J¼7.1 Hz,
4.5.3. Ethyl 8-chloro-3-[(2,2-dimethylpropanoyl)amino]quinoline-2-
OCH2CH3), 4.43 (2H, q, J¼7.1 Hz, OCH2CH3), 7.97 (1H, dd, J¼8.9 Hz,
J¼2.0 Hz, Ar-H), 8.27 (1H, dd, J¼8.9 Hz, J¼0.7 Hz, Ar-H), 8.59 (1H, br
s, Ar-H), 9.17 (1H, s, H-4), 10.56 (1H, s, NH); 13C NMR (125 MHz,
carboxylate (3h). Yield 446 mg, 47%. Pale-yelꢀlo1w solid; mp 131–
134 ꢁC. Rf (hexane/AcOEt 5:1) 0.27; IR (KBr, cm
) nmax: 3303, 2975,
1686, 1673,1555,1525,1290,1216,1086; 1H NMR (400 MHz, DMSO-

704
R. Bujok et al. / Tetrahedron 66 (2010) 698–708
d6)
d
1.29 (9H, s, t-Bu), 1.39 (3H, t, J¼7.1 Hz, OCH2CH3), 4.43 (2H, q,
(20), 57 (100), 41 (15); HRMS (EI): Mþ, found 402.0951.
C18H1835ClF3N2O3 requires 402.0958.
J¼7.1 Hz, OCH2CH3), 7.66 (1H, dd, J¼8.2 Hz, J¼7.5 Hz, H-6), 7.93 (1H,
dd, J¼7.5 Hz, J¼1.2 Hz, Ar-H), 8.01 (1H, dd, J¼8.2 Hz, J¼1.2 Hz, Ar-H),
9.07 (1H, s, H-4), 10.57 (1H, s, NH); 13C NMR (100 MHz, DMSO-d6)23
4.5.8. Ethyl 8-bromo-6-chloro-3-[(2,2-dimethylpropanoyl)amino]qui-
d
14.0, 27.0, 61.9, 127.0, 127.7, 129.1, 129.2, 130.5, 132.7, 132.8, 138.8,
noline-2-carboxylate (3l). Yield 563 mg, 48%. Orange solid; mp
140.9, 165.8, 177.1; MS (EI, 70 eV, m/z (%)): 336 (21), 334 (61, Mþ),
290 (22), 279 (21), 278 (10), 277 (60), 261 (18), 231 (14), 207 (10),
205 (38), 203 (13), 180 (29), 179 (14), 178 (99), 176 (15), 175 (11), 114
(11), 57 (100), 41 (20). Anal. Calcd for C17H19ClN2O3: C, 60.99; H,
5.72; N, 8.37. Found: C, 60.80; H, 5.64; N, 8.26.
162–168 ꢁC (decomp.). Rf (hexane/AcOEt 5:1) 0.41; IR (KBr, cmꢀ1
)
nmax: 3291, 2960, 1698, 1689, 1557, 1434, 1300, 1172, 1081; 1H NMR
(400 MHz, DMSO-d6)
d
1.29 (9H, s, t-Bu), 1.38 (3H, t, J¼7.1 Hz,
OCH2CH3), 4.43 (2H, q, J¼7.1 Hz, OCH2CH3), 8.20 (1H, d, J¼2.2 Hz, Ar-
H), 8.25 (1H, d, J¼2.2 Hz, Ar-H), 9.04 (1H, s, H-4), 10.63 (1H, s, NH);
13C NMR (100 MHz, DMSO-d6)23
d 14.0, 27.0, 62.0, 125.7, 126.2, 126.7,
4.5.4. Ethyl 8-bromo-3-[(2,2-dimethylpropanoyl)amino]quinoline-2-
carboxylate (3i). Yield 365 mg, 34%. Pale-yellow solid; mp 126–
130.6, 132.4, 133.2, 133.6, 138.3, 141.2, 165.5, 177.1; MS (ESI, MeOH):
413 (MþH)þ, 435 (MþNa)þ. Anal. Calcd for C17H18BrClN2O3: C, 49.36;
H, 4.39; N, 6.77. Found: C, 49.18; H, 4.53; N, 6.68.
129 ꢁC. Rf (hexane/AcOEt 2:1) 0.48; IR (KBr, cmꢀ1
)
nmax: 3304,
2965, 1690, 1678, 1554, 1526, 1438, 1288; 1H NMR (400 MHz,
DMSO-d6)
d
1.29 (9H, s, t-Bu), 1.39 (3H, t, J¼7.2 Hz, OCH2CH3),
4.5.9. 6-tert-Butyl 2-ethyl 8-chloro-3-[(2,2-dimethylpropanoyl)ami-
no]quinoline-2,6-dicarboxylate (3m). Yield 491 mg, 40%. Pale-yel-
low solid; mp 218–219 ꢁC (AcOEt). Rf (hexane/AcOEt 8:1) 0.33; IR
4.43 (2H, q, J¼7.2 Hz, OCH2CH3), 7.59 (1H, dd, J¼8.1 Hz, J¼7.5 Hz,
H-6), 8.05 (1H, dd, J¼8.1 Hz, J¼1.2 Hz, Ar-H), 8.12 (1H, dd,
J¼7.5 Hz, J¼1.2 Hz, Ar-H), 9.05 (1H, s, H-4), 10.56 (1H, s, NH); 13C
(KBr, cmꢀ1
)
nmax: 3297, 2981, 1719, 1689, 1560, 1272, 1154, 1086; 1H
NMR (100 MHz, DMSO-d6)23
d
14.0, 27.0, 61.9, 124.3, 127.7, 127.8,
NMR (500 MHz, CD3COCD3) d 1.37 (9H, s, t-BuCONH–), 1.48 (3H, t,
129.7, 130.4, 132.7, 132.8, 139.7, 141.2, 165.7, 177.1; MS (EI, 70 eV,
m/z (%)): 381 (18), 380 (89), 379 (19), 378 (89, Mþ), 336 (42), 335
(13), 334 (41), 324 (13), 323 (84), 322 (11), 321 (79), 307 (21), 305
(23), 277 (20), 275 (19), 251 (38), 250 (11), 249 (50), 247 (16), 225
(11), 224 (88), 223 (15), 222 (100), 221 (16), 197 (10), 195 (11), 141
(11), 114 (10), 57 (39), 41 (16); HRMS (EI): Mþ, found 378.0570.
C17H1979BrN2O3 requires 378.0579.
J¼7.1 Hz, OCH2CH3), 1.66 (9H, s, t-BuO–), 4.56 (2H, q, J¼7.1 Hz,
OCH2CH3), 8.23 (1H, d, J¼1.5 Hz, Ar-H), 8.58 (1H, d, J¼1.5 Hz, Ar-H),
9.66 (1H, s, H-4), 11.10 (1H, br s, NH); 13C NMR (125 MHz, THF-d8)
d
13.4, 26.7, 27.3, 40.05, 62.2, 81.6, 125.8, 127.2, 128.7, 130.5, 132.3,
134.4, 135.6, 137.5, 140.2, 163.3, 167.2, 177.1; MS (EI, 70 eV, m/z (%)):
436 (22), 435 (17), 434 (56, Mþ), 390 (11), 378 (10), 361 (25), 321
(67), 249 (20), 224 (14), 222 (61), 57 (100), 41 (20). Anal. Calcd for
C22H27ClN2O5: C, 60.76; H, 6.26; N, 6.44. Found: C, 60.85; H, 6.22; N,
6.45.
