Synthesis of pyrroles with fused carbocycles or heterocycles from Weinreb N-vinyl-α-amino amides

Article abstract of DOI:10.1055/s-2005-916037

Pyrroles fused to diverse carbocycles and heterocycles were prepared from Weinreb N-vinyl-α-amino carboxamides integrated in cyclic systems. The selective reaction of the carboxamide group with organometallic compounds allowed us to obtain a great variety

Full text of DOI:10.1055/s-2005-916037

3152
PAPER
Synthesis of Pyrroles with Fused Carbocycles or Heterocycles from Weinreb
N-Vinyl-a-amino Amides
F
use
d
Pyrroles
u
from
W
einre
i
b
N
-Vin
s
yl-
a
-amino Am
C
ides alvo, Alfonso González-Ortega,* Rodrigo Navarro, Mónica Pérez, María Carmen Sañudo
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Dr Mergelina s/n, 47002 Valladolid, Spain
Fax +34(983)423013; E-mail: algon@qo.uva.es
Received 31 May 2005; revised 13 June 2005
units that can be found in numerous compounds with a
Abstract: Pyrroles fused to diverse carbocycles and heterocycles
wide range of biological activity, such as antimitotic,4 an-
were prepared from Weinreb N-vinyl-a-amino carboxamides inte-
tibiotic,5 bioluminescent,6,7 antipsychotic8 or plant growth
grated in cyclic systems. The selective reaction of the carboxamide
regulators.9 The keto substrates chosen 1–9 (Figure 1) and
group with organometallic compounds allowed us to obtain a great
variety of the carbonyl intermediates analogous to the Knorr synthe- the intermediates derived from them show a variety of
sis, which were thermally cyclized. The principal limitation of the
structural characteristics – carbocycles, heterocycles,
method was due to the insolubility of some metallic intermediates
five- or six-membered cycles, ketone derivatives, ester
as well as to the low nucleophilicity and stability of the enamine
derivatives – which have allowed us to make important
during the cyclization process.
observations regarding the behavior of the synthetic pro-
cess and, above all, concerning some limitations which
had not been observed in previous studies.
Key words: Knorr pyrrole synthesis, Weinreb amides, fused pyr-
roles
In our synthetic design we can distinguish three stages: a)
formation of the key intermediates 14–25; b) reaction of
In a previous paper of ours, we developed a versatile vari-
these intermediates with organometallic compounds; and
ant of the Knorr synthesis for pyrroles in which Weinreb
c) cyclization of the ketones 28–40 to the pyrroles 41–50
a-amino amides were used instead of the traditional a-
(Scheme 2).
amino ketones (Scheme 1).1 The key intermediate of the
synthetic sequence is the N-methoxy-N-methylcarboxam-
ide derivative A, which by means of its reaction with or-
O
O
O
ganometallic compounds, allows us to obtain pyrrole
building blocks.
Y
Cl
L
O
L
OCH3
N
OCH3
N
3 L = Cl
4 L = OH
1 L = Cl
2 L = OH
5 Y = Cl
6 Y = Me
W
O
O
W
∆
CH3
CH3
+
O
O
– NH3
H2N
H2N
A
N
H
O
O
O
W = CN, CO2Et, COR
W
N
H
CO2Et
RM
Br
Br
7
8
9
R
O
W
R
∆
Figure 1 Precursor conjugated ketones chosen for preparing fused
– H2O
pyrroles
N
N
H
H
Scheme 1
OCH3
OCH3
N
O
O
O
N
O
CH3
CH3
Initially the procedure was developed starting from acy-
clic enamines1 and later it was successfully applied to the
synthesis of [1]benzopyrano[4,3-b]pyrrol-4(1H)-ones2
and pyrrolizines.3Now, starting from cyclic enamines we
have tried to prepare 6,7-dihydro-1H-indol-4(5H)-ones,
5,6-dihydrocyclopenta[b]pyrrol-4(1H)-ones, [1]benzopy-
Et3N/EtOH
r.t., 24 h
+
X
X
HN
R1
R2
N
R1
R2
L
1–9
10–13
14–25
10 R1 = R2 = H
13 R1NH-CHR2-
11 R1 = H, R2 = Me
12 R1 = Me, R2 = H
R3Li
HN
rano[2,3-b]pyrrol-4(1H)-ones,
4(1H)-ones, 1H-furo[3,4-b]pyrrol-4(6H)-ones and 2-
pyrano[4,3-b]pyrrol-
O
O
R3
R3
O
acylindoles. These bi- or tricyclic moieties are interesting
∆
R2
X
X
– H2O
R2
N
N
R1
R1
SYNTHESIS 2005, No. 18, pp 3152–3158
x
x.
x
x
.
