A new method for the synthesis of multisubstituted pyrroles of biological interest by double nucleophilic addition to α,β-unsaturated imines

Article abstract of DOI:10.1002/ejoc.200901055

Double nucleophilic addition reactions of dialkoxy ketene silyl acetals proceeded with α,β-unsaturated imines to give 1,4-and 1,2-double addition products, and their subsequent transformations afforded multisubstituted pyrroles in good yields. Application

Full text of DOI:10.1002/ejoc.200901055

FULL PAPER
DOI: 10.1002/ejoc.200901055
A New Method for the Synthesis of Multisubstituted Pyrroles of Biological
Interest by Double Nucleophilic Addition to α,β-Unsaturated Imines
Atsushi Takahashi,[a] Shiho Kawai,[a] Iwao Hachiya,[a] and Makoto Shimizu*[a]
Keywords: Nucleophilic addition / Nitrogen heterocycles / Synthetic methods
Double nucleophilic addition reactions of dialkoxy ketene
silyl acetals proceeded with α,β-unsaturated imines to give
1,4- and 1,2-double addition products, and their subsequent
transformations afforded multisubstituted pyrroles in good
yields. Application of this procedure to the synthesis of an
imidazole glycerol phosphate dehydratase inhibitor (IGPDI),
a physiologically active 2,3,5-trisubstituted pyrrole, is also
described.
is expected that the use of dialkoxy ketene silyl acetals as
initial nucleophiles in the 1,4- and 1,2-double nucleophilic
addition[5] would make the synthesis of γ-amino carbonyl
compounds much easier. Herein we describe an efficient
synthesis of γ-amino carbonyl compounds and their trans-
formation into 2,3,5-trisubstituted pyrroles with useful bio-
logical activity.
Introduction
Pyrrole structures are found in many biologically impor-
tant compounds[1] and are also used as monomers in the
preparation of electronic materials such as electroconduc-
tive polymers.[2] Several methods for the construction of
multisubstituted pyrrole rings have been published to
date,[3] but they are often tedious procedures and therefore
simple approaches are highly desired for their preparation.
One of the most simple and effective approaches to the
construction of pyrrole rings appears to involve the cycliza-
tion of γ-amino carbonyl compounds followed by dehydro-
genation. Although the most direct synthetic approach to
Results and Discussion
The following topics are described in this article.
1) The synthesis of γ-amino carbonyl derivatives by the
γ-amino carbonyl compounds uses nucleophilic addition to double nucleophilic addition of dialkoxy ketene silyl acetals
γ-oxoimines, this method may suffer from side-reactions and a variety of second nucleophiles to α,β-unsaturated
such as hydrolysis of the imino moiety and non-regioselec- imines.
tive nucleophilic addition. However, to avoid these prob-
2) The conversion into multisubstituted pyrroles by cycli-
lems we have recently developed a strategy that involves a zation of the 1,4- and 1,2-double addition products into
double nucleophilic addition to α,β-unsaturated imines.[4] It dihydropyrroles followed by dehydrogenation.
[a] Department of Chemistry for Materials, Graduate School of
Engineering, Mie University,
3) The application of the present method to the synthesis
of multisubstituted pyrroles of biological interest, namely,
imidazole glycerol phosphate dehydratase inhibitors
(IGPDIs).[6]
Tsu, Mie 514-8507, Japan
Fax: +81-59-231-9413
E-mail: mshimizu@chem.mie-u.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901055.
Eur. J. Org. Chem. 2010, 191–200
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
191

A. Takahashi, S. Kawai, I. Hachiya, M. Shimizu
FULL PAPER
Table 1. Double nucleophilic addition reactions of dialkoxy ketene
silyl acetal 2 with α,β-unsaturated imines 1.
Double Nucleophilic Addition Reactions to α,β-Unsaturated
Imines
Initially the use of dialkoxy ketene silyl acetal 2 as both
the first and second nucleophiles was examined. The reac-
tions of α,β-unsaturated imines 1 proceeded with dialkoxy
ketene silyl acetal 2 (3.0 equiv.) in CH2Cl2 in the presence
of aluminium chloride (1.0 equiv.) and 4 Å molecular sieves
containing H2O at –78 °C to room temperature gave the
double nucleophilic addition product 3 in good yield and
stereoselectivity. The results of these double nucleophilic
addition reactions are summarized in Table 1.