4.5.5. Ethyl 8-bromo-3-[(2,2-dimethylpropanoyl)amino]quinoline-2-
carboxylate 1-oxide (6i)24. Yield 101 mg, 9%. Yellow oil. Rf (hexane/
AcOEt 5:1) 0.22; IR (film in CH2Cl2, cmꢀ1
)
nmax: 3276, 2970, 1740,
1702, 1672, 1629, 1481, 1239, 1137; 1H NMR (500 MHz, DMSO-d6)
1.23 (9H, s, t-Bu), 1.27 (3H, t, J¼7.1 Hz, OCH2CH3), 4.23 (2H, q,
4.5.10. Ethyl 5,8-dichloro-3-[(2,2-dimethylpropanoyl)amino]quinoline-
2-carboxylate (3n). Yield 325 mg, 31%. Yellow-orange solid; mp
d
172–175 ꢁC (decomp.). Rf (hexane/AcOEt 2:1) 0.55; IR (KBr, cmꢀ1
)
J¼7.1 Hz, OCH2CH3), 7.09 (1H, dd, J¼8.7 Hz, J¼7.0 Hz, H-6), 7.68 (1H,
dd, J¼8.7 Hz, J¼0.6 Hz, Ar-H), 7.79 (1H, dd, J¼7.0 Hz, J¼0.6 Hz, Ar-
H), 8.50 (1H, s, H-4), 10.28 (1H, s, NH); MS (EI, 70 eV, m/z (%)): 396
(28), 394 (26, Mþ), 324 (16), 323 (95), 322 (16), 321 (96), 283 (13),
269 (10), 266 (11), 264 (11), 238 (16), 210 (12), 165 (19), 57 (100), 41
(21); HRMS (EI): Mþ, found 394.0544. C17H1979BrN2O4 requires
394.0528.
nmax: 3273, 2965, 1692, 1562, 1328, 1092; 1H NMR (400 MHz, DMSO-
d6)
d
1.29 (9H, s, t-Bu), 1.39 (3H, t, J¼7.1 Hz, OCH2CH3), 4.44 (2H, q,
J¼7.1 Hz, OCH2CH3), 7.88 (1H, d, J¼8.1 Hz, Ar-H), 7.94 (1H, d, J¼8.1 Hz,
Ar-H), 9.38 (1H, s, H-4),10.78 (1H, s, NH); 13C NMR (100 MHz, DMSO-
d6)23
d 14.0, 27.0, 62.1, 123.3, 128.2, 128.3, 128.8, 129.2, 132.3, 134.1,
138.9, 140.8, 165.5, 177.4; MS (EI, 70 eV, m/z (%)): 370 (14), 368 (44,
Mþ), 326 (10), 324 (15), 313 (33), 311 (51), 297 (12), 295 (16), 239
(12), 214 (18), 57 (100), 41 (22); HRMS (EI): Mþ, found 368.0684.
C17H1835Cl2N2O3 requires 368.0694.
4.5.6. Ethyl 8-chloro-3-[(2,2-dimethylpropanoyl)amino]-5-{[(2,2-dime-
thylpropanoyl)oxy]methyl}quinoline-2-carboxylate (3j). Yield 598 mg,
47%. Yellow solid; mp 102–105 ꢁC. Rf (hexane/AcOEt 2:1) 0.46; IR (KBr,
4.5.11. Ethyl 6-chloro-8-cyano-3-[(2,2-dimethylpropanoyl)amino]qui-
noline-2-carboxylate (3o). Yield 236 mg, 23%. Orange solid; mp
1
cmꢀ1
)
nmax: 3313, 2964, 1733, 1694, 1540, 1296, 1144, 1039; H NMR
(500 MHz, DMSO-d6)
d
1.13 (9H, s, OC(O)t-Bu),1.27 (9H, s, NHt-Bu),1.38
135–138 ꢁC. Rf (hexane/AcOEt 5:1) 0.27; IR (KBr, cmꢀ1
)
nmax: 3281,
2966, 2238, 1742, 1705, 1542, 1292, 1208, 1086, 1020; 1H NMR
(400 MHz, DMSO-d6)
(3H, t, J¼7.1 Hz, OCH2CH3), 4.43 (2H, q, J¼7.1 Hz, OCH2CH3), 5.46 (2H, s,
Ar-CH2), 7.70 (1H, d, J¼7.7 Hz, Ar-H), 7.90 (1H, d, J¼7.7 Hz, Ar-H), 9.24
d
1.27 (9H, s, t-Bu), 1.37 (3H, t, J¼7.2 Hz,
(1H, s, H-4), 10.62 (1H, s, NH); 13C NMR (125 MHz, DMSO-d6)23
d
13.9,
OCH2CH3), 4.42 (2H, q, J¼7.2 Hz, OCH2CH3), 8.50 (1H, d, J¼2.2 Hz, Ar-
26.9, 61.9, 63.1,123.5,128.3,128.8,129.7,131.4,133.2,133.3,138.7,140.0,
165.6, 177.0; MS (EI, 70 eV, m/z (%)): 448 (20, Mþ), 391 (18), 365 (19),
364 (16), 363 (76), 347 (23), 319 (15), 317 (21), 292 (13), 279 (15), 263
(16), 57 (100), 41 (18); HRMS (EI): Mþ, found 448.1752. C23H2935ClN2O5
requires 448.1765.
H), 8.56 (1H, d, J¼2.2 Hz, Ar-H), 9.09 (1H, s, H-4),10.64 (1H, br s, NH);
13C NMR (100 MHz, DMSO-d6)23
d 13.9, 26.9, 62.2, 113.7, 115.6,
126.9, 129.9, 131.6, 132.6, 134.0, 135.9, 140.0, 142.3, 165.3, 177.2;
MS (EI, 70 eV, m/z (%)): 359 (12, Mþ), 203 (22), 85 (14), 57 (100), 41
(17); HRMS (EI): Mþ, found 359.1041. C18H1835ClN3O3 requires
359.1037.
4.5.7. Ethyl 8-chloro-3-[(2,2-dimethylpropanoyl)amino]-5-(trifluoro-
methyl)quinoline-2-carboxylate (3k). Yield 535 mg, 47%. Yellow
4.5.12. 8-tert-Butyl 2-ethyl 6-chloro-3-[(2,2-dimethylpropanoyl)ami-
no]quinoline-2,8-dicarboxylate (3p). Yield 250 mg, 20%. Pale-yellow
solid; mp 166–168 ꢁC (decomp.). Rf (hexane/AcOEt 5:1) 0.12; IR
solid; mp 110–113 ꢁC. Rf (hexane/AcOEt 2:1) 0.56; IR (KBr, cmꢀ1
)
nmax: 3281, 2955, 1699, 1563, 1317, 1169, 1145, 1085; 1H NMR
(400 MHz, DMSO-d6)
d
1.30 (9H, s, t-Bu), 1.40 (3H, t, J¼7.1 Hz,
(KBr, cmꢀ1
)
nmax: 3286, 2974, 1726, 1694, 1546, 1298, 1176, 1159; 1H
OCH2CH3), 4.43 (2H, q, J¼7.1 Hz, OCH2CH3), 8.04 (1H, d, J¼8.1 Hz,
Ar-H), 8.11 (1H, d, J¼8.1 Hz, Ar-H), 9.40 (1H, s, H-4), 10.83 (1H, s,
NMR (500 MHz, CD3COCD3)
d 1.35 (9H, s, NHt-Bu), 1.46 (3H, t,
J¼7.1 Hz, OCH2CH3), 1.67 (9H, s, Ot-Bu), 4.53 (2H, q, J¼7.1 Hz,
OCH2CH3), 7.72 (1H, d, J¼2.3 Hz, Ar-H), 8.12 (1H, d, J¼2.3 Hz, Ar-H),
9.48 (1H, s, H-4), 11.19 (1H, br s, NH); 13C NMR (125 MHz, DMSO-
NH); 13C NMR (100 MHz, DMSO-d6)23
d 14.0, 26.9, 62.2, 122.0, 123.1
(q, JC–F¼31 Hz, C–CF3), 123.6 (q, JC–F¼273 Hz, CF3), 126.3, 127.6,
128.3, 134.4, 138.4, 138.5, 140.4, 165.4, 177.6; MS (EI, 70 eV, m/z (%)):
404 (13), 402 (37, Mþ), 358 (11), 347 (13), 345 (37), 329 (13), 246
d6)23
d
14.5, 27.5, 28.3, 62.4, 82.9, 125.9, 127.9, 128.3, 130.5, 133.4,
134.0, 136.7, 138.2, 140.2, 166.1, 166.3, 177.6; MS (EI, 70 eV, m/z (%)):

R. Bujok et al. / Tetrahedron 66 (2010) 698–708
705
436 (12), 434 (36, Mþ), 361 (19), 336 (67), 335 (32), 334 (100), 321
(49), 306 (14), 305 (17), 303 (16), 288 (14), 277 (18), 261 (16), 260
(13), 252 (17), 251 (14), 250 (28), 249 (25), 231 (12), 222 (20), 204
(18), 178 (10), 176 (14), 57 (93), 41 (31), 40 (14). Anal. Calcd for
C22H27ClN2O5: C, 60.76; H, 6.26; N, 6.44. Found: C, 60.75; H, 6.24; N,
6.28.