2
0
0
5
41–50
28–40
Advanced online publication: 06.10.2005
DOI: 10.1055/s-2005-916037; Art ID: Z09905SS
Scheme 2
© Georg Thieme Verlag Stuttgart · New York

PAPER
Fused Pyrroles from Weinreb N-Vinyl-a-amino Amides
3153
stituents proceeded satisfactorily (65–89%) at room tem-
perature in ethanol–triethylamine (Table 1). The
Preparation of the Key Intermediates
In general, all the key intermediates 14–25 were prepared carbocyclic intermediates 14–18 were also obtained, but
by reaction of b-chlorocycloalkenyl ketones 1, 3, 5, 6 or with lower yields (55–75%), starting from a solution of
b-bromo-a,b-unsaturated esters 7, 8 with N-methoxy-N- the corresponding b-diketones 2 and 4 with the previous
methyl a-amino carboxamides (hydrobromide deriva- carboxamides 10–13 in methanol at room temperature.
tives) 10–13 through a conjugated addition–elimination
(Scheme 2). The interchange of halogen for nitrogen sub-
Table 1 Enamines 14–25 Prepared
Substrates Product
Yield (%) Mp (°C) 1H NMR (CDCl3); d, J (Hz)
1 + 10
1 + 11
1 + 12
89
81
78
117
119
125
1.79–1.83 (m, 2 H), 2.14 (t, 2 H, J = 6.5), 2.28 (t, 2 H, J = 6.2), 3.07 (s,
3 H), 3.57 (s, 3 H), 3.80 (d, 2 H, J = 4.1), 4.88 (s, 1 H), 5.68 (br, 1 H,
NH)
O
O
O
O
Z
N
H
14
15
1.36 (d, 3 H, J = 6.7), 1.94–2.00 (m, 2 H), 2.31–2.36 (m, 4 H), 3.22 (s,
3 H), 3.74 (s, 3 H), 4.41 (q, 1 H, J = 6.7), 5.10 (s, 1 H), 5.42 (br, 1 H,
NH)
O
Z
Me
N
H
1.94–1.98 (m, 2 H), 2.22–2.26 (m, 2 H), 2.39–2.45 (m, 2 H), 2.99 (s, 3
H), 3.17 (s, 3 H), 3.71 (s, 3 H), 4.19 (s, 2 H), 5.13 (s, 1 H)
O
Z
N
Me
16
17
3 + 10
58
56
189
2.34–2.37 (m, 2 H), 2.58–2.61 (m, 2 H), 3.18 (s, 3 H), 3.69 (s, 3 H), 3.96
(d, 2 H, J = 3.3), 4.94 (s, 1 H), 7.26 (br, 1 H, NH)
O
O
Z
N
H
3 + 13
>300
The NMR spectrum presented broad duplicated signals with a low mag-
netic response. The equilibrium between the two pseudo-planar confor-
mations of the enamine group (C=CNR2) plays an important role in the
number and type of NMR signals.
O
O
N
Z
18
5 + 10
6 + 12
86
85
197
82
3.31 (s, 3 H), 3.76 (s, 3 H), 4.23 (s, 2 H), 5.76 (s, 1 H), 6.10 (br, 1 H,
NH), 7.48 (d, 1 H, J = 8.7), 7.66 (dd, 1 H, J = 2.5, 8.7), 8.21 (d, 1 H,
J = 2.5)
O
O
Z
Cl
N
H
O
O
19
2.38 (s, 3 H), 3.10 (s, 3 H), 3.19 (s, 3 H), 3.77 (s, 3 H), 4.36 (s, 2 H),
5.40 (s, 1 H), 7.12 (d, 1 H, J = 8.6), 7.30 (dd, 1 H, J = 2.1, 8.6), 7.91 (d,
1 H, J = 2.1)
O
Z
Me
N
O
Me
20
7 + 10
74
148
2.15 (s, 3 H), 3.25 (s, 3 H), 3.75 (s, 3 H), 3.96 (d, 2 H, J = 4.0), 4.93 (s,
1 H), 5.56 (br, 1 H, NH), 5.63 (s, 1 H)
O
O
Z
O
Me
N
H
21
Synthesis 2005, No. 18, 3152–3158 © Thieme Stuttgart · New York

