N-functionalization of azoles through coupling reactions with alkoxydienyl and alkoxystyryl boronic esters

Article abstract of DOI:10.1002/ejoc.200600872

Alkoxydienyl boronates 1a and 1b and alkoxystyryl boronate 2 have been used in various copper mediated cross-coupling reactions with azoles. A variety of N-alkoxydienyl- and N-styrylazoles have been synthesized under mild conditions. The process utilizes

Full text of DOI:10.1002/ejoc.200600872

FULL PAPER
DOI: 10.1002/ejoc.200600872
N-Functionalization of Azoles through Coupling Reactions with Alkoxydienyl
and Alkoxystyryl Boronic Esters
Annamaria Deagostino,[a] Cristina Prandi,*[a] Chiara Zavattaro,[a] and Paolo Venturello[a]
Keywords: Azoles / Vinyl boronates / Cross-coupling / C–N bond formation / Copper catalysis
Alkoxydienyl boronates 1a and 1b and alkoxystyryl boronate
2 have been used in various copper mediated cross-coupling
reactions with azoles. A variety of N-alkoxydienyl- and N-
styrylazoles have been synthesized under mild conditions.
The process utilizes Cu(OAc)2 in the presence of CsF in
CH2Cl2 at room temperature.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
imidazoles in the presence of catalytic [Cu(OH)·
TMEDA]2Cl2.
Introduction
N-Functionalized aromatic azacycles are important com-
pounds in naturally occurring products, as well as in many
biologically active pharmaceuticals.[1] Transition metal-
catalyzed cross-coupling reactions are well established for
C–N bond formation, but examples involving heterocycles
remain rare in these experiments.[2] Traditionally, Ullmann-
type coupling between aryl halides and N-containing het-
erocycles represents a straightforward and inexpensive
method by which to arylate azacycles, but the scope of the
reaction is limited by the high temperatures required, by the
use of 2 equiv or more of aryl halide necessary to provide
satisfactory yields, and by the poor tolerance for several
important functional groups.[3] Although Pd-catalyzed aryl-
ation of azoles is well documented, the scope of this reac-
tion is restricted by C-arylation side reactions and by the
high cost of the catalyst.[4] Cu-mediated N-arylation of
imidazoles was proposed by Buchwald,[5] who reported that
the coupling reaction proceeds fairly smoothly in the pres-
ence of Cu(OTf)2·benzene complex as a Cu source and
1,10-phenanthroline as a ligand. Moreover, simple diamine
ligands for CuI have also been used for the arylation of
indoles,[6] pyrroles, pyrazoles, indazoles, imidazoles, and tri-
azoles.[7] Recent developments reported by Chan and
Lam[8] have demonstrated that arylboronic acids can be ef-
fective as arylating agents when stoichiometric quantities of
Cu(OAc)2 are used; these experimental conditions have
been applied to the arylation of azoles,[9] pyrrole and methyl
indole-2-carboxylate derivatives,[10] sterically hindered imid-
azoles,[11] and electron-deficient pyrroles.[12] More recently,
heteroarenes have been arylated with catalytic Cu(OAc)2 in
the presence of stoichiometric amounts of mild oxidizing
agents,[13] while Collman[14] has reported the arylation of
In contrast, there are fewer examples of C–N bond for-
mation as a method for N-vinylation through the use of
boronic acids or esters. Lam[15] reported the vinylation of
benzimidazole and indazole with either stoichiometric or
catalytic Cu(OAc)2 in the presence of oxidants, while N-
vinylation of aziridines with alkenylboronic acid was
achieved by Yudin.[16] In addition, N-vinylation has also
been achieved by coupling between vinyl bromides and li-
thiated azoles[17] or, more recently, azoles in the presence of
catalytic Cu.[18] Pd-catalyzed reactions with vinyl triflates
have been also reported.[19] In the past few years we have
been developing a general method for the synthesis of al-
koxydienyl and alkoxystyryl boronates,[20] which have
proven to be useful substrates in Suzuki–Miyaura cross-
coupling reactions. Here we report the extension of the syn-
thetic applications of this class of vinyl boronates to the
formation of C–N bonds.