(9H, s, t-Bu), 1.39 (3H, t, J¼7.2 Hz, OCH2CH3), 4.44 (2H, q, J¼7.2 Hz,
OCH2CH3), 7.83 (1H, dd, J¼8.3 Hz, J¼7.2 Hz, H-6), 8.36–8.40 (2H, m,
Ar-H), 9.13 (1H, s, H-4), 10.58 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6)23
d 14.0, 27.0, 62.1, 111.8, 116.9, 128.1, 128.5, 129.1, 133.0,
133.3, 136.1, 141.5, 142.4, 165.4, 177.1; MS (EI, 70 eV, m/z (%)): 325
(32, Mþ), 281 (23), 268 (31), 252 (11), 222 (11), 197 (11), 196 (12),
194 (10), 170 (13), 169 (100), 167 (10), 57 (37), 41 (11); HRMS (EI):
Mþ, found 325.1422. C18H19N3O3 requires 325.1426.
4.5.13. 8-tert-Butyl 2-ethyl 6-chloro-3-[(2,2-dimethylpropanoyl)-
amino]quinoline-2,8-dicarboxylate 1-oxide (6p). Yield 92 mg, 7%.
Orange solid; mp 149–152 ꢁC. Rf (hexane/AcOEt 5:1) 0.33; IR (KBr,
4.5.18. Ethyl 6-cyano-3-[(2,2-dimethylpropanoyl)amino]quinoline-
cmꢀ1
)
nmax: 3335, 2977, 1703, 1680, 1623, 1482, 1286, 1217, 1140; 1H
2-carboxylate (3t). Yield 148 mg, 16%. Yellow-orange solid; mp
NMR (400 MHz, DMSO-d6)
d
1.24 (9H, s, NHt-Bu), 1.28 (3H, t,
155–158 ꢁC. IR (KBr, cmꢀ1
)
nmax: 3316, 2966, 2231, 1694, 1630, 1534,
J¼7.1 Hz, OCH2CH3), 1.59 (9H, s, Ot-Bu), 4.24 (2H, q, J¼7.1 Hz,
1296, 1186, 1085; 1H NMR (400 MHz, DMSO-d6)
d
1.29 (9H, s, t-Bu),
OCH2CH3), 6.09 (1H, s, Ar-H), 7.94 (1H, s, Ar-H), 8.11 (1H, s, Ar-H),
1.38 (3H, t, J¼7.2 Hz, OCH2CH3), 4.42 (2H, q, J¼7.2 Hz, OCH2CH3), 8.01
(1H, dd, J¼8.8 Hz, J¼1.8 Hz, Ar-H), 8.19–8.23 (1H, m, Ar-H), 8.73 (1H,
d, J¼2.0 Hz, Ar-H), 9.09 (1H, s, H-4), 10.57 (1H, s, NH); 13C NMR
10.34 (1H, s, NH); 13C NMR (125 MHz, DMSO-d6)23
d 14.0, 26.7, 27.7,
60.7, 82.4, 109.3, 117.7, 121.0, 124.1, 128.9, 136.1 152.4, 161.6, 162.0,
165.8, 176.4; MS (EI, 70 eV, m/z (%)): 450 (8, Mþ), 323 (11), 321 (30),
264 (16), 85 (18), 57 (100); HRMS (EI): Mþ, found 450.1563.
C22H2735ClN2O6 requires 450.1558.
(100 MHz, DMSO-d6)23
d 14.0, 27.0, 62.1, 111.3, 118.5, 127.6, 128.4,
129.5, 130.7, 133.0, 134.4, 143.2, 143.5, 165.5, 177.1; MS (EI, 70 eV, m/z
(%)): 325 (28, Mþ), 268 (35), 252 (14), 169 (29), 85 (12), 57 (100),
41 (21); HRMS (EI): Mþ, found 325.1433. C18H19N3O3 requires
325.1426.
4.5.14. Ethyl 8-chloro-6-methoxy-3-[(2,2-dimethylpropanoyl)ami-
no]quinoline-2-carboxylate (3q). Yield 137 mg, 13%. Oranꢀge1 solid;
3292, 2965, 1693, 1675, 1610, 1310, 1205, 1156, 1090; 1H NMR
mp 126–129 ꢁC. Rf (hexane/AcOEt 5:1) 0.22; IR (KBr, cm
)
nmax
:
4.5.19. Ethyl 6-fluoro-3-[(2,2-dimethylpropanoyl)amino]quinoline-
2-carboxylate (3u). The reaction was carried out according to the
general procedure except, that after addition of all reactants, the
reaction was warmed to room temperature, stirred overnight and
then quenched.
(400 MHz, DMSO-d6)
d
1.29 (9H, s, t-Bu), 1.38 (3H, t, J¼7.2 Hz,
OCH2CH3), 3.93 (3H, s, OMe), 4.43 (2H, q, J¼7.2 Hz, OCH2CH3), 7.43
(1H, d, J¼2.6 Hz, Ar-H), 7.62 (1H, d, J¼2.6 Hz, Ar-H), 9.11 (1H, s, H-
4), 10.75 (1H, s, NH); 13C NMR (100 MHz, DMSO-d6)
d
14.0, 27.0,
Yield 155 mg, 17%. Pale-orange solid; mp 138–140 ꢁC. Rf (hex-
39.5, 56.1, 61.9, 104.7, 121.7, 125.3, 131.8, 133.8, 133.9, 134.8, 136.5,
158.8, 166.2, 177.1; MS (EI, 70 eV, m/z (%)): 366 (6), 364 (14, Mþ),
320 (13), 307 (17), 261 (16), 235 (28), 210 (12), 208 (34), 57 (100),
41 (35); HRMS (EI): Mþ, found 364.1186. C18H2135ClN2O4 requires
364.1190.