3154
L. Calvo et al.
PAPER
Table 1 Enamines 14–25 Prepared (continued)
Substrates Product
Yield (%) Mp (°C) 1H NMR (CDCl3); d, J (Hz)
7 + 12
7 + 13
8 + 10
8 + 12
72
64
69
77
175
2.08 (s, 3 H), 2.96 (s, 3 H), 3.12 (s, 3 H), 3.68 (s, 3 H), 4.17 (s, 2 H),
4.86 (br, 1 H), 5.68 (br, 1H)
O
O
Z
O
Me
N
Me
22
94
2.05-2.20 (m, 2 H), 2.23 (s, 3 H), 2.28–2.38 (m, 2 H), 3.22 (s, 3 H),
3.50–3.72 (m, 2 H), 3.81 (s, 3 H), 4.69 (s, 1 H), 4.97 (s, 1 H), 5.42
(s, 1 H)
O
O
N
Z
O
Me
23
169
229
3.25 (s, 3 H), 3.76 (s, 3 H), 4.00 (d, 2 H, J = 2.9), 4.70 (s, 1 H), 4.71 (s,
2 H), 5.88 (br, 1 H, NH)
O
O
Z
O
N
H
24
2.87 (s, 3 H), 3.09 (s, 3 H), 3.63 (s, 3 H), 4.00 (s, 2 H), 4.40–4.70
(m, 3 H)
O
O
Z
O
N
Me
25
a Z = N(OMe)Me.
δ
OCH3
N
Li
OCH3
N
O
O
O
O
N
Reaction with Organometallic Compounds
CH3
CH3
X
X
δ
N
R1
R2
27
R2
While the nature of the ring substituent did not play a sig-
nificant part in the previous stage, it did in the reaction of
14–25 with organometallic compounds and in the subse-
quent cyclization of the resulting ketones 28–40. The sec-
ondary enaminones derived from six-membered cycles
(3-aminocyclohex-2-enones 14, 15, 3-amino-4H-1-ben-
zopyran-4-one 19 and 2H-pyran-2-one 21) gave excellent
26
partial deactivation
of the C = O bond
total deactivation
of the C = O bond
Figure 2 Intermediate structures 26 and 27 illustrating the deactiva-
tion of C=O group (cf. Scheme 2)
yields in their reaction with organometallic compounds. The most important limitations in the reaction with orga-
As was to be expected, the ketone or ester group was com- nometallic compounds have been found starting from the
pletely deactivated (intermediate 26) with the first mole of five-membered cycles, both carbocycles 17, 18 as well as
organometallic reagent,2,3 and if an excess of reagent is heterocycles 24, 25, which in general remained not trans-
used, only the Weinreb-amide was transformed into a car- formed due to the insolubility of the metallic intermedi-
bonyl group. Normally a strict control of the temperature ates. Only it was possible to convert the tertiary enamine
and proportion of reagents is unnecessary to obtain satis- 25 to 40 (70%) in an ultrasonic bath. The failure in these
factory yields.
cases was not, therefore, due to a lack of selectivity in the
reaction of the organometallic compounds with the Wein-
reb amides, but rather to a problem of insolubility.
Starting from the enamines 16, 20, 22 and 23 (also derived
from six-membered cycles) as we had already shown with
other tertiary enamines,2,3 the deactivation of the carbonyl The hydrolysis of the organometallic intermediates occurs
group toward the organometallic reagents is only partial with total or partial simultaneous cyclization to pyrroles.