All the 1,4- and 1,2-double addition products were ob-
tained in moderate-to-good yields (entries 1–4). The use of
the 4-(dimethylamino)phenyl derivative resulted in a de-
crease in the yield and stereoselectivity (entry 4). This may
be due to the less selective coordination of the Lewis acid
to two nitrogen atoms, the imino and 4-(dimethylamino)-
phenyl groups. The best result was obtained by using N-(4-
methoxyphenyl)crotylideneamine (entry 2; PMP = 4-meth-
oxyphenyl).
Entry
1
RЈ
t [h]
Product % Yield[a] syn/anti[b]
R
1
2
3
Ph
Me
Ph
Ph
PMP
PMP
CHPh2
4-
Me2NC6H4
8.5
9.5
9.5
3a
3b
3c
85
77
80
87:13
99:1
75:25
4
13.5
3d
66
76:24
[a] Isolated yields. [b] Determined by HPLC and/or 1H NMR spec-
troscopy.
silyl cyanide (5) underwent 1,2-addition in a highly regio-
selective manner. Only a small amount of the 1,2-addition
product of the dialkoxy ketene silyl acetal was obtained.
Cyclization of the 1,4- and 1,2-Double Addition Products
into Dihydropyrroles Followed by Dehydrogenation
The use of two different nucleophiles was next examined,
with dialkoxy ketene silyl acetal 2 employed as the first nu-
The 1,4- and 1,2-double adducts 3, 6 and 7 were con-
cleophile and the ketene silyl thioacetal 4 or trimethylsilyl verted into multisubstituted pyrroles by cyclization first to
cyanide (5) as the second. The results are collected in dihydropyrroles 8, 9 and 10, respectively, with acids such as
Table 2. Note that dialkoxy ketene silyl acetal 2 underwent H2SO4, TFA or methanesulfonic acid followed by dehydro-
1,4-addition and the ketene silyl thioacetal 4 and trimethyl- genation with DDQ.[7] Table 3 summarizes the synthesis of
Table 2. Double nucleophilic addition reactions of α,β-unsaturated imines 1 with dialkoxy ketene silyl acetal 2 and another nucleophile
4 or 5.
Entry
1
2 [equiv.]
4 or 5
t [h]
6 or 7
% Yield[a]
syn/anti[b]
R
RЈ
1
2
3
4
5
6
Ph
Ph
Ph
Me
Ph
Me
PMP
1.3
1.3
1.3
1.3
1.0
1.0
4
4
4
4
5
5
11.5
9.5
9.5
9.5
9.5
6a
6b
6c
6d
7a
7b
80
63
62
70
55
95
90:10
55:45
85:15
67:33
94:6
4-Me2NC6H4
2,4-(MeO)2C6H3
PMP
PMP
PMP
16.0
88:12
1
[a] Isolated yields. [b] Determined by HPLC and/or H NMR spectroscopy.
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Eur. J. Org. Chem. 2010, 191–200

Multisubstituted Pyrroles from α,β-Unsaturated Imines
Table 3. Conversion of 3, 6 and 7 into multisubstituted dihydropyrrole and pyrrole.
Entry
Reagent
R
RЈ
Dihydropyrrole
Yield [%][a]
t [h]
Pyrrole
% Yield[a]
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
6a
6b
6c
6d
7a
7b
Ph
Me
Ph
Ph
Ph
Ph
Ph
Me
Ph
Me
PMP
PMP
CHPh2
4-Me2NC6H4
PMP
4-Me2NC6H4
2,4-(MeO)2C6H3
PMP
PMP
PMP
8a
8b
88
69[b]
96
13.0
13.0
13.0
13.0
12.5
12.5
12.5
12.5
12.0
12.0
11a
11b
11c
11d
12a
12b
12c
12d
13a
13b
quant.
95
quant.
66
62
93
97
69
74
82
8c
8d
quant.
73
9a
9b
67[c]
79[c]
86
9c
9d
10a
10b
quant.[c]
86[c]
10
[a] Isolated yields. [b] H2SO4/H2O = 2:1. The reaction time was 6.5 h. [c] H2SO4/H2O = 1:1.
the multisubstituted pyrroles 11, 12 and 13. For the cycliza-
tion of some of the 1,4- and 1,2-double adducts, milder con-
ditions were needed due to the instability of the intermedi-
ates (entries 2, 6, 7, 9 and 10). The subsequent dehydroge-
nation of the dihydropyrroles with DDQ gave multisubsti-
tuted pyrroles in good-to-excellent yields.