Results and Discussion
Boronates 1a, 1b, and 2 (Figure 1) were synthesized start-
ing from 1,1-diethoxybut-2-ene, 1,1-diethoxy-3-methylbut-
2-ene, and 1-(2,2-dimethoxyethyl)benzene, respectively,[20]
in the presence of 2.5 equiv. of LIC/KOR base (LIC = BuLi
and KOR = tBuOK).[21] The boronates were isolated as 2,2-
dimethylpropane-1,3-diol derivatives and, in the cases of 1a
and 2, as pure (E) isomers. Imidazole was found to provide
[a] Dipartimento di Chimica Generale ed Organica Applicata
dell’Università,
Via P. Giuria 7, 10125 Torino, Italy
E-mail: cristina.prandi@unito.it
Figure 1. Boronic esters used in the C–N cross-coupling.
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N-Functionalization of Azoles with Boronic Esters
FULL PAPER
good reactivity in the coupling reaction, and was conse- azole and 1a both with CuI in the presence of 1,10-phenan-
quently chosen as a substrate for a series of screening ex- throline as a ligand[23] (Entry 6) and with Cu(OAc)2·H2O
periments.
10% (Entry 7).[24] In both cases very poor levels of conver-
The role of the base was also investigated. In all prob-
The experimental conditions developed by Chan and sion were achieved.
Lam[22] necessitate an excess of boronic acid. Because of
the commercial unavailability of the boronic esters 1a, 1b, ability the basic medium plays a double function, both de-
and 2 we were interested in developing coupling conditions protonating the heterocycle-CuII complex and acting as a
that could permit the use of no more than 1.0 equiv. of ligand for the Cu intermediate. While in the cases of
the boronate. For this purpose, the initially chosen reaction Cs2CO3 and tBuOK the role as base prevails, Et3N, pyri-
conditions were the same as those described by Chan and dine, and DMAP could reasonably be effective ligands. The
Lam, except for the concentration of the boronate:[8a] imid- results obtained are reported in Table 1 (Entries 8–12):
azole (1.0 equiv.), Cu(OAc)2 (1.5 equiv.), and Et3N higher yields were obtained with Cs2CO3 and tBuOK. A
(1.0 equiv.) were stirred in CH2Cl2 at room temperature for remarkable amount of the homocoupling product derived
10 min. A solution of 1a (1.0 equiv.) in CH2Cl2 was added from 1a was observed when pyridine was used as a base
and the mixture was stirred at room temperature to provide (Entry 10). Moreover, we speculated that the presence of
(E)-1-(1-ethoxybuta-1,3-dienyl)-1H-imidazole in 38% yield fluoride anions might increase the rate of the transmet-
(Table 1, Entry 1), but incomplete conversion was observed. alation step, and to our delight the combination of tBuOK
A search for other possible catalysts and conditions for this (1.0 equiv.) and CsF (1.0 equiv.) afforded an 88% yield (En-
vinylation chemistry was therefore undertaken, and initially try 12). Consequently, in a typical procedure, Cu(OAc)2
we observed that the use of 0.3 equiv. Cu(OAc)2 instead of (0.3 equiv.), freshly sublimated tBuOK (1.0 equiv.), CsF
1.0 equiv. or more (Entry 2) in an open air vessel slightly (1.0 equiv.), and imidazole (1.0 equiv.) in CH2Cl2 were
improved the yield. Such an enhancement of the yield ob- stirred in a vessel open to air. Dienylboronate (1.0 equiv.)