(compare structures 26 and 27 in Figure 2). As a conse- Consequently, no attempt was made to isolate the ketones
quence, control of the selective reaction of the Weinreb 28–40 from the reaction mixture and the process was con-
amide group with organometallic reagents was less satis- tinued at reflux in chloroform in the presence of silica gel
factory than with the secondary enamines. Only the less in order to obtain a complete transformation to pyrroles
basic organolithium compounds at –40 °C (e.g. MeLi and 41–50 (Table 2). Only the ketones 35, 37 and 40, which
RC≡CLi) allowed us to prepare the corresponding ke- could not be cyclized, were isolated and purified for their
tones.
characterization.
Synthesis 2005, No. 18, 3152–3158 © Thieme Stuttgart · New York

PAPER
Fused Pyrroles from Weinreb N-Vinyl-a-amino Amides
3155
Table 2 Preparation of Pyrroles 41–50 from 14–25
Reaction with Organometallic Compounds
Cyclization
Amide RM
Ratio
Temp
(°C)
Time
(min)
Ketone
Yield (%)
Solvent
(Reflux)
Time
(min)
Product Yield (%)
14
14
MeLi
1:1.5
–40
25
28 (75)a
toluene
60
O
Me
N
H
41 (73)
1:2
–40
50
29 (72)a
xylene
60
O
S
Li
S
N
H
42 (53)
O
15
15
15
i-PrMgBr
1:2
1:2
1:2
–40
–40
–40
50
40
30
30 (77)a
31 (71)a
32 (68)a
toluene
toluene
toluene
60
60
60
i-Pr
Me
N
H
43 (66)
O
BuLi
Bu
Me
N
H
44 (81)
S
Li
O
S
S
S
Me
N
H
45 (63)
O
16
16
MeLi
1:2
1:2
–40
–40
20
40
33 (68)a
34 (72)a
CHCl3
CHCl3
60
60
Me
N
Me
46 (75)
O
BuC≡CLi
C
CBu
N
Me
47 (65)
–
b
17
18
19
–
–
–
b
–
–
–
c
MeLi
1:2
1:2
–40
–40
20
40
–
O
O
Cl
Me
O
N
H
35 (90)
20
MeLi
36 (82)a
O
O
Me
Me
N
Me
48 (77)
Synthesis 2005, No. 18, 3152–3158 © Thieme Stuttgart · New York

3156
L. Calvo et al.
PAPER
Table 2 Preparation of Pyrroles 41–50 from 14–25 (continued)
Reaction with Organometallic Compounds
Cyclization
Amide RM
Ratio
Temp
(°C)
Time
(min)
Ketone
Yield (%)
Solvent
(Reflux)
Time
(min)
Product Yield (%)
c
21
22
EtMgBr
1:3
–30
40
–
–
O
Et
O
O
N
H
Me
37 (85)
MeLi
MeLi
1:2.5
1:2
–40
30
38 (72)a
CHCl3
CHCl3
3.5
O
O
Me
O
N
Me
Me
49 (80)
23
–40
–40
50
60
39 (70)a
3
Me
N
O
Me
50 (88)
–
24
25
–-b
–
c
MeLi
1:2.5
–
–
O
Me
O
O
N
Me
40 (70)
a Estimated from 1H NMR spectra of the reaction mixture. Not isolated.
b Various RM and experimental conditions were tried without success.
c Various experimental conditions were tried without success.
Cyclization
xylene) which required longer times to acquire higher
temperature.
The easy cyclization of the ketones 28–40 to the pyrroles
41–50 not only depended on the electrophilicity of the
carbonyl group (R3: H > alkyl > aryl), but also on the na-
ture of the initial cycle and the nature of R1, to the point
where these last two factors limited the viability of the cy-
clization in some cases. In general, the Knorr intermedi-
ates derived from tertiary amines 33, 34, 36, 38, 39 (R1 π
H) were cyclized in refluxing chloroform or toluene to
give the corresponding pyrroles 46–50. Only in the specif-
ic case of the 4-[N-methyl-N-(2-oxopropyl)amino]furan-
2(5H)-5-one (40) did all the attempts at cyclization failed.
This abnormal behavior was attributed to the low nucleo-
philicity of the enamine when it was integrated in the fura-
none cycle.