ane/AcOEt 2:1) 0.36; IR (KBr, cmꢀ1
)
nmax: 3308, 2965, 1683, 1543,
1446, 1307, 1202, 1147; 1H NMR (400 MHz, CD3COCD3)
d
1.36 (9H, s,
t-Bu), 1.47 (3H, t, J¼7.1 Hz, OCH2CH3), 4.53 (2H, q, J¼7.1 Hz,
OCH2CH3), 7.53–7.59 (1H, m, Ar-H), 7.68–7.72 (1H, m, Ar-H), 8.09–
8.14 (1H, m, Ar-H), 9.48 (1H, s, H-4), 11.14 (1H, br s, NH); 13C NMR
(100 MHz, CD3COCD3)
d
14.4, 27.6, 40.9, 63.0, 111.0 (d, JC–F¼22 Hz),
4.5.15. Ethyl 8-chloro-6-methoxy-3-[(2,2-dimethylpropanoyl)ami-
no]quinoline-2-carboxylate 1-oxide (6q). Yield 140 mg, 13%. Yellow-
brown solid; mp 133–137 ꢁC. Rf (hexane/AcOEt 2:1) 0.42; IR (KBr,
119.8 (d, JC–F¼26 Hz), 124.5 (d, JC–F¼6 Hz), 131.9 (d, JC–F¼11 Hz),
133.7 (d, JC–F¼10 Hz), 135.7, 136.5 (d, JC–F¼3 Hz), 140.9, 163.0 (d, JC–
¼248 Hz), 168.2, 178.1; MS (EI, 70 eV, m/z (%)): 318 (26, Mþ), 261
F
cmꢀ1
)
nmax: 3286, 2963, 1711, 1677, 1422, 1619, 1554, 1177; 1H NMR
(26), 215 (13), 162 (18), 160 (12), 57 (100), 41 (17); HRMS (EI): Mþ,
found 318.1371. C17H19FN2O3 requires 318.1380.
(400 MHz, DMSO-d6)
d
1.25 (9H, s, t-Bu), 1.27 (3H, t, J¼7.1 Hz,
OCH2CH3), 3.82 (3H, s, OMe), 4.23 (2H, q, J¼7.1 Hz, OCH2CH3), 6.04
(1H, s, Ar-H), 6.80 (1H, d, J¼2.0 Hz, Ar-H), 7.44 (1H, d, J¼2.0 Hz, Ar-
4.5.20. Ethyl 6-chloro-3-[(2,2-dimethylpropanoyl)amino]quinoline-
2-carboxylate (3v). Yield 51 mg, 5%. Orange solid; mp 142–145 ꢁC.
H), 10.25 (1H, s, NH); 13C NMR (100 MHz, DMSO-d6)23
d
14.1, 26.8,
56.1, 60.6, 93.9, 108.1, 117.1, 120.9, 127.1, 137.0, 153.0, 156.7, 160.0,
165.9, 176.5; MS (EI, 70 eV, m/z (%)): 382 (5), 380 (18, Mþ), 251 (11),
225 (10), 224 (14), 223 (25), 57 (100), 41 (35); HRMS (EI): Mþ, found
380.1123. C18H2135ClN2O5 requires 380.1139.
Rf (hexane/AcOEt 2:1) 0.42; IR (KBr, cmꢀ1
)
nmax: 3307, 2968, 1701,
1684, 1630, 1536, 1304, 1200, 1089; 1H NMR (400 MHz, DMSO-d6)
d
1.29 (9H, s, t-Bu), 1.38 (3H, t, J¼7.1 Hz, OCH2CH3), 4.42 (2H, q,
J¼7.1 Hz, OCH2CH3), 7.74 (1H, dd, J¼9.0 Hz, J¼2.4 Hz, H-7), 8.08 (1H,
d, J¼9.0 Hz, H-8), 8.18 (1H, d, J¼2.4 Hz, H-5), 9.02 (1H, s, H-4), 10.61
4.5.16. 8-tert-Butyl 2-ethyl 3-[(2,2-dimethylpropanoyl)amino]quino-
(1H, s, NH); 13C NMR (100 MHz, DMSO-d6)23
d 14.0, 27.0, 61.9, 126.0,
line-2,8-dicarboxylate (3r). Yield 231 mg, 20%. Yellow-orange oil. Rf
126.1, 129.7, 129.9, 131.4, 132.9, 133.6, 140.3, 141.2, 165.9, 177.0; MS
(ESI, MeOH): 357 (MþNa)þ; HRMS (ESI): (MþNa)þ, found 357.0962.
C17H19ClN2O3Na requires 357.0976.
(hexane/AcOEt 2:1) 0.48; IR (KBr, cmꢀ1
)
nmax: 3323, 2976, 1698,
1540, 1301, 1166, 1094; 1H NMR (500 MHz, CD3COCD3)
d
1.38 (9H, s,
NHt-Bu), 1.49 (3H, t, J¼7.1 Hz, OCH2CH3), 1.70 (9H, s, Ot-Bu), 4.56
(2H, q, J¼7.1 Hz, OCH2CH3), 7.73 (1H, dd, J¼8.2 Hz, J¼7.0 Hz, H-6),
7.81 (1H, dd, J¼7.0 Hz, J¼1.2 Hz, Ar-H), 8.08 (1H, dd, J¼8.2 Hz,
J¼1.2 Hz, Ar-H), 9.56 (1H, s, H-4), 11.17 (1H, br s, NH); 13C NMR
4.6. Ethyl 3-[(2,2-dimethylpropanoyl)amino]-4-
(5-fluoro-2-nitrosophenyl)but-2-enoate (5uH)
(125 MHz, CD3COCD3)
d
14.6, 27.7, 28.5, 40.9, 63.1, 82.3, 125.3, 128.0,
The reaction was carried out according to the general procedure
for step-by-step synthesis of 3. After workup and column chro-
matography the product was dissolved in AcOEt (30 mL), washed
with 10% K2CO3 (15 mL), water (2ꢂ10 mL), dried and evaporated to
dryness.
129.4, 130.1, 130.8, 135.5, 136.5, 137.1, 140.5, 168.2, 168.3, 178.2; MS
(EI, 70 eV, m/z (%)): 400 (36, Mþ), 327 (23), 301 (19), 300 (82), 287
(26), 271 (10), 269 (14), 254 (10), 245 (15), 243 (13), 216 (30), 215
(19), 170 (20), 142 (18), 57 (100), 41 (23); HRMS (EI): Mþ, found
400.2005. C22H28N2O5 requires 400.1998.
5uH: Yield 720 mg, 27%. Green solid; mp 81–83 ꢁC (decomp.) Rf
(hexane/AcOEt 32:1) 0.30; IR (film, cmꢀ1
)
nmax: 3230, 2969, 1705,
4.5.17. Ethyl 8-cyano-3-[(2,2-dimethylpropanoyl)amino]quinoline-
1672, 1632, 1501, 1246; 1H NMR (500 MHz, CD3COCD3)
d
1.20–1.24
2-carboxylate (3s). Yield 150 mg, 16%. Yellow solid; mp 124–127 ꢁC.
(12H, m, t-Bu þOCH2CH3), 4.15 (2H, q, J¼7.1 Hz, OCH2CH3), 4.95 (1H,
s,¼CH–COOEt), 5.51 (2H, s, Ar-CH2), 6.45 (1H, dd, J¼9.0 Hz,
J¼5.6 Hz, Ar-H), 7.10–7.15 (1H, m, Ar-H), 7.48 (1H, dd, J¼9.0 Hz,
Rf (hexane/AcOEt 5:1) 0.38; IR (KBr, cmꢀ1
)
nmax: 3297, 2975, 2233,
1708, 1686, 1547, 1297, 1103; 1H NMR (400 MHz, DMSO-d6)
d
1.29

706
R. Bujok et al. / Tetrahedron 66 (2010) 698–708
J¼2.7 Hz, Ar-H), 11.62 (1H, br s, NH); 13C NMR (125 MHz,
DMSO-d6)
d
7.42 (3H, t, JN–H¼50.8 Hz, NHþ3 ), 7.62–7.71 (2H, m, Ar-
CD3COCD3)
d
13.6, 26.6, 34.6, 40.1, 59.8, 98.5, 110.2 (d, JC–F¼11 Hz),
H), 8.13 (1H, d, J¼8.8 Hz, Ar-H), 8.28–8.32 (1H, m, Ar-H), 8.74 (1H, d,
114.2 (d, JC–F¼24 Hz), 117.6 (d, JC–F¼23 Hz), 145.3 (d, JC–F¼10 Hz),
156.4, 161.6 (d, JC–F¼3 Hz), 167.3 (d, JC–F¼257 Hz), 168.8, 176.7; 15N
NMR (50.7 MHz, CD3COCD3): ꢀ249.1 (NH), 525.4 (NO); MS (ESI,
MeOH): 359 (MþNa)þ; HRMS (ESI): (MþNa)þ, found 359.1367.