tained with a smaller amount of Cu source is probably due in CH2Cl2 was then added dropwise and the reaction pro-
to the fact that the acetate anion, in addition to being a gress was monitored by TLC. After 1 h at room tempera-
ligand, can also act as a nucleophile, a hypothesis supported ture the boronate had been consumed, and the crude reac-
by the isolation of 1-ethoxybuta-1,3-dienyl acetate as a by- tion product was elaborated by addition of a solution of
product when an excess of Cu(OAc)2 was used (Entry 1). ammonia (10%) in saturated aqueous NH4Cl to free the
We also tried to operate with catalytic quantities of heterocycles from Cu salts. We also investigated the effects
Cu(OAc)2 (Entries 3 and 4) in the presence of equimolar of molecular sieves, and found that they do not improve the
amounts of mild oxidizing agents. Unfortunately, competi- reaction yield (Entry 13).[14a]
tive oxidation of the boronic esters also occurred,[13] and
In view of the results obtained for 1H-imidazole, the N-
no appreciable amount of the expected coupling product vinylation reactions of pyrazole, indazole, benzimidazole,
was obtained. It was also found (Entry 5) that switching to and pyrrole derivatives were also examined (Table 2). In ge-
a less polar solvent, such as toluene, resulted in a poorer neral, more nucleophilic heterocycles undergo coupling
yield. In addition, we examined the coupling between imid- with fairly good yields (Table 2, Entries 1–4). Moreover,
Table 1. Optimization for N-vinylation of imidazole.[a]
Entry
Solvent
Base
Catalyst
T
Yield [%][b]
1
2
3
4
5
6
7
8
DCM
DCM
DCM
DCM
PhMe
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Et3N
Et3N
Et3N
Et3N
Et3N
Cs2CO3
Cs2CO3
Cs2CO3
DMAP
pyridine
tBuOK
tBuOK/CsF
Cu(OAc)2 1.0 equiv.
Cu(OAc)2 0.3 equiv.
Cu(OAc)2 0.05 equiv., TEMPO
Cu(OAc)2 0.05 equiv., NMO
Cu(OAc)2 0.3 equiv.
CuI/1,10-phenanthroline
Cu(OAc)2·H2O
Cu(OAc)2 0.3 equiv.
Cu(OAc)2 0.3 equiv.
Cu(OAc)2 0.3 equiv.
Cu(OAc)2 0.3 equiv.
Cu(OAc)2 0.3 equiv.
Cu(OAc)2 0.3 equiv.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
38
52
–
–
25
15
11
58
30
40
62
88
75
9
10
11
12
13
tBuOK/CsF (mol. sieves, 4 Å)
[a] Reaction conditions: 1a (1.0 mmol), solvent (5 mL). [b] Average of two runs, refers to products isolated by flash chromatography on
1
SiO2, estimated to be Ͼ97% pure by H and 13C NMR analyses.
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A. Deagostino, C. Prandi, C. Zavattaro, P. Venturello
FULL PAPER
Table 2. Functionalized azoles obtained by cross-coupling of alkoxyboronates 1a, 1b, and 2 with diverse N–H-containing heteroarenes.[a]
[a] Reaction conditions: boronate (1.0 equiv.), heteroarene (1.0 equiv.), base (1.0 equiv.), CsF (1.0 equiv.), Cu(OAc)2 (0.3 equiv.), CH2Cl2
(5.0 mL). Spectral data are in accordance with the assigned structures. [b] Products purified by flash chromatography. [c] Two isomers
were detected in a 3:1 ratio (1H NMR integration). [d] Different conditions were tested to improve the yield: Py and Et3N do not promote
the reaction. Compound 3e proved to be very unstable; it has been identified only by 1H NMR and GC-MS. [e] Product detected by
1
GC-MS and H NMR analyses, after flash chromatography purification. [f] Reaction conducted without base.
only small amounts of the desired products were isolated product. As far as indole derivatives are concerned, the
from the complex reaction mixture in the cases of pyrrole presence of an electron-withdrawing substituent in posi-
and indole (Entries 5–6); similar results have been reported tion 2 gave rise to an acceptable yield of N-functionalized
previously.[9] From the enhanced reactivity of electron-de- derivative (Entry 12): in contrast, very little conversion was
ficient azoles, we assumed that electron-deficient pyrrole observed in the cases of unsubstituted indole (Entry 6) or
and indole derivatives might exhibit higher reactivities, and indoles substituted in position 3 (Entries 10 and 11). The
to evaluate this hypothesis a variety of electron-deficient experimental conditions that we had established were then
substrates were examined. Pyrrole-2-carbaldehyde, 1-(pyr- applied to boronates 1b and 2 (Table 2, Entries 13 and 14,
rol-2-yl)ethanone, and methyl pyrrole-2-carboxylate under- and 15–17, respectively). In all cases the reaction yields ob-
went coupling reactions under the aforementioned experi- tained were satisfactory and confirm the general applica-
mental conditions, affording the corresponding coupled bility of the proposed method. In the case of boronate 1b,
products in good yields (Entries 7–9). Furthermore, in the the elimination process lacks complete (E) stereoselectivity,
case of 1-pyrrol-2-ylethanone the initially obtained yields the (Z) minor isomer also being obtained (10%), as a conse-
were unsatisfactory, probably as a consequence of the fact quence of which the coupling products 3k and 3l were reco-
that a strongly basic medium (tBuOK 1.0 equiv.) is not vered as mixtures of (E) and (Z) isomers in 9:1 ratios, as
1
compatible with the enolizable acetyl group.