Synthesis of Monopyrrole Aldehyde
As an application of the present methodology, the syn-
thesis of a monopyrrole aldehyde 14 with herbicidal activity
(Schemes 1 and 2)[8] was next examined.
Scheme 2. Strategy for the synthesis of monopyrrole aldehyde 14.
Scheme 1. Monopyrrole aldehydes with biological activity.
In the first step, the double nucleophilic addition of
ketene silyl acetal 2 and trimethylsilyl cyanide (5) to N-(4-
methoxyphenyl)crotylideneamine was examined. Under the
best conditions, the 1,4- and 1,2-double adduct 7b was ob-
tained in 95% yield (Scheme 3).
Scheme 3. Double nucleophilic addition reaction of ketene silyl
acetal 2 and trimethylsilyl cyanide (5) with N-(4-methoxyphenyl)-
crotylideneamine.
In the second step, the 1,4- and 1,2-double adduct 7b was
converted into the dihydropyrrole 10b under the influence role 16 were obtained (entries 1 and 2), whereas under less
of H2SO4 (Table 4). By using a mixture of conc. H2SO4/ acidic conditions (concd. H2SO4/H2O = 1:1) the product
H2O in a ratio of 3:1 only small amounts of the dihydropyr- yield was much improved (entry 3).
Eur. J. Org. Chem. 2010, 191–200
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193

A. Takahashi, S. Kawai, I. Hachiya, M. Shimizu
FULL PAPER
Table 4. Optimization of the cyclization conditions for the syntehsis
of dihydropyrrole10b.
The PMP group was converted into an easily removable
protecting group[10] at an earlier stage of the synthesis. We
first attempted to replace the PMP group with an acetyl
group, but the acetamide was obtained in only 5% yield. In
the end, protection with the Boc group was found to be
suitable for obtaining the desired product 16 in 84%yield
(Scheme 6).
Entry
H2SO4/H2O
t [h]
% Yield
1
2
3
4
3:1
3:1
1:1
1:1
0.5
1.0
1.0
1.5
14
16
86
58
The dihydropyrrole 10b was readily converted into the
pyrrole 13b by dehydrogenation with DDQ (Scheme 4).
Scheme 6. Replacement of the PMP with Boc group.
It was expected that a concomitant cyclization would
take place on deprotection of the Boc group with acid.
However, the desired dihydropyrrole 17 was not formed
(Table 5).
Scheme 4. Dehydrogenation of dihydropyrrole 10b.
Table 5. Deprotection of the Boc protecting group and cyclization.
Although chemoselective reduction of the cyano moiety
proved to be highly difficult under a variety of conditions,
it could be chemoselectively reduced to aldehyde 15 with
Raney Ni W4 in the presence of NaPH2O2/H2O/acetic acid/
pyridine.[9]
Entry Acid
Conditions
% Yield
1
2
3
H2SO4/H2O (1:1)
CH3SO3H
TFA
room temp., 0.5 h
0 °C, 1.5 h
0 °C, 1.5 h
–
–
–
Table 6. Deprotection of the Boc-protecting group and cyclization
in the presence of an oxidant.
In the final step, the deprotection of the PMP group was
examined under various oxidation or reduction conditions
[CAN, O3, (NH4)2S2O8/AgNO3, Na/liqu. NH3, etc]. How-
ever, the removal of the PMP group was problematic and
the desired monopyrrole aldehyde 14 was not obtained. At-
tempted removal of the PMP group from the dihydropyr-
role 10b was also unsuccessful and therefore we modified Entry
Conditions
% Yield
our strategy (Scheme 5).
1
2
3
4
5
6
7
8
DDQ, H2SO4/H2O (3:1), 0 °C to ca. r.t., 10.5 h
DDQ, H2SO4/H2O (1:1), 0 °C to ca. r.t., 10.5 h
CAN, H2SO4/H2O (1:1), 0 °C to ca. r.t., 10.0 h
TFA, r.t., 2.0 h; DDQ, r.t., 3.0 h
TFA, r.t., 3.5 h; DDQ, r.t., 10.0 h
TFA, r.t., 1.0 h; DDQ, 72 °C, 2.0 h
TFA, CH3CN, r.t., 12.0 h; DDQ, r.t., 4.0 h
TFA, CH3CN, 72 °C, 14.0 h; DDQ, CH3CN,
r.t., 4.5 h
–
27
–
37
41
33
39
3
9
CH3SO3H, CH3CN, 0 °C, 1.5 h; DDQ,
CH3CN, r.t., 2.5 h
92
Scheme 5. Modified strategy for the synthesis of monopyrrole alde-
hyde 14.