C17H21FN2O4Na requires 359.1378.
J¼2.3 Hz, Ar-H); 13C NMR (125 MHz, DMSO-d6)
d 119.3, 122.0, 123.9
(q, JC–F¼273 Hz, CF3), 124.6, 124.7, 128.3 (q, JC–F¼32 Hz, C–CF3),
129.0, 134.9, 143.6; MS (EI, 70 eV, m/z (%)): 213 (15), 212 (100, Mþ),
185 (18), 38 (17), 36 (55); HRMS (EI): Mþ, found 212.0557.
C10H7F3N2 requires 212.0561.
4.7. Cyclisation of 5uH to 3u
4.8.5. 6,8-Dichloroquinolin-3-amine (7f). Yield 58 mg, 67%. Light
beige powder; mp 210–214 ꢁC (toluene). Rf (hexane/AcOEt 1:1)
4.7.1. Reaction with Me3SiCl. To
a
solution of 5uH (168 mg,
0.20; IR (KBr, cmꢀ1 nmax: 3443, 3320, 3210, 1618, 1481, 1423; 1H
)
0.50 mmol) in DMF (2.5 mL), Et3N (0.280 mL, 204 mg, 2.0 mmol)
and Me3SiCl (0.160 mL, 137 mg, 1.26 mmol) were added sub-
sequently. The solution was stirred at room temperature for 80 min.
Water (5 mL) was added and the mixture was extracted with AcOEt
(3ꢂ7 mL). The combined extracts were washed with water
(2ꢂ10 mL), dried and evaporated. The product was purified by
column chromatography (SiO2, hexane/AcOEt, 4:1) and 38 mg
(24%) of the pure 3u was obtained.
NMR (400 MHz, DMSO-d6) d 6.12 (2H, br s, NH2), 7.14 (1H, d,
J¼2.6 Hz, Ar-H), 7.52 (1H, d, J¼2.3 Hz, Ar-H), 7.75 (1H, d, J¼2.3 Hz,
Ar-H), 8.54 (1H, d, J¼2.6 Hz, Ar-H); 13C NMR (100 MHz, DMSO-d6)
d
110.4, 123.6, 123.7, 130.2, 131.5, 133.5, 134.9, 144.1, 144.2; MS (EI,
70 eV, m/z (%)): 216 (10), 214 (63), 213 (14), 212 (100, Mþ), 187 (14),
185 (21),150 (16),123 (11),114 (11); HRMS (EI): Mþ, found 211.9915.
C9H635Cl2N2 requires 211.9908.
4.8.6. 8-Fluoroquinolin-3-amine
hydrochloride
(7g$HCl). Yield
nmax:
4.7.2. Reaction with pivaloyl chloride. To a solution of 5uH (133 mg,
0.40 mmol) in THF (3 mL), Et3N (0.070 mL, 51 mg, 0.50 mmol) and
t-BuCOCl (0.07 mL, 69 mg, 0.57 mmol) were subsequently added.
The solution was stirred overnight at room temperature. The re-
action was worked-up as above and 14 mg (11%) of 3u was
obtained.
89 mg, w100%. Brown solid; mp 225–235 ꢁC. IR (KBr, cmꢀ1
)
3311, 3183, 2428, 1641, 1616, 1563, 1283; 1H NMR (400 MHz,
CD3OD)
d
5.0 (3H, br s, NHþ3 þOH from solvent), 7.49 (1H, ddd,
J¼11.0 Hz, J¼7.8 Hz, J¼1.0 Hz, Ar-H), 7.65–7.71 (1H, m, Ar-H), 7.77
(1H, d, J¼8.4 Hz, Ar-H), 8.10–8.11 (1H, m, Ar-H), 8.70 (1H, d,
J¼2.5 Hz, Ar-H); 13C NMR (100 MHz, CD3OD)
d
113.8 (d, J¼16.4 Hz),
123.0 (d, J¼15.1 Hz),123.8 (d, J¼4.3 Hz),124.0 (d, J¼2.6 Hz),131.0 (d,
J¼8.2 Hz), 133.4, 136.5, 145.8, 154.0 (d, J¼253.7 Hz) MS (ESI, MeOH):
163 (MþH)þ, 185 (MþNa)þ; HRMS (ESI): (MþNa)þ, found 185.0477.
C9H7FN2Na requires 185.0485.
4.8. Hydrolysis of 3 into 7
4.8.1. General procedure. A suspension of 3 (0.40–0.45 mmol) in
20% HCl (16 mL) was heated to reflux for the time specified in
Table 4. Fresh portions of 20% HCl (16 mL) was added after one
day. To isolate the products as hydrochlorides, the mixture was
evaporated to dryness under high vacuum and the residue was
washed with hot AcOEt (2ꢂ10 mL). The product was dissolved in
MeOH, filtered and the filtrate was evaporated to dryness. To
obtain products as free bases, the reaction mixture was neutral-
ised with solid K2CO3 to attain pH¼8. The mixture was then
extracted with AcOEt, the extract was dried and the solvent
evaporated. The products were purified by column chromatog-
raphy (SiO2/AcOEt).
4.8.7. 8-Chloroquinolin-3-amine hydrochloride (7h$HCl). Yield
96 mg, w100%. Brown solid; mp 240–245 ꢁC. IR (KBr, cmꢀ1
) nmax:
3302, 3135, 2553, 1654, 1622, 1549, 1270; 1H NMR (400 MHz,
DMSO-d6)
d
7.42 (3H, t, JN–H¼50.8 Hz, NHþ3 ), 7.54–7.58 (1H, m, Ar-
H), 7.76 (1H, dd, J¼7.4 Hz, J¼1.2 Hz, Ar-H), 7.84–7.90 (2H, m, Ar-H),
8.83 (1H, d, J¼2.6 Hz, Ar-H); 13C NMR (100 MHz, DMSO-d6)
d 120.5,
126.2, 127.3, 128.0, 129.8, 130.5, 135.6, 138.7, 142.8; MS (EI, 70 eV,
m/z (%)): 180 (33), 179 (15), 178 (100, Mþ), 151 (17), 116 (11), 89 (12),
36 (27); HRMS (EI): Mþ, found 178.0300. C9H735ClN2 requires
178.0298.
4.8.2. Pyrido[3,4-g]quinolin-3-amine (7a). Yield 64 mg, 72%. Pale-
4.8.8. (3-Amino-8-chloroquinolin-5-yl)methanol
(7j). Hydrolysis
brown solid; mp 199–201 ꢁC. Rf (AcOEt) 0.08; IR (KBr, cmꢀ1
)
d
nmax
5.93
:
was carried out in 20% H2SO4 at 120 ꢁC for 2 days, then worked-up
as described in the general procedure.