deduced from their H NMR spectra. Moreover, methyl 1-
The reaction was then conducted in the absence of any (1-methoxy-2-phenylvinyl)-1H-pyrrole-2-carboxylate (3o)
base. Even under these conditions, however, alkoxydienyl was isolated by flash chromatography, and its stereochemis-
dimer (15%) was also recovered along with the desired try was confirmed by ROESY experiments. It is noteworthy
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N-Functionalization of Azoles with Boronic Esters
FULL PAPER
(E)-1-(1-Ethoxybuta-1,3-dienyl)-1H-benzo[d]imidazole (3c): This
compound (139 mg, 65%) was obtained as a pale yellow oil: 1H
NMR (200 MHz, CDCl3, TMS): δ = 8.01 (s, 1 H), 7.75 (d, J =
7.8 Hz, 2 H), 7.40 (d, J = 7.8 Hz, 2 H), 6.00 (dt, J = 16.3, 10.1 Hz,
1 H), 5.65 (d, J = 10.1 Hz, 1 H), 5.15 (dd, J = 16.3, 1.5 Hz, 1 H),
4.85 (dd, J = 10.1, 1.5 Hz, 1 H), 4.05 (q, J = 6.5 Hz, 2 H), 1.45 (t,
J = 6.5 Hz, 3 H) ppm. 13C NMR (50.33 MHz, CDCl3, TMS): δ =
147.35, 139.88, 135.96, 130.95, 127.12, 123.88, 121.55, 120.78,
114.36, 110.88, 100.39, 64.66, 14.23 ppm. MS (E/I): m/z (%) = 214
(5) [M]+, 185 (100), 169 (25), 118 (94), 68 (12). C13H14N2O: C
72.87, H 6.59, N 13.07; found C 72.51, H 6.55, N 13.15.
that the optimized experimental conditions are well
matched with useful functional groups that could be sub-
jected to further synthetic elaboration.
Conclusions
In summary, we have explored the reactivity of alkoxydi-
enyl- and alkoxystyrylboronic esters in C–N cross-coupling
reactions with various azoles. The good yields and the mild
conditions of this methodology make it a promising method
for N-functionalization of heterocycles. We are currently ex-
ploring the experimental conditions to perform the un-
masking reaction of the vinyl ether functionality in order
to expand the scope of this synthetic sequence.
(E)-1-(1-Ethoxybuta-1,3-dienyl)-1H-indazole (3d): A mixture of two
diastereoisomers (124 mg, 58%) was obtained as a pale yellow oil:
1H NMR (200 MHz, CDCl3, TMS) major isomer: δ = 8.01 (s, 1
H), 7.80–7.75 (m, 2 H), 7.35–7.29 (m, 2 H), 5.95 (dt, J = 16.4,
10.0 Hz, 1 H), 5.64 (d, J = 10.0 Hz, 1 H), 5.20 (dd, J = 16.4, 1.5 Hz,
1 H), 4.95 (dd, J = 10.0, 1.5 Hz, 1 H), 3.95 (q, J = 6.5 Hz, 2 H), 1.46
(t, J = 6.5 Hz, 3 H) ppm. 13C NMR (50.33 MHz, CDCl3, TMS): δ
= 148.22, 140.75, 136.83, 131.82, 127.99, 124.75, 122.43, 121.65,
115.23, 111.75, 101.26, 65.54, 15.11 ppm. MS (E/I): m/z (%) = 214
(86) [M]+, 185 (100), 157 (77), 119 (44), 69 (42). C13H14N2O: C
72.87, H 6.59, N 13.07; found C 72.62, H 6.62, N 13.12.