Scheme 7. Reduction of the cyano group of the pyrrole 18.
194
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Eur. J. Org. Chem. 2010, 191–200

Multisubstituted Pyrroles from α,β-Unsaturated Imines
Scheme 8. Summary of the synthesis of IGPDI 14.
Typical Procedure for the Double Nucleophilic Addition Reaction
Leading to Diesters 3. Synthesis of Diethyl 3-(4-Methoxyphen-
ylamino)-5-phenyl-2,2,6,6-tetraethoxyheptane-1,7-dioate (3a): Un-
der argon, a suspension of AlCl3 (40.0 mg, 0.30 mmol) and molecu-
lar sieves (4 Å) containing H2O (1 equiv.) in CH2Cl2 (3.0 mL) were
stirred at 0 °C for 15 min. A solution of N-(4-methoxyphenyl)-
cinnamylideneamine (71.1 mg, 0.30 mmol) in CH2Cl2 (1.0 mL) was
added to the resulting suspension at –78 °C and the mixture was
stirred for 10 min. A solution of 1,2,2-triethoxy-1-(trimethylsiloxy)-
ethylene (2; 223 mg, 0.90 mmol) in CH2Cl2 (1.0 mL) was added to
the mixture, which was gradually warmed to room temperature
over 8.5 h. Saturated aqueous NaHCO3 (10 mL) was added to
quench the reaction. The mixture was extracted with ethyl acetate
(15 mLϫ3) and the combined extracts were dried with Na2SO4
and concentrated in vacuo to give a crude product. Purification
by TLC on silica gel (n-hexane/ethyl acetate = 4:1) gave the title
compound 3a (150.7 mg, 85%) as a mixture of syn and anti iso-
mers[4a,11] (87:13, determined by HPLC).
Thus, the in situ formation of the more stable pyrrole
from the dihydropyrrole was next attempted by using an
oxidant (Table 6). In the presence of methanesulfonic acid
and DDQ, the desired pyrrole 18 was obtained in excellent
yield (entry 9).
Finally, treatment of the pyrrole 18 with Raney NiW4 in
the presence of NaPH2O2/H2O/acetic acid/pyridine led to
the desired monopyrrole aldehyde 14 in 73% yield
(Schemes 7 and 8).
Conclusions
An efficient double nucleophilic addition of dialkoxy ke-
tene silyl acetal to α,β-unsaturated imines has been devel-
oped and the subsequent conversion into multisubstituted
pyrroles by cyclization to dihydropyrroles followed by deyd-
rogenation has successfully been achieved. IGPDI, a physi-
ologically active multisubstituted pyrrole, was synthesized
by transformation of the double nucleophilic addition prod-
uct. Thus, the present strategy offers a useful addition to
the existing methodologies for the synthesis of pyrroles of
biological interest.
Diethyl
3-(4-Methoxyphenylamino)-5-phenyl-2,2,6,6-tetraethoxy-
1
heptane-1,7-dioate (3a): Yellow oil. H NMR (CDCl3): δ = 0.96 (t,
J = 6.9 Hz, 3 H, CH3),1.09–1.34 (m, 15 H, CH3), 1.75–1.80 (m, 1
H, CHH), 2.24–2.37 (m, 1 H, CHH), 3.28–3.34 (m, 4 H), 3.44–3.64
(m, 5 H), 3.71 (s, 3 H, OCH3), 3.71–3.81 (br. s, 1 H, NCH), 3.95–
4.19 (m, 5 H), 6.30–6.33 (m, 2 H, Ar), 6.61–6.64 (m, 2 H, Ar),
7.15–7.28 (m, 5 H, Ar) ppm. 13C NMR (CDCl3): δ = 13.9, 14.1,
14.9, 15.1, 15.2, 15.3, 31.4, 47.3, 55.7, 56.8, 58.1, 58.3, 58.7, 59.4,
60.8, 61.3, 103.1, 103.5, 114.3, 115.1, 126.9, 127.6, 130.3, 138.2,
143.4, 151.7, 168.5, 169.0 ppm. IR (neat): ν = 2979, 2934, 2899,
˜
1745, 1618, 1513, 1450, 1390, 1238, 1085, 821, 755 cm–1. HRMS
(EI): calcd. for C32H47NO9 [M]+ 589.3251; found 589.3253.