Attempts to prepare 2-acylindoles via the key intermedi-
ate 51 deserve a separate discussion (Scheme 3). This was
obtained starting from 9 by reaction with isopropylmag-
nesium chloride/N,O-dimethylhydroxylamine.10 Formal-
ly, the synthetic design shown in Scheme 3 presents the
same basic principle: the deactivation by conjugation of
the acetyl groups in the amide intermediates (e.g. 52)
should allow the transformation, respectively, of 9 in 51
and 51 in 52. Unfortunately, the expected deactivation did
not take place and the carboxamide 51, which was ob-
tained in low yield (25%)11 afforded 54 by attack of the or-
ganolithium compound both at the carboxamide group as
well as at the acetyl group. Everything indicates that the
deactivation of the acetyl group in 52 is less efficient than
On the other hand, the secondary enamines 28–32, 35, 37 in 26 (Figure 2), given that the resonance structure implies
(R1 = H), thermally less reactive and less stable than the loss of the aromatic character.
tertiary enamines, behaved differently. Thus, the interme-
diates derived from the carbocycles 28–32 gave good
Melting points were measured on a Reichert-Jung Thermo Galen
yields of pyrroles in toluene or chloroform under reflux,
but their analogues derived from heterocycles 35, 37 did
not cyclize in the same conditions and were degraded
when solvents with a higher boiling point were used (e.g.
and are uncorrected. IR spectra were obtained on a Perkin-Elmer
1720 X spectrometer. NMR spectra were recorded on a Bruker
AC300 spectrometer, and chemical shifts are given downfield from
SiMe4 as an internal standard. 13C NMR spectra were carried out
Synthesis 2005, No. 18, 3152–3158 © Thieme Stuttgart · New York

PAPER
Fused Pyrroles from Weinreb N-Vinyl-a-amino Amides
3157
Ketones 28–40 and Pyrroles 41–50 from 14–25; General Proce-
dure
Me
N
Me
i-PrMgCl
O
O
OMe
N
BuLi
OMe
N
To a magnetically stirred solution of amides 14–25 (2.22 mmol) in
anhyd THF (35 mL) was added dropwise the organometallic com-
pound under N2 (see Table 2). At the end of the reaction (monitored
by TLC), the mixture was hydrolyzed. The organic layer was sepa-
rated, washed with H2O, dried (Na2SO4) and evaporated. Except 35,
37 and 40 [recrystallized from EtOAc (for 35) or from CH2Cl2–Et2O
(for 37, 40)], the carbonyl intermediates were not isolated and the
residue was carried over to cyclization treatment. Thus, the reaction
mixtures of 28–34, 36, 38, 39 (ca. 2.2 mmol) and silica gel (5 ×
w/w) in the appropriate solvent (50 mL) were heated in a rotary
evaporator, slowly distilling the solvent (see Table 2). The silica gel
was removed by filtration and washed thoroughly with hot acetone.
The solvent was removed in vacuo, and the concentrate was chro-
matographed on silica gel using CH2Cl2–Et2O (20:1) (for 42, 44,
45), CH2Cl2–Et2O (10:1) (for 47) or CH2Cl2 (for 50) as eluent, or re-
crystallized from EtOH (for 41), from CH2Cl2–Et2O (for 43, 46, 49)
or from toluene (for 48) (Tables 2 and 3).
9
MeONHMe
Me
N
H
Me
51
52
O
O
Bu
Me
BuLi
OH
Bu
Bu
O
Bu
N
H
N
O
54
H
53
Scheme 3
with complete 1H decoupling and the assignments were made by ad-
ditional DEPT experiments.
The starting compounds were purchased from commercial suppliers
(2, 4) or prepared by literature procedures (1,12 3,12 5,13 6,13 7,14 8,15
916).
2-(2-Acetylphenylamino)-N-methoxy-N-methylacetamide (51)
To a magnetically stirred mixture of 9 (0.50 g, 2.26 mmol), N,O-
dimethylhydroxylamine hydrochloride (3.50 g, 1.55 mmol) in an-
hyd THF (40 mL) at –20 °C, was added dropwise a solution of i-
PrMgCl in THF (9.05 mmol, 2 M). The mixture was kept for 40 min
at –10 °C and quenched with 20% wt aq NH4Cl. The aqueous layer
was extracted with CH2Cl2 (2 × 50 mL) and the combined organic
layers were dried (Na2SO4) and concentrated. The residue was chro-
matographed (silica gel, CH2Cl2–Et2O, 15:1) to give 51 (25%)
(Table 3).