3334, 3184, 1604, 1501, 1276; 1H NMR (400 MHz, DMSO-d6)
(2H, br s, NH2), 7.66 (1H, dd, J¼8.2 Hz, J¼4.5 Hz, Ar-H), 7.77 (1H, dd,
J¼9.2 Hz, J¼0.6 Hz, Ar-H), 7.97 (1H, dd, J¼9.2 Hz, J¼0.6 Hz, Ar-H),
8.07 (1H, d, J¼2.6 Hz, Ar-H), 8.51 (1H, d, J¼2.6 Hz, Ar-H), 8.91–8.95
Yield 90 mg, 57%. Pale-brown solid; mp >265 ꢁC. Rf (hexane/
AcOEt 1:1) 0.22; IR (KBr, cmꢀ1
)
nmax: 3404, 3328, 3225, 2868, 1611,
1112; 1H NMR (500 MHz, DMSO-d6)
d
4.77 (2H, d, J¼5.4 Hz, CH2OH),
(2H, m, Ar-H); 13C NMR (100 MHz, DMSO-d6)
d
109.4, 121.2, 123.7,
5.26 (1H, t, J¼5.4 Hz, CH2OH), 5.89 (2H, br s, NH2), 7.34–7.37 (2H, m,
125.5, 125.9, 131.1, 131.7, 138.4, 141.4, 143.9, 147.7, 150.0; MS (ESI,
MeOH): 196 (MþH)þ; HRMS (ESI): (MþH)þ, found 196.0867.
C12H10N3 requires 196.0869.
Ar-H), 7.43 (1H, d, J¼7.6 Hz, Ar-H), 8.51 (1H, d, J¼2.6 Hz, Ar-H); 13C
NMR (125 MHz, DMSO-d6)
d 60.6, 108.5, 123.0, 124.6, 128.8, 131.3,
135.2, 136.2, 142.9, 143.0; MS (EI, 70 eV, m/z (%)): 210 (26), 209 (16),
208 (100, Mþ), 207 (13), 193 (12), 192 (11), 191 (35), 181 (14), 180
(13), 179 (41), 173 (54), 156 (10), 145 (37), 144 (24), 118 (10), 117 (15),
116 (12), 89 (12); HRMS (EI): Mþ, found 208.0398. C10H935ClN2O
requires 208.0403.
4.8.3. Benzo[g]quinolin-3-amine (7b). Yield 50 mg, 56%. Pale-
brown solid; mp 151–153 ꢁC. Rf (AcOEt) 0.21; IR (KBr, cmꢀ1
)
nmax
3346, 3050, 1628, 1600, 1401, 825; 1H NMR (400 MHz, DMSO-d6)
5.82 (2H, br s, NH2), 7.60–7.76 (4H, m, Ar-H), 7.92–7.96 (1H, m, Ar-
H), 8.09 (1H, d, J¼2.4 Hz, Ar-H), 8.48 (1H, d, J¼2.4 Hz, Ar-H), 8.52–
8.56 (1H, m, Ar-H); 13C NMR (100 MHz, DMSO-d6)
109.5, 122.8,
:
d
4.8.9. 8-Chloro-5-(trifluoromethyl)quinolin-3-amine hydrochloride
d
(7k$HCl). Yield 105 mg, 84%. Brown solid; mp>270 ꢁC. IR (KBr,
124.7, 126.1, 126.2, 126.9, 127.9, 128.3, 128.6, 131.8, 139.2, 140.7,
143.5; MS (ESI, MeOH): 195 (MþH)þ; HRMS (ESI): (MþH)þ, found
195.0915. C13H11N2 requires 195.0917.
cmꢀ1 nmax: 3296, 3177, 1644, 1552, 1277, 1131, 1097; 1H NMR
)
(400 MHz, DMSO-d6)
d
7.38 (1H, m, Ar-H), 7.41 (3H, t, JN–H¼50.7 Hz,
NHþ3 ), 7.60 (1H, d, J¼8.0 Hz, Ar-H), 7.81 (1H, d, J¼8.0 Hz, Ar-H), 8.67
(1H, d, J¼2.4 Hz, Ar-H); 13C NMR (125 MHz, DMSO-d6)
d 107.3, 121.1
4.8.4. 6-(Trifluoromethyl)quinolin-3-amine
(7e$HCl). Yield 98 mg, 91%. Brown solid; mp 178–184 ꢁC. IR (KBr,
cmꢀ1 nmax: 3293, 2539, 1632, 1578, 1305, 1122; 1H NMR (400 MHz,
hydrochloride
(q, JC–F¼30 Hz, C–CF3), 122.4, 124.2 (q, JC–F¼273 Hz, CF3), 125.8 (q,
JC–F¼6 Hz), 127.1, 136.1, 137.6, 144.2, 144.5; MS (EI, 70 eV, m/z (%)):
248 (32), 247 (12), 246 (100, Mþ), 225 (10), 207 (12), 38 (11), 36
)

R. Bujok et al. / Tetrahedron 66 (2010) 698–708
707
(46); HRMS (EI): (Mþ) found 246.0174. C10H635ClF3N2 requires
246.0172.
(2H, q, J¼7.1 Hz, OCH2), 6.74 (2H, br s, NH2), 7.51 (1H, d, J¼0.4 Hz, H-
4), 7.63 (1H, d, J¼2.3 Hz, H-7), 7.84 (1H, dd, J¼2.3, 0.4 Hz, H-5); 13C
NMR (100 MHz, DMSO-d6)
d 14.1, 61.3, 116.5, 123.5, 125.2, 132.2,
4.8.10. 8-Bromo-6-chloroquinolin-3-amine hydrochloride (7l$HCl).
132.3, 133.9, 134.4, 134.7, 144.5, 165.9; MS (EI, 70 eV, m/z (%)): 286
(20), 284 (30, Mþ), 212 (100), 185 (35), 148 (13); HRMS (EI): Mþ,
found 284.0110. C12H1035Cl2N2O2 requires 284.0119.
Yield 90 mg, 81%. Brown solid; mp 230–235 ꢁC. IR (KBr, cmꢀ1
)
nmax
:
3359, 3159, 2797, 1633, 1544, 1274, 1085; 1H NMR (400 MHz,
DMSO-d6)
d
7.42 (1H, d, J¼2.2 Hz, Ar-H), 7.45 (3H, t, JN–H¼50.7 Hz,
NHþ3 ), 7.80 (1H, d, J¼2.2 Hz, Ar-H), 7.92 (1H, d, J¼2.2 Hz, Ar-H), 8.66
(1H, d, J¼2.2 Hz, Ar-H); 13C NMR (100 MHz, DMSO-d6)
d 114.2,
4.10. Ethyl 3-aminoquinoline-2-carboxylate (9)
124.6, 124.8, 128.1, 130.9, 131.0, 136.4, 141.4, 144.7; MS (ESI, MeOH):
257 (MþH)þ; HRMS (ESI): (MþH)þ, found 256.9473.
C9H779Br35ClN2 requires 256.9476.
To a solution of 8 (215 mg, 0.75 mmol) in AcOEt (30 mL) was
added Et3N (1 mL), and 10% Pd/C (50 mg). The mixture was stirred
under H2 atmosphere at room temperature for 12 h. The catalyst
was then filtered off, the filtrate was washed with water and dried
with Na2SO4. The solvent was evaporated and the crude product
was purified by column chromatography, to obtain 142 mg (88%).
9: Yellow crystals; mp 163–166 ꢁC (AcOEt) (lit.11a 148–150 ꢁC).
4.8.11. 3-Amino-8-chloroquinoline-6-carboxylic acid hydrochloride
(7m$HCl). Yield 120 mg, w100%. Brown solid; mp >265 ꢁC. IR (KBr,
cmꢀ1 nmax: 3419, 3092, 1716, 1639, 1559, 1291, 1206; 1H NMR
)
(400 MHz, DMSO-d6)
d
7.36–7.60 (4H, HþNHþ3 ), 7.92 (1H, d,
1H NMR (600 MHz, DMSO-d6)
d
1.37 (3H, t, J¼7.1 Hz, OCH2CH3), 4.40
J¼1.7 Hz, Ar-H), 8.34 (1H, d, J¼1.7 Hz, Ar-H), 8.74 (1H, d, J¼2.7 Hz,
Ar-H); 13C NMR (100 MHz, DMSO-d6)
d 115.5, 123.8, 128.0, 129.1,
(2H, q, J¼7.1 Hz, OCH2), 6.41 (2H, br s, NH2), 7.40 (1H, ddd, J¼8.4, 6.8,
1.3 Hz, Ar-H), 7.47 (1H, ddd, J¼8.2, 6.8, 1.1 Hz, Ar-H), 7.51 (1H, s, Ar-
H), 7.66 (1H, app. d, J¼8.2 Hz, Ar-H), 7.85 (1H, app. d, J¼8.4 Hz, Ar-
H). Anal. Calcd for C12H12N2O2: C, 66.65; H, 5.59; N, 12.95. Found: C,
66.37; H, 5.40; N, 12.81.