Experimental Section
Diethyl
3-(4-Methoxyphenylamino)-5-methyl-2,2,6,6-tetraethoxy-
General: Infrared spectra were determined with a JASCO FT/ IR-
460 plus spectrometer. 1H and 13C NMR spectra were recorded
with a JEOL EX-270 or EX-500 spectrometer using tetramethylsil-
ane as an internal standard. High-resolution mass spectra were re-
corded with a JEOL MS-700D spectrometer in EI mode at 70 eV.
Dichloromethane, 1,4-dioxane and pyridine were distilled from cal-
cium hydride and stored over molecular sieves (4 Å). THF was dis-
tilled from benzophenone ketyl immediately before use. MeOH was
distilled from magnesium and stored over molecular sieves (3 Å).
The products were purified by column chromatography on silica
gel (Merck Silica Gel 60) and/or by preparative TLC on silica gel
(Merck Kiesel Gel PF254).
heptane-1,7-dioate (3b): Colourless oil (58.1 mg, 77% yield). 1H
NMR (CDCl3): δ = 0.95 (d, J = 6.7 Hz, 3 H, CHCH3), 1.10 (t, J
= 7.0 Hz, 3 H, CH3), 1.08–1.32 (m, 15 H, CH3), 2.21 (ddd, J = 5.5,
5.5, 14.7 Hz, 1 H, CHH), 2.48 (ddd, J = 6.7, 6.7, 14.7 Hz, 1 H,
CHH), 3.40–3.82 (m, 9 H), 3.72 (s, 3 H, OCH3), 4.04 (dd, J = 4.5,
8.6 Hz, 1 H, NCH), 4.12–4.25 (m, 4 H, CH2), 6.63–6.66 (m, 2 H,
Ar), 6.71–6.73 (m, 2 H, Ar) ppm. 13C NMR (CDCl3): δ = 14.1,
14.2, 15.1, 15.2, 45.2, 15.4, 16.2, 33.4, 34.1, 55.8, 56.7, 57.7, 58.6,
58.7, 59.4, 61.0, 61.2, 103.4, 105.1, 114.5, 114.8, 142.9, 151.7, 168.4,
169.1 ppm. IR (neat): ν = 2979, 2935, 1740, 1514, 1238, 1180, 1065,
˜
821 cm–1. HRMS (EI): calcd. for C27H45NO9 [M]+ 527.3094; found
527.3110.
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A. Takahashi, S. Kawai, I. Hachiya, M. Shimizu
FULL PAPER
Diethyl 3-(Diphenylmethylamino)-5-phenyl-2,2,6,6-tetraethoxyhept-
ane-1,7-dioate (3c): Colourless oil (72.5 mg, 80% yield). H NMR
(CDCl3): δ = 1.05 (t, J = 6.9 Hz, 3 H, CH3), 1.12 (t, J = 7.3 Hz, 3 yield). H NMR (CDCl3): δ = 1.10–1.27 (m, 9 H, CH3), 1.42 (s, 5
H, CH3), 1.14 (t, J = 6.9 Hz, 3 H, CH3), 1.19 (t, J = 6.9 Hz, 3 H, H, tBu), 1.45 (s, 4 H, tBu), 2.06–2.17 (m, 2 H, CH2), 2.38–2.42 (m,
Ethyl 6-(tert-Butylthiocarbonyl)-2,2-diethoxy-5-[4-(dimethylamino)-
1
phenylamino]-3-phenylhexanoate (6b): Yellow oil (51.9 mg, 63%
1
CH3), 1.21 (t, J = 7.3 Hz, 3 H, CH3), 1.23 (t, J = 6.9 Hz, 3 H,