Weinreb Amides 14–25 from 1–9; General Procedure
A mixture of halo derivative 1–9 (10.6 mmol), Weinreb a-amino
amide (hydrobromide derivatives) 10–13 (11.6 mmol) and Et3N
(3.08 mL, 22.2 mmol) in anhyd CH2Cl2 (40 mL) was stirred at r.t.
(ca. 24 h). At the end of the reaction, monitored by TLC, the solu-
tion was concentrated in vacuo, and the residue was dissolved in
CH2Cl2–H2O (1:1, 100 mL). The aqueous layer was extracted with
CH2Cl2 (2 × 50 mL) and the combined organic layers were dried
(Na2SO4) and evaporated to dryness. The residue was purified by
chromatography on silica gel using THF (for 14–16, 22), acetone
(for 18), CH2Cl2–THF (5:1) (for 21), CH2Cl2–Et2O (5:1) (for 23) as
eluent, or recrystallized from CH2Cl2–Et2O (for 17, 20, 24, 25) or
from toluene (for 19) (Table 1).
1-[2-(1-Hydroxy-1-methylpentyl)phenylamino]hexan-2-one
(54)
The title compound was prepared by a procedure analogous to that
described for the ketone 35, starting from 51 (0.52 g, 2.22 mmol)
and BuLi (4.16 mL, 1.6 M in toluene, 6.66 mmol) in anhyd THF (35
mL) at –40 °C. The crude product was purified by chromatography
on silica gel using CH2Cl2–Et2O (30:1) as eluent; yield: 53%; oil;
Rf 0.35 (CH2Cl2–Et2O, 35:1) (Table 3).
Table 3 Physical and Spectral Data for Compounds 35, 37, 40–51 and 54
Producta Mp (°C) IR (KBr) (cm–1)
1H NMR (CDCl3); d, J (Hz)
13C NMR (CDCl3), d
35
37
161
oil
1722, 1618, 1563
3426, 1715, 1690
2.17 (s, 3 H), 4.23 (s, 2 H), 5.29 (s, 1 H), 7.45 27.0 (CH3), 50.4 (CH2), 84.8 (CH), 119.0 (CH),
(d, 1 H, J = 8.7), 7.64 (dd, 1 H, J = 2.1, 8.7),
7.81 (d, 1 H, J = 2.1), 8.27 (br, 1 H, NH)
123.8 (CH), 124.4 (C), 129.0 (C), 132.0 (CH),
151.7 (C), 163.7 (C), 173.0 (C), 203.6 (C)
1.08 (t, 3 H, J = 7.3), 2.09 (s, 3 H), 2.49 (q, 2 H, 7.4 (CH3), 19.7 (CH3), 33.4 (CH2), 50.9 (CH2),
J = 7.3), 3.91 (d, 2 H, J = 4.3), 4.79 (s, 1 H),
5.65 (s, 1 H), 5.86 (br, 1 H, NH)
81.0 (CH), 98.9 (CH), 156.9 (C), 161.0 (C),
164.9 (C), 204.7 (C)
40
41
105
203
1716, 1619
2.13 (s, 3 H), 2.88 (s, 3 H), 3.98 (s, 2 H), 4.40– 27.1 (CH3), 39.7 (CH3), 61,9 (CH2), 66.8 (CH2),
4.70 (m, 3 H) 82.1 (CH), 169.2 (C), 175.2 (C), 201.9 (C)
3210, 1627, 1481
2.12–2.16 (m, 2 H), 2.30 (s, 3 H), 2.45 (t, 2 H, 11.6 (CH3), 22.5 (CH2), 23.9 (CH2), 38.4 (CH2),
J = 6.0), 2.78 (t, 2 H, J = 6.0), 6.41 (s, 1 H),