130.1, 132.2, 138.1, 142.1, 145.7, 166.2; MS (ESI, MeOH): 223 (MþH)þ;
HRMS (ESI): (MþH)þ, found 232.0274. C10H835ClN2O2 requires
232.0269.
4.8.12. 5,8-Dichloroquinolin-3-amine hydrochloride (7n$HCl). Yield
92 mg, 81%. Brown solid; mp >265 ꢁC. IR (KBr, cmꢀ1
) nmax: 3285,
References and notes
3154, 2556, 1640, 1546, 1405, 1265; 1H NMR (400 MHz, DMSO-d6)
d
7.36 (3H, t, JN–H¼51.0 Hz, NHþ3 ), 7.43–7.49 (2H, m, Ar-H), 7.56 (1H,
1. For representative examples see: (a) Renau, T. E.; Leger, R.; Yen, R.; She, M. W.;
Sangalang, J.; Gannon, C. L.; Chamberland, S.; Lomovskaya, O.; Lee, V. J. Bioorg.
Med. Chem. 2002, 12, 763; (b) Renau, T. E.; Leger, R.; Flamme, E. M.; She, M. W.;
´
d, J¼8.0 Hz, Ar-H), 8.62 (1H, d, J¼2.2 Hz, Ar-H); 13C NMR (100 MHz,
´
DMSO-d6)
d 108.0, 123.4, 126.5, 126.7, 128.5, 131.5, 136.4, 144.1,
Gannon, C. L.; Mathias, K. M.; Lomovskaya, O.; Chamberland, S.; Lee, V. J.; Ohta,
T.; Nakayama, K.; Ishida, Y. Bioorg. Med. Chem. 2001, 11, 663; (c) Renau, T. E.;
Leger, R.; Flamme, E. M.; Sangalang, J.; She, M. W.; Yen, R.; Gannon, C. L.;
Griffith, D.; Chamberland, S.; Lomovskaya, O.; Hecker, S.; Lee, V. J.; Ohta, T.;
Nakayama, K. J. Med. Chem. 1999, 42, 4928; (d) Fujita, Y.; Tsuda, Y.; Li, T.;
Motoyama, T.; Takahashi, M.; Shimizu, Y.; Yokoi, T.; Sasaki, Y.; Ambo, A.; Kita, A.;
Jinsmaa, Y.; Bryant, S. D.; Lazarus, L. H.; Okada, Y. J. Med. Chem. 2004, 47, 3591;
(e) Selwood, D. L.; Brummell, D. G.; Glen, R. C.; Goggin, M. C.; Reynolds, K.;
Tatlock, M. A.; Wishart, G. Bioorg. Med. Chem. 2001, 11, 1089; (f) Wu, T. Y. H.;
Hassig, C.; Wu, Y.; Ding, S.; Schultz, P. G. Bioorg. Med. Chem. 2004, 14, 449; (g)
Moreno, A.; Perez, S.; Galiano, S.; Juanenea, L.; Erviti, O.; Frigola, C.; Aldana, I.;
Monde, A. Eur. J. Med. Chem. 2004, 39, 49; (h) Swanson, D. M.; Dubin, A. E.; Shah,
C.; Nasser, N.; Chang, L.; Dax, S. L.; Jetter, M.; Breitenbucher, J. G.; Liu, C.; Mazur,
C.; Lord, B.; Gonzales, L.; Hoey, K.; Rizolio, M.; Bogenstaetter, M.; Codd, E. E.;
Lee, D. H.; Zhang, S.-P.; Chaplan, S. R.; Carruthers, N. I. J. Med. Chem. 2005, 48,
1857; (i) Anandan, S.-K.; Ward, J. S.; Brokx, R. D.; Bray, M. R.; Patel, D. V.; Xiao,
X.-X. Bioorg. Med. Chem. 2005, 15, 1969; (j) Kiselyov, A. S.; Piatnitski, E. L.; Samet,
A. V.; Kisliy, V. P.; Semenov, V. V. Bioorg. Med. Chem. 2007, 17, 1369; (k) Suzuki,
T.; Kouketsu, A.; Itoh, Y.; Hisakawa, S.; Maeda, S.; Yoshida, M.; Nakagawa, H.;
Miyata, N. J. Med. Chem. 2006, 49, 4809.
144.3; MS (ESI, MeOH): 213 (MþH)þ; HRMS (ESI): (MþH)þ, found
212.9990. C9H735Cl2N2 requires 212.9981.
4.8.13. 3-Amino-6-chloroquinoline-8-carboxylic acid hydrochloride
(7p$HCl). Yield 114 mg, 93%. Brown solid; mp >265 ꢁC. IR (KBr,
cmꢀ1
DMSO-d6)
)
nmax: 3166, 1683, 1548, 1404, 1184; 1H NMR (400 MHz,
d
7.45 (3H, t, JN–H¼50.7 Hz, NHþ3 ), 7.61 (1H, d, J¼2.6 Hz,
Ar-H), 8.01 (1H, d, J¼2.4 Hz, Ar-H), 8.23 (1H, d, J¼2.3 Hz, Ar-H), 8.76
(1H, d, J¼2.7 Hz, Ar-H); 13C NMR (100 MHz, DMSO-d6)
d 115.3,
124.9, 128.7, 129.5, 131.2, 131.9, 133.4, 141.1, 144.0, 165.8; MS (ESI,
MeOH): 223 (MþH)þ; 245 (MþNa)þ; HRMS (ESI): (MþH)þ, found
223.0262. C10H835ClN2O2 requires 223.0269.
4.8.14. 3-Amino-8-chloroquinolin-6-ol (7q). Yield 79 mg, 86%.
Brown solid; mp 121–126 ꢁC (decomp.). Rf (AcOEt) 0.34; IR (KBr,
cmꢀ1
)
nmax: 3389, 3017, 1618, 1502, 1365, 1156; 1H NMR (400 MHz,
2. Glushkov, R. G.; Davydova, N. K. Pharm. Chem. J. 1992, 26, 325.
3. (a) Magnus, P.; Parry, D.; Iliadis, T.; Eisenbeis, S. A.; Fairhurst, R. A. J. Chem. Soc.,
Chem. Commun. 1994, 1543; (b) Morley, J. S.; Simpson, J. C. E. J. Chem. Soc. 1948,
2024; (c) Uhle, F. C.; Jacobs, W. A. J. Org. Chem. 1945, 10, 76; (d) Magnus, P.;
Eisenbeis, S. A.; Fairhurst, R. A.; Iliadis, T.; Magnus, N. A.; Parry, D. J. Am. Chem.
Soc. 1997, 119, 5591; (e) Claim 3708213 FRG; Chem. Abstr. 1989, 110, 57533 v; (f)
Popp, F. D.; Schuyler, P. J. Chem. Soc. 1964, 522.