CH3), 1.68 (br. s, 1 H, NH), 1.81 (ddd, J = 5.0, 5.3, 14.5 Hz, 1 H, 3.28–3.30 (br., 1 H, NH), 3.53–3.66 (m, 4 H, CH2), 3.97–4.17 (m,
CHH), 2.60–2.70 (m, 1 H, CHH), 2.79–2.90 (m, 2 H), 3.10–3.21 3 H), 6.36–6.41 (m, 2 H, Ar), 6.62–6.70 (m, 2 H, Ar), 7.15–7.26
(m, 1 H, NCH), 3.41–3.71 (m, 8 H, CH2), 3.94–4.08 (m, 2 H, CH2), (m, 5 H, Ar) ppm. 13C NMR (CDCl3): δ = 14.0, 15.2, 15.3, 29.6,
4.12–4.25 (m, 2 H, CH2), 4.17–4.22 (m, 2 H, CH2), 4.92 (s, 1 H, 42.2, 47.9, 48.0, 51.1, 58.7, 60.9, 103.5, 115.7, 115.8, 115.9, 126.9,
Ph2CH), 6.91–6.95 (m, 2 H, Ar), 7.06–7.33 (m, 13 H, Ar) ppm. 13
1 H, CHH), 2.57–2.62 (m, 1 H, CHH), 2.80 [s, 6 H, (NCH3)2],
C
127.8, 127.9, 129.6, 129.8, 138.4, 168, 198.6 ppm. IR (neat): ν =
˜
NMR (CDCl3): δ = 13.9, 14.2, 15.1, 15.2, 15.2, 15.2, 31.4, 48.1,
55.3, 57.6, 58.3, 58.6, 60.7, 61.0, 63.6, 104.0, 105.2, 126.4, 126.5,
127.5, 127.7, 127.8, 128.0, 128.0, 130.0, 140.1, 144.6, 144.8, 168.5,
2976, 1743, 1675, 1518, 1255, 1059, 701 cm–1. HRMS (EI): calcd.
for C31H46N2O5S [M]+ 558.3127; found 558.3104.
Ethyl 6-(tert-Butylthiocarbonyl)-2,2-diethoxy-5-(2,4-dimethoxyphen-
ylamino)-3-phenylhexanoate (6c): Yellow oil (49.9 mg, 62% yield).
1H NMR (CDCl3): δ = 1.12–1.31 (m, 11 H), 1.41 (s, 9 H, tBu),
2.10–2.41 (m, 3 H, CH3), 2.62–2.66 (m, 1 H), 3.34 (br. s, 1 H, NH),
3.50–3.68 (m, 4 H, CH2), 3.72 (s, 3 H, OCH3), 3.80 (s, 2 H, OCH3),
3.87 (s, 1 H, OCH3), 4.03–4.13 (m, 2 H, CH2), 6.16–6.60 (m, 3 H,
Ar), 7.11–7.26 (m, 5 H, Ar) ppm. 13C NMR (CDCl3): δ = 14.2,
15.4, 15.5, 29.8, 35.7, 48.0, 48.1, 50.3, 30.5, 55.7, 56.0, 58.8, 61.6,
99.4, 103.7, 103.9, 104.2, 112.1, 126.7, 127.0, 127.9, 128.6, 129.8,
168.8 ppm. IR (neat): ν = 3061, 2979, 2933, 2898, 1742, 1602, 1492,
˜
1451, 1391, 1078, 755, 702 cm–1. HRMS (EI): calcd. for
C38H51NO8 [M]+ 649.3615; found 649.3589.
Diethyl 3-[4-(Dimethylamino)phenylamino]-5-phenyl-2,2,6,6-tetra-
1
ethoxyheptane-1,7-dioate (3d): Yellow oil (55.7 mg, 66% yield). H
NMR (CDCl3): δ = 0.96 (t, J = 6.9 Hz, 3 H, CH3), 1.10 (dd, J =
6.7, 7.3 Hz, 3 H, CH3), 1.14–1.24 (m, 9 H, CH3), 1.27 (dd, J = 6.7,
7.3 Hz, 3 H, CH3), 1.80–1.87 (m, 1 H, CHH), 2.28–2.35 (m, 1 H,
CHH), 2.79 [s, 6 H, N(CH3)2], 3.27–3.34 (m, 4 H, CH2), 3.46–3.55
(m, 4 H, CH2), 3.60–3.63 (m, 1 H, NCH), 3.65–3.80 (br. s, 1 H,
NH), 3.96–4.00 (m, 1 H, CH), 4.10–4.18 (m, 4 H, CH2), 6.32–6.34
(m, 2 H, Ar), 6.59–6.61 (m, 2 H, Ar), 7.19–7.27 (m, 5 H, Ar) ppm.