8.47 (br, 1 H, NH)
116.2 (CH), 116.7 (C), 117.8 (C), 143.4 (C),
193.8 (C)
42
43
155
196
3205, 1655, 1585
3214, 1617, 1466
2.12–2.19 (m, 2 H), 2.47 (t, 2 H, J = 5.9), 2.79 22.4 (CH2), 27.9 (CH2), 37.2 (CH2), 122.7 (CH),
(t, 2 H, J = 6.3), 6.43 (s, 1 H), 7.10 (dd, 1 H, 127.3 (CH), 128.2 (CH), 128.7 (CH), 142.7 (C),
J = 3.5, 5.2), 7.39 (d, 1 H, J = 3.5), 7.44 (d, 1 H, 152.4 (C), 199.4 (C)
J = 5.2)
1.28 (d, 6 H, J = 7.0), 2.07–2.11 (m, 2 H), 2.21 11.6 (CH3), 22.1 (2CH3), 23.1 (CH2), 23.8
(s, 3 H), 2.42–2.46 (m, 2 H), 2.73–2.77 (m, 2
(CH2), 25.3 (CH), 39.1 (CH2), 118.0 (C), 123.1
H), 3.28–3.32 (m, 1 H, J = 7.0), 8.50 (br, 1 H, (C), 124.8 (C), 142.8 (C), 194.9 (C)
NH)
Synthesis 2005, No. 18, 3152–3158 © Thieme Stuttgart · New York

3158
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PAPER
Table 3 Physical and Spectral Data for Compounds 35, 37, 40–51 and 54 (continued)
Producta Mp (°C) IR (KBr) (cm–1) 1H NMR (CDCl3); d, J (Hz)
13C NMR (CDCl3), d
44
172
3221, 1622, 1599,
1468
0.91 (t, 3 H, J = 7.2), 1.32–1.39 (m, 2 H), 1.48– 10.9 (CH3), 14.0 (CH3), 22.6 (CH2), 22.9 (CH2),
1.53 (m, 2 H), 2.08–2.12 (m, 2 H), 2.14 (s, 3 H), 24.0 (CH2), 24.5 (CH2), 33.1 (CH2), 38.7 (CH2),
2.43 (t, 2 H, J = 6.2), 2.62 (t, 2 H, J = 7.3), 2.74 118.3 (C), 119.1 (C), 124.1 (C), 142.2 (C), 194.9
(t, 2 H, J = 6.2)
(C)
45
287
3210, 1627, 1595,
1467
1.60–1.64 (m, 1 H), 1.92–2.02 (m, 2 H), 2.02– 12.2 (CH3), 22.1 (CH2), 23.5 (CH2), 25.1 (CH2),
2.07 (m, 1 H), 2.24 (t, 2 H, J = 5.9), 2.31 (s, 3 31.7 (2CH2), 38.4 (CH2), 40.9 (CH), 114.3 (C),
H), 2.64 (t, 2 H, J = 5.9), 2.74–2.94 (m, 4 H), 115.3 (C), 128.9 (C), 141.8 (C), 193.9 (C)
6.16 (s, 1 H), 11.20 (br, 1 H, NH)
46
47
131
155
1639
2.10–2.16 (m, 2 H), 2.28 (s, 3 H), 2.42 (t, 2 H, 11.3 (CH3), 21.6 (CH2), 23.5 (CH2), 33.0 (CH3),
J = 5.9), 2.69 (t, 2 H, J = 6.2), 3.48 (s, 3 H),
6.28 (s, 1 H)
38.2 (CH2), 118.7 (C), 120.7 (CH), 143.5 (C),
194.9 (C)
1654, 1548
0.92 (t, 3 H, J = 7.2), 1.42–1.64 (m, 4 H), 2.05– 13.6 (CH3), 19.4 (CH2), 21.6 (CH2), 22.0 (CH2),
2.16 (m, 2 H), 2.40–2.44 (m, 4 H), 2.68 (t, 2 H, 23.2 (CH2), 30.9 (CH2), 33.4 (CH3), 37.9 (CH2),
J = 6.2), 3.50 (s, 3 H), 6.65 (s, 1 H)
73.3 (C), 90.9 (C), 103.0 (C), 120.9 (C), 126.7
(CH), 142.8 (C), 192.9 (C)
48
184
1640, 1609
2.44 (s, 3 H), 2.46 (s, 3 H), 3.65 (s, 3 H), 6.24 11.6 (CH3), 21.0 (CH3), 31.0 (CH3), 105.5 (C),