DMSO-d6)
d
5.75 (2H, br s, NH2), 6.77 (1H, d, J¼2.6 Hz, Ar-H), 6.95
(1H, d, J¼2.6 Hz, Ar-H), 7.04 (1H, d, J¼2.5 Hz, Ar-H), 8.28 (1H, d,
J¼2.5 Hz, Ar-H), 9.94 (1H, s, Ar-H); 13C NMR (100 MHz, DMSO-d6)
d
105.9, 110.2, 116.2, 132.0, 132.03, 132.9, 140.8, 143.3, 155.1; MS (EI,
70 eV, m/z (%)): 196 (33), 194 (100, Mþ), 167 (14), 158 (5), 131 (13),
104 (9); HRMS (EI): Mþ, found 194.0239. C9H735ClON2 requires
194.0247.
4. Fanta, P. E. Org. Synth. Coll. 1963, IV, 844.
5. (a) Marco-Contelles, J.; Pe´rez-Mayoral, E.; Samadi, A.; Carreiras, M.; Soriano, E.
Chem. Rev. 2009, 109, 2652; (b) Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37;
(c) Abdel-Mohsen, S. A.; Geis, A. J. Chem. Res., Synop 2007, 689.
6. (a) Clemo, G. R.; Swan, G. A. J. Chem. Soc. 1945, 867; (b) Renshaw, R. R.;
Friedman, H. L. J. Am. Chem. Soc. 1939, 61, 3320; (c) Tabart, M.; Picaut, G.;
Lavergne, M.; Wentzler, S.; Malleron, J.-L.; Dutka-Malen, S.; Berthaut, N. Bioorg.
Med. Chem. Lett. 2003, 13, 1329.
4.9. Ethyl 3-amino-6,8-dichloroquinoline-2-carboxylate (8)
A solution of 3f (1.33 g, 3.6 mmol) in anhydrous EtOH (15 mL)
and Me3SiCl (10 mL) was heated at 90 ꢁC in an ampoule for 4 days.
After cooling down, the solvent was evaporated and to the residue
was added AcOEt (50 ml) and saturated NaHCO3. The aqueous layer
was separated and extracted with AcOEt (2ꢂ50 mL). Combined
organic extracts were dried with Na2SO4 and the solvent was
evaporated. The crude product was chromatographed to yield
690 mg (67%) of the product.
7. Reidlinger, G. H.; Junek, H. Synthesis 1991, 835.
8. (a) Chelucci, G.; Chelucci, G.; Manca, I.; Pinna, G. A. Tetrahedron Lett. 2005, 46,
767; (b) Ubeda, J. I.; Villacampa, M.; Avendano, C. Synthesis 1998, 1176; (c)
Conley, R. A.; Barton, D. L.; Stefanick, S. M.; Lam, M. M.; Lindaberry, G. C.; Ka-
sulanis, C. F.; Cesco-Cancian, S.; Currey, S.; Fabian, A. C.; Levineet, S. D. J.
Heterocycl. Chem. 1995, 32, 761; (d) Adelstein, G. W.; Yan, C. H.; Haack, R. A.; Yu,
S.; Gullikson, G.; Price, D. V.; Anglin, C.; Decktor, D. L.; Tsai, H.; Keith, R. H. J.
Med. Chem. 1988, 31, 1215; (e) Turner, J. J. Org. Chem. 1990, 55, 4744; (f) Frank, K.
E.; Aube, J. J. Org. Chem. 2000, 65, 655; (g) Muchowski, J. M.; Venuti, M. C. J. Org.
Chem. 1980, 45, 4798; (h) Carretero, J. C.; Ruano, J. L. G.; Vicioso, M. Tetrahedron
1992, 48, 7373; (i) Hewawasam, P.; Chen, N.; Ding, M.; Natale, J. T.; Boissard, C.
G.; Yeola, S.; Gribkoff, V. K.; Starrett, J.; Dworetzky, S. I. Bioorg. Med. Chem. Lett.
2004, 14, 1615; (j) Schlosser, M.; Ginanneschi, A.; Leroux, F. Eur. J. Org. Chem.
2006, 13, 2956.
8: Yellow solid; mp 137–140 ꢁC. Rf (hexane/AcOEt 2:1) 0.32; IR
(KBr, cmꢀ1 nmax: 3477, 3370, 2973, 2926, 1691, 1608, 1258, 1199; 1H
)
NMR (400 MHz, DMSO-d6)
d
1.37 (3H, t, J¼7.1 Hz, OCH2CH3), 4.42

708
R. Bujok et al. / Tetrahedron 66 (2010) 698–708
9. (a) Hashimoto, M.; Ujiie, S.; Mori, A. Chem. Lett. 2003, 32, 114; (b) Overman, L.
16. Bobin, M.; Kwast, A.; Wro´bel, Z. Tetrahedron 2007, 63, 11048.
E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem. Soc. 1991, 113, 2598; (c)
Overman, L. E.; Angle, S. J. Org. Chem. 1985, 50, 4021; (d) Ref. 6c; (e) Stanetty, P.;
Krumpak, B.; Rodler, I. K. J. Chem. Res., Miniprint 1995, 9, 2111; (f) Nakao, K.;
Shimizu, R.; Kubota, H.; Yasuhara, M.; Hashimura, Y.; Suzuki, T.; Fujita, T.;
Ohmizu, H. Bioorg. Med. Chem. 1998, 6, 849.
17. Shabana, R.; Rasmussen, J. B.; Lawesson, S.-O. Bull. Soc. Chim. Belg. 1981, 90, 75.
18. (a) Weiler, L. J. Am. Chem. Soc. 1970, 92, 6702; (b) Seebach, D.; Ehrig, V. Angew.
Chem. 1974, 86, 446; Angew. Chem., Int. Ed. Engl. 1974, 13, 401.
19. This side-product has been identified as ethyl 2-(2,2-dimethylpropanoyl)-
3-[(2,2-dimethylpropanoyl)amino]but-2-enoate. Orange oil. 1H NMR
10. (a) Horner, J. K.; Henry, D. W. J. Med. Chem. 1968, 11, 946; (b) Zhang, Z.; Tan, J.;
Wang, Z. Org. Lett. 2008, 10, 173.
11. (a) Wang, Y. D.; Boschelli, D. H.; Johnson, S.; Honores, E. Tetrahedron 2004, 60,
2937; (b) Westphal, G.; Scheybal, A.; Lipke, B.; Weber, F. G. Pharmazie 1976, 31,
770.
12. (a) Wro´bel, Z. Tetrahedron Lett. 1997, 38, 4913; (b) Wro´bel, Z. Tetrahedron 1998,
54, 2607; (c) Wro´bel, Z. Eur. J. Org. Chem. 2000, 521; (d) Wro´bel, Z. Tetrahedron
Lett. 2000, 41, 7365.
(400 MHz, DMSO-d6)
d
1.14 (9H, s), 1.20 (9H, s), 1.20 (3H, t, J¼7.1 Hz), 2.19
(3H, s), 4.18 (2H, q, J¼7.1 Hz), 11.44 (1H, br s); MS (ESI, MeOH): 320
(MþNa)þ; HRMS (ESI): (MþNa)þ, found 320.1816. C16H27NO4Na requires
320.1832.
20. Ma˛kosza, M.; Wojciechowski, K. Chem. Rev. 2004, 104, 2631.
21. Luebbers, T.; Angehrn, P.; Gmuender, H.; Herzig, S. Bioorg. Med. Chem. 2007, 16,
4708.
22. Sandmeyer, T. Chem. Ber. 1887, 20, 1497.
13. Korda, A.; Wro´bel, Z. Synlett 2003, 1465.
23. A signal of the quaternary carbon atom of the pivaloyl group (ca. 40 ppm)
overlapped with those of DMSO, and was not identified.
24. A compound was not isolated in pure form.
´
14. Wrobel, Z. Pol. J. Chem. 1998, 72, 2384.
15. (a) Wro´ bel, Z. Synlett 2001, 1927; (b) Wro´bel, Z. Synlett 2004, 1929.