13C NMR (CDCl3): δ = 13.9, 14.1, 14.9, 15.1, 15.2, 15.3, 31.4, 42.4,
47.2, 56.9, 57.9, 58.4, 58.7, 59.4, 60.7, 61.2, 103.1, 103.6, 115.2,
130.0, 131.4, 138.6, 148.4, 152.1, 168.9, 198.5 ppm. IR (neat): ν =
˜
2976, 1744, 1676, 1517, 1457, 1206, 1157, 1036, 755 cm–1. HRMS
(EI): calcd. for C31H45NO7 S [M]+ 575.2917; found 575.2890.
Ethyl
6-(tert-Butylthiocarbonyl)-2,2-diethoxy-5-(4-methoxyphen-
ylamino)-3-methylhexanoate (6d): Colourless oil (46.0 mg, 70%
yield). 1H NMR (CDCl3): δ = 0.98 (dd, J = 7.0, 23.5 Hz, 3 H,
CH3), 1.19–1.36 (m, 9 H, CH3), 1.43 (s, 9 H, tBu), 2.00 (ddd, J =
4.3, 7.3, 14.6 Hz, 1 H, CHH), 2.12–2.25 (m, 1 H, CHH), 2.44 (dd,
J = 7.6, 14.3 Hz, 1 H, CHH), 2.62 (dd, J = 2.0, 5.5 Hz, 2 H), 2.79
(dd, J = 4.3, 14.3 Hz, 1 H), 3.42–3.60 (m, 4 H, CH2), 3.86 (t, J =
6.3 Hz, 1 H), 4.12–4.26 (m, 2 H, CH2), 6.56–6.61 (m, 2 H, Ar),
6.74–6.78 (m, 2 H, Ar) ppm. 13C NMR (CDCl3): δ = 14.2, 15.1,
15.2, 29.6, 35.0, 36.7, 48.0, 48.5, 51.3, 55.6, 57.2, 58.2, 61.1, 104.1,
115.6, 126.8, 127.5, 130.4, 138.3, 168.5, 169.1 ppm. IR (neat): ν =
˜
2980, 2936, 2898, 1742, 1518, 1450, 1391, 1370, 1123, 1087, 911,
816, 733, 647 cm–1. HRMS (EI): calcd. for C33H50N2O8 [M]+
602.3567; found 602.3598.
Typical Procedure for the Double Nucleophilic Addition Reactions
Leading to Esters 6. Synthesis of Ethyl 6-(tert-Butylthiocarbonyl)-
2,2-diethoxy-5-(4-methoxyphenylamino)-3-phenylhexanoate
(6a):
Under argon, a suspension of AlCl3 (18.7 mg, 0.14 mmol) and mo-
lecular sieves (4 Å) containing H2O (1 equiv.) in CH2Cl2 (1.5 mL)
was stirred at 0 °C for 15 min. A solution of N-(4-methoxyphenyl)
cinnamylideneamine (1, 33.2 mg, 0.14 mmol) in CH2Cl2 (1.0 mL)
was added to the resulting solution at –78 °C and the mixture was
stirred for 10 min. A solution of 1,2,2-triethoxy-1-(trimethylsiloxy)-
ethylene (2; 44.7 mg, 0.18 mmol) in CH2Cl2 (1.0 mL) was added to
the mixture. After stirring for 5 min, a solution of 1-tert-butylthio-
1-(trimethylsiloxy)ethylene (4; 49.0 mg, 0.24 mmol) in CH2Cl2
(1.0 mL) was added to the resulting mixture. The mixture was grad-
ually warmed to room temperature over 11.5 h. Saturated aqueous
NaHCO3 (5 mL) was added to quench the reaction and the mixture
was extracted with ethyl acetate (10 mLϫ3). The combined ex-
tracts were dried with Na2SO4 and concentrated in vacuo to give
a crude product. Purification by TLC on silica gel (n-hexane/ethyl
acetate = 5:2) gave the title compound 6a (61.0 mg, 80%) as a mix-
ture of syn and anti isomers (90:10, determined by HPLC).
114.7, 115.0, 141.0, 152.1, 168.2, 198.6 ppm. IR (neat): ν = 2975,
˜
1740, 1676, 1512, 1239, 1120, 1063 cm–1. HRMS (EI): calcd. for
C25H41NO6S [M]+ 483.2655; found 483.2635.