(s, 1 H), 7.33 (d, 1 H, J = 8.4), 7.40 (dd, 1 H,
J = 1.9, 8.4), 8.12 (d, 1 H, J = 1.9)
115.2 (C), 115.9 (CH), 116.7 (CH), 123.4 (C),
126.2 (CH), 133.3 (CH), 149.6 (C), 152.2 (C),
174.3 (C)
49
50
51
154
168
111
1711, 1633, 1501
1703, 1630
2.26 (s, 3 H), 2.34 (s, 3 H), 3.57 (s, 3 H), 6.12 10.6 (CH3), 20.0 (CH3), 32.9 (CH3), 93.3 (CH),
(s, 1 H), 6.45 (s, 1 H)
106.1 (C), 118.6 (C), 123.1 (CH), 139.9 (C),
155.5 (C), 160.9 (C)
2.23 (s, 3 H), 2.27 (s, 3 H), 2.54 (q, 2 H,
J = 6.9), 2.79 (t, 2 H, J = 6.9), 3.89 (t, 2 H,
J = 6.9), 6.07 (s, 1 H)
10.0 (CH3), 19.8 (CH3), 22.2 (CH2), 27.6 (CH2),
44.0 (CH2), 94.0 (CH), 108.4 (C), 109.3 (C),
134.6 (C), 137.1 (C), 154.2 (C), 161.2 (C)
3299, 1669, 754
2.59 (s, 3 H), 3.24 (s, 3 H), 3.76 (s, 3 H), 4.15 27.9 (CH3), 32.5 (CH3), 44.0 (CH2), 61.5 (CH3),
(d, 2 H, J = 5.1), 6.62–6.66 (m, 2 H), 7.37 (dd, 111.8 (CH), 114.6 (CH), 118.3 (C), 132.7 (CH),
1 H, J = 1.6, 8.5), 7.77 (dd, 1 H, J = 1.6, 8.2), 134.8 (CH), 149.9 (C), 171.4 (C), 200.5 (C)
9.34 (br s, 1 H)
54
oil
3366, 1719, 744
0.84–0.94 (m, 6 H), 1.26–1.41 (m, 6 H), 1.57– 13.8 (CH3), 14.0 (CH3), 22.3 (CH2), 23.0 (CH2),
1.67 (m, 4 H), 1.65 (s, 3 H), 2.50 (t, 2 H, J = 7.4), 25.8 (CH2), 26.6 (CH2), 28.3 (CH3), 39.8 (CH2),
3.99 (s, 2 H), 6.47 (dd, 1 H, J = 0.8, 8.1), 6.66 40.3 (CH2), 54.0 (CH2), 111.4 (CH), 116.4 (CH),
(td, 1 H, J = 0.8, 6.6), 7.07–7.16 (m, 2 H)
126.7 (CH), 128.2 (CH), 129.4 (C), 146.1 (C),
208.0 (C).
a Satisfactory microanalyses obtained: C 0.30, H 0.30, N 0.30.
(8) Masaguer, C. F.; Raviña, E. Tetrahedron Lett. 2002, 43,
7929.
(9) Dudinov, A.; Kozhinov, D. V.; Krayushkin, M. Russ. Chem.
Bull. 2001, 50, 1259.
(10) Williams, M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.;
Dolling, U. H.; Grabowski, E. J. Tetrahedron Lett. 1995, 36,
5461.
(11) In the preparation of 53 we did not optimize the procedure or
search for alternative methods for the low yield of their later
transformation to indoles.
(12) Mewshaw, R. E. Tetrahedron Lett. 1989, 30, 3753.
(13) Levas, M.; Levas, E. C. R. Acad. Sci. 1960, 250, 2819.
(14) Cervera, M.; Moreno-Mañas, M.; Pleixats, R. Tetrahedron
1990, 46, 7885.
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Synthesis 2005, No. 18, 3152–3158 © Thieme Stuttgart · New York