Experimental Section
Chromatographic separations were carried out on silica gel by flash
column techniques; Rf values refer to TLC carried out on 0.25 mm
silica gel plates (Merck F254), with the same eluent as indicated
for the column chromatography. 1H NMR spectra and NOESY
2D experiments were recorded at 200 MHz, 13C NMR spectra at
50.33 MHz. MS spectra were recorded at an ionizing voltage of
70 eV. THF was distilled from Na/benzophenone. Compounds 1a,
1b, and 2[19] were prepared as reported.
(E)-1-(1-Ethoxybuta-1,3-dienyl)-1H-pyrrole (3e): This compound
(34 mg, 21%) was obtained as a pale yellow oil: 1H NMR
(200 MHz, CDCl3, TMS) major isomer: δ = 6.85–6.79 (m, 2 H),
6.25–6.19 (m, 2 H superimposed to 6.25; dt, J = 16.1, 10.1 Hz, 1
H), 5.25 (d, J = 10.1 Hz, 1 H), 5.10 (dd, J = 16.1, 1.5 Hz, 1 H),
4.85 (dd, J = 10.1, 1.5 Hz, 1 H), 3.95 (q, J = 6.8 Hz, 2 H), 1.40 (t,
J = 6.8 Hz, 3 H) ppm. MS (E/I): m/z (%) = 163 (26) [M]+, 134
(100), 106 (44), 68 (66).
Cross-Coupling Reactions. General Procedure: Cu(OAc)2 (0.3 mmol,
0.3 equiv., 54 mg), freshly sublimated tBuOK (1.0 equiv., 112 mg),
CsF (1.0 equiv., 152 mg), and the corresponding azole (1.0 equiv.)
in DCM (5 mL) were stirred in a vessel open to air. The boronate
(1.0 equiv.), dissolved in CH2Cl2 (2 mL), was then added dropwise
and the reaction progress was monitored by TLC. After 1 h at room
temperature the boronate had usually been completely consumed.
The crude reaction product was elaborated by addition of a solu-
tion of ammonia in saturated NH4Cl (10%) to free the heterocycles
from copper salts. The mixture was then extracted with DCM
(3ϫ20 mL) and dried with anhydrous K2CO3. Evaporation of the
solvent afforded a green-yellow oil, which was purified by flash
chromatography (EtOAc/petroleum ether, 1:4, 1% Et3N).
(E)-1-(1-Ethoxybuta-1,3-dienyl)-1H-indole (3f): This compound
(5 mg, 2.3%) was obtained as a pale yellow oil: 1H NMR
(200 MHz, CDCl3, TMS): δ = 7.72–7.29 (m, 2 H), 7.44–7.31 (m, 4
H), 5.95 (dt, J = 16.0, 10.0 Hz, 1 H), 5.60 (d, J = 10.0 Hz, 1 H),
5.20 (dd, J = 16.0, 1.5 Hz, 1 H), 4.95 (dd, J = 10.0, 1.5 Hz, 1 H),
4.05 (q, J = 6.8 Hz, 2 H), 1.35 (t, J = 6.8 Hz, 3 H) ppm. MS (E/I):
m/z (%) = 213 (10) [M]+, 116 (72), 97 (14), 69 (44).
(E)-1-(1-Ethoxybuta-1,3-dienyl)-1H-pyrrole-2-carbaldehyde
(3g):
This compound (162 mg, 85%) was obtained as a yellow oil: 1H
NMR (200 MHz, CDCl3, TMS): δ = 9.59 (s, 1 H), 7.07 (dd, J =
3.9, 1.6 Hz, 1 H), 7.00 (brs, 1 H), 6.35 (dd, J = 3.9, 1.6 Hz, 1 H),
5.83 (dt, J = 16.8, 10.4 Hz, 1 H), 5.5 (d, J = 10.42 Hz, 1 H), 5.1
(dd, J = 16.8, 1.7 Hz, 1 H), 4.86 (dd, J = 10.4, 1.7 Hz, 1 H), 4.02
(q, J = 7.06, Hz, 2 H), 1.35 (t, J = 7.09 Hz, 3 H) ppm. 13C NMR
(50.33 MHz, CDCl3, TMS): δ = 178.36, 147.81, 132.46, 130.47,
130.12, 121.57, 114.54, 110.38, 110.60, 64.97, 14.16 ppm. MS (EI):
m/z (%) = 191 (15) [M]+, 162 (88), 134 (54), 94 (45), 68 (100).
C11H13NO2: C 69.09, H 6.85, N 7.32; found C 69.43, H 6.35, N
7.26.
(E)-1-(1-Ethoxybuta-1,3-dienyl)-1H-imidazole (3a): This compound
(144 mg, 88%) was obtained as a colorless oil: 1H NMR (200 MHz,
CDCl3, TMS): δ = 7.65 (s, 1 H), 7.10 (s, 2 H), 6.15 (dt, J = 16.1,
10.2 Hz, 1 H), 5.34 (d, J = 10.2 Hz, 1 H), 5.15 (dd, J = 16.1, 1.5 Hz,
1 H), 4.95 (dd, J = 10.2, 1.5 Hz, 1 H), 3.85 (q, J = 6.5 Hz, 2 H), 1.36
(t, J = 6.5 Hz, 3 H) ppm. 13C NMR (50.33 MHz, CDCl3, TMS):
δ = 146.06, 137.29, 129.98, 128.98, 119.14, 115.09, 97.88, 64.79,
14.28 ppm. MS (E/I): m/z (%) = 164 (29) [M]+, 135 (100), 107 (45),
68 (75). C9H12N2O: C 65.83, H 7.37, N 17.06; found C 65.79, H
7.73, N 16.85.
(E)-1-[1-(1-Ethoxybuta-1,3-dienyl)-1H-pyrrol-2-yl]ethanone
(3h):
This compound (119 mg, 58%) was obtained as a yellow oil: 1H
NMR (200 MHz, CDCl3, TMS): 1H NMR (200 MHz, CDCl3,
TMS): δ = 6.95–6.54 (m, 1 H), 6.85–6.76 (m, 1 H), 6.00–5.85 (m,
1 H), 5.71 (dt, J = 16.96, 10.20, Hz, 1 H), 5.40 (d, J = 10.20 Hz, 1
H), 5.04 (dd, J = 16.96, 1.81 Hz, 1 H), 4.74 (dd, J = 10.20, 1.81 Hz,
1 H), 3.98 (q, J = 6.97 Hz, 2 H), 2.38 (s, 3 H), 1.29 (t, J = 6.97 Hz, 3
H) ppm. 13C NMR (50.33 MHz, CDCl3, TMS): δ = 186.29, 149.75,
131.63, 130.65, 130.23, 119.46, 113.35, 109,09, 99.69, 64.95, 26.45,
14.21 ppm. MS (EI): m/z (%) = 205 (14) [M]+, 134 (100), 110 (11),
94 (78), 68 (59). C12H15NO2: C 70.22, H 7.37, N 6.82; found C
70.26, H 7.15, N 6.54.
(E)-1-(1-Ethoxybuta-1,3-dienyl)-1H-pyrazole (3b): This compound
(128 mg, 78%) was obtained as a colorless oil: 1H NMR (200 MHz,
CDCl3, TMS): δ = 7.75 (d, J = 5.2 Hz, 2 H), 6.55 (dt, J = 16.2,
10.1 Hz, 1 H), 6.32 (t, J = 5.2 Hz, 1 H), 5.44 (d, J = 10.1 Hz, 1 H),
5.15 (dd, J = 16.2, 1.5 Hz, 1 H), 4.95 (dd, J = 10.1, 1.5 Hz, 1 H),
3.95 (q, J = 6.8 Hz, 2 H), 1.46 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(50.33 MHz, CDCl3, TMS): δ = 146.55, 140.91, 130.96, 130.24,
114.54, 106.12, 97.18, 64.81, 14.30 (q) ppm. MS (E/I): m/z (%) =
164 (12) [M]+, 135 (100), 107 (35), 68 (67). C9H12N2O: C 65.83, H
7.37, N 17.06; found C 65.89, H 7.41, N 16.98.
Eur. J. Org. Chem. 2007, 1318–1323
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A. Deagostino, C. Prandi, C. Zavattaro, P. Venturello
FULL PAPER
Methyl (E)-1-(1-Ethoxybuta-1,3-dienyl)-1H-pyrrole-2-carboxylate
(3i): This compound (168 mg, 76%) was obtained as a yellow oil:
1H NMR (200 MHz, CDCl3, TMS): δ = 6.94 (ddd, J = 3.80, 1.73,
0.40 Hz, 1 H), 6.82–6.76 (m, 1 H), 6.16 (ddd, J = 3.80, 1.73,
0.40 Hz, 1 H), 5.74 (td, J = 16.89, 10.50 Hz, 1 H), 5.39 (d, J =
10.50 Hz, 1 H), 5.03 (dd, J = 16.89, 1.84 Hz, 1 H), 4.74 (dd, J =
10.50, 1.84 Hz, 1 H), 3.92 (q, J = 7.02 Hz, 2 H), 3.72 (s, 3 H), 1.26
(t, J = 7.02 Hz, 3 H) ppm. 13C NMR (50.33 MHz, CDCl3, TMS):
δ = 159.98, 149.08, 130.63, 129.00, 123.25, 118.18, 113.61, 109.05,
100.19, 64.79, 51.03, 14.22 ppm. MS (EI): m/z (%) = 221 (29)
[M]+, 192 (34), 162 (90), 134 (67), 94 (96). C12H15NO3: C 65.14, H
6.83, N 6.33; found C 65.26, H 6.75, N 6.24.
6.55 (m, 1 H), 6.31–6.14 (m, 1 H), 5.70 (s, 1 H), 3.88 (s, 3 H), 2.44
(s, 3 H) ppm. 13C NMR (50.33 MHz, CDCl3, TMS): δ = 186.85,
149.65, 134.39, 131.23, 129.54, 128.25, 127.13, 125.80, 120.09,
110.17, 98.47, 56.79, 26.65 ppm. MS (EI): m/z (%) = 241 (82)
[M]+, 226 (96), 156 (100), 89 (46). C15H15NO2: C 74.67, H 6.27, N
6.16; found C 73.23, H 5.14, N 5.81.
(E)-Methyl 1-(1-Methoxy-2-phenylvinyl)-1H-pyrrole-2-carboxylate
(3o): This compound (213 mg, 83%) was obtained as a yellow oil:
1H NMR (200 MHz, CDCl3, TMS): δ = 7.25–6.96 (m, 4 H), 6.76
(dd, J = 2.75, 1.74 Hz, 1 H), 6.66 (dd, J = 1.74, 0.52 Hz, 1 H),
6.64–6.60 (m, 1 H), 6.22 (dd, J = 3.83, 2.75 Hz, 1 H), 5.74 (s, 1 H),
3.87 (s, 3 H), 3.81 (s, 3 H) ppm. 13C NMR (50.33 MHz, CDCl3,
TMS): δ = 160.12, 148.79, 133.99, 128.15, 128.07, 126.93, 125.79,
122.40, 118.72, 110.01, 98.92, 56.43, 51.14 ppm. MS (EI): m/z (%)
= 257 (100) [M]+, 198 (38), 164 (85), 121 (80). C15H15NO3: C 70.02,
H 5.88, N 5.44; found C 70.44, H 5.34, N 5.76.
Ethyl (E)-1-(1-Ethoxybuta-1,3-dienyl)-1H-indole-2-carboxylate (3j):
This compound (122 mg, 43%) was obtained as a yellow oil. The
spectra were recorded after flash chromatography purification and
Kugelrohr distillation. 1H NMR (200 MHz, CDCl3, TMS): δ =
7.71 (d, J = 6.5 Hz, 1 H), 7.41–7.15 (m, 4 H), 5.95 (dt, J = 16.0,
10.0 Hz, 1 H), 5.65 (d, J = 10.0 Hz, 1 H), 5.22 (dd, J = 16.0, 1.5 Hz,
1 H), 4.95 (dd, J = 10.0, 1.5 Hz, 1 H), 4.24 (q, J = 6.7, 2 H), 4.04
(q, J = 7.0, 2 H), 1.26 (t, J = 6.7 Hz, 3 H), 1.15 (t, J = 7.0 Hz, 3
H) ppm. 13C NMR (50.33 MHz, CDCl3, TMS): δ = 160.49, 146.99,
138.91, 131.11, 128.66, 126.09, 125.67, 122.23, 121.43, 113.69,
112.07, 112.03, 101.32, 64.61, 60.50, 14.27, 14.12 ppm. MS (EI):
m/z (%) = 285 (16) [M]+, 212 (100), 184 (90), 143 (50), 115 (31).
C17H19NO3: C 71.56, H 6.71, N 4.91; found C 71.45, H 6.34, N
4.23.
Acknowledgments
This work was supported by grants from the Università di Torino
and the Ministero dell'Università e della Ricerca (MIUR).
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(E)-1-(1-Ethoxy-3-methylbuta-1,3-dienyl)-1H-pyrrole-2-carb-
aldehyde (3k): This compound (182 mg, 89%) was obtained as a
yellow oil: 1H NMR (200 MHz, CDCl3, TMS): major diastereoiso-
mer: δ = 9.74 (s, 1 H), 7.03 (dd, J = 3.85, 2.66 Hz, 1 H), 6.94–6.56
(m, 1 H), 6.30 (dd, J = 3.85, 2.66 Hz, 1 H), 5.47 (s, 1 H), 4.73 (s,
1 H), 4.67 (s, 1 H), 3.96 (q, J = 7.02 Hz, 2 H), 1.35 (s, 3 H), 1.31
(t, J = 7.02 Hz, 3 H) ppm. 13C NMR (50.33 MHz, CDCl3, TMS):
δ = 178.38, 146.24, 138.55, 132.58, 130.81, 121.85, 114.96, 110.35,
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[M]+, 148 (100), 120 (38), 82 (78). C12H15NO2: C 70.22, H 7.37, N
6.82; found C 70.56, H 7.36, N 6.34.
(E)-1-(1-Ethoxy-3-methylbuta-1,3-dienyl)-1H-benzo[d]imidazole
(3l): This compound (162 mg, 71%) was obtained as a pale yellow
1
oil: H NMR (200 MHz, CDCl3, TMS): major diastereoisomer: δ
= 8.16 (s, 1 H), 7.74 (d, J = 8.08 Hz, 1 H), 7.42–7.34 (m, 2 H),
7.27–7.15 (m, 1 H), 5.74 (s, 1 H), 4.81 (s, 1 H), 4.74 (s, 1 H), 3.92
(q, J = 7.00, 2 H), 1.35 (t, J = 7.00 Hz, 3 H), 1.18 (s, 3 H) ppm.
13C NMR (50.33 MHz, CDCl3, TMS): δ = 145.37, 140.44, 138.21,
135.73, 127.13, 123.75, 121.47, 120.73, 115.63, 110.17, 104.70,
64.50, 20.06, 14.27 ppm. MS (EI): m/z (%) = 228 (1) [M]+, 199
(100), 183 (28), 118 (40). C14H16NO2: C 73.66, H 7.06, N 12.27;
found C 73.54, H 7.76, N 12.76.
(E)-1-(1-Methoxy-2-phenylvinyl)-1H-pyrrole-2-carbaldehyde (3m):
This compound (147 mg, 65%) was obtained as a yellow oil: 1H
NMR (200 MHz, CDCl3, TMS): δ = 9.62 (s, 1 H), 7.19–7.05 (m,
4+1 H), 6.86 (ddd, J = 2.55, 1.59, 0.76 Hz, 1 H), 6.65 (dd, J =
2.05, 0.42 Hz, 1 H), 6.63–6.60 (m, 1 H), 6.32 (dd, J = 3.92, 2.55 Hz,
1 H), 5.79 (s, 1 H), 3.89 (s, 3 H) ppm. 13C NMR (50.33 MHz,
CDCl3, TMS): δ = 178.36, 147.72, 133.54, 131.67, 129.77, 128.22,
127.02, 126.08, 122.28, 111.23, 99.31, 56.54 ppm. MS (EI): m/z (%)
= 227 (37) [M]+, 212 (57), 183 (11), 94 (100). C14H13NO2: C 73.99,
H 5.77, N 6.16; found C 73.23, H 5.14, N 6.34.
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Received: October 4, 2006
Published Online: January 17, 2007
Eur. J. Org. Chem. 2007, 1318–1323
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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