Typical Procedure for Double Nucleophilic Addition Reactions Lead-
ing to Esters 7. Synthesis of Ethyl 5-Cyano-2,2-diethoxy-5-(4-meth-
oxyphenylamino)-3-methylpentanoate (7b): Under argon, a suspen-
sion of AlCl3 (133.0 mg, 1.0 mmol) and molecular sieves (4 Å) con-
taining H2O (1 equiv.) in CH2Cl2 (10.0 mL) was stirred at 0 °C for
15 min. A solution of N-(4-methoxyphenyl)crotylideneamine (1,
175.0 mg, 1.0 mmol) in CH2Cl2 (3.0 mL) was added to the resulting
mixture at –78 °C and the mixture was stirred for 10 min. A solu-
tion of 1,2,2-triethoxy-1-(trimethylsiloxy)ethylene (2; 248 mg,
1.0 mmol) in CH2Cl2 (3.0 mL) was added to it. After stirring for
5 min a solution of TMSCN (5; 138.0 mg, 1.4 mmol) in CH2Cl2
(3.0 mL) was added to the resulting mixture. The mixture was grad-
ually warmed to room temperature over 16.0 h. Saturated aqueous
NaHCO3 (30 mL) was added to quench the reaction. The mixture
was extracted with ethyl acetate (20 mLϫ3) and the combined ex-
tracts were dried with Na2SO4 and concentrated in vacuo to give
a crude product. Purification by TLC on silica gel (n-hexane/ethyl
acetate = 4:1) gave the title compound 7b (270.0 mg, 95%) as a
mixture of syn and anti isomers (88:12, determined by HPLC).
Ethyl
6-(tert-Butylthiocarbonyl)-2,2-diethoxy-5-(4-methoxyphen-
1
ylamino)-3-phenylhexanoate (6a): Yellow oil. H NMR (CDCl3): δ
= 1.13–1.27 (m, 9 H, CH3), 1.40 (s, 9 H, tBu), 2.12–2.23 (m, 2 H,
CH2), 2.40–2.44 (m, 1 H, CHH), 3.58–2.61 (m, 1 H, CHH), 3.25–
3.30 (br. s, 1 H, NH), 3.53–3.71 (m, 4 H, CH2), 3.75 (s, 3 H, OCH3),
4.00–4.16 (m, 2 H, CH2), 6.36–6.40 (m, 2 H, Ar), 6.66–6.70 (m, 2
H, Ar), 7.13–7.26 (m, 5 H, Ar) ppm. 13C NMR (CDCl3): δ = 14.0, Ethyl
5-Cyano-2,2-diethoxy-5-(4-methoxyphenyl)amino-3-phenyl-
15.2, 15.3, 29.6, 35.3, 48.0, 48.1, 49.5, 51.0, 55.7, 58.8, 61.0, 103.5, pentanoate (7a): Yellow oil (35.1 mg, 55% yield). 1H NMR
114.8, 115.6, 127.0, 127.9, 129.6, 129.8, 138.4, 141.3, 152.3, 168.8,
(CDCl3): δ = 1.15–1.22 (m, 6 H, CH3), 1.26 (t, J = 1.8, 7.0 Hz, 3
H, CH3), 2.37–2.52 (m, 1 H, CHH), 2.59–2.70 (m, 1 H, CHH),
3.34 (d, J = 10.7 Hz, 1 H), 3.55–3.76 (m, 5 H), 3.74 (s 3 H, OCH3),
3.79–3.95 (m, 1 H, NCH), 4.01–4.12 (m, 2 H, CH2), 6.49–6.54 (m,
198.6 ppm. IR (neat): ν = 2976, 1742, 1676, 1512, 1239, 1080,
˜
756 cm–1. HRMS (EI): calcd. for C30H43NO6S [M]+ 545.2811;
found 545.2805.
196
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 191–200

Multisubstituted Pyrroles from α,β-Unsaturated Imines
2 H, Ar), 6.75–6.78 (m, 2 H, Ar), 7.20–7.32 (m, 5 H, Ar) ppm. 13C
NMR (CDCl3): δ = 14.0, 15.3, 34.7, 46.4, 47.8, 55.6, 59.2, 59.3,
61.3, 103.1, 114.9, 115.9, 116.5, 120.1, 127.7, 128.4, 129.4, 137.3,
Ar), 7.61–7.64 (m, 2 H, Ar) ppm. 13C NMR (CDCl3): δ = 14.3,
15.3, 15.4, 59.0, 59.2, 61.3, 62.0, 63.0, 103.1, 126.5, 126.7, 127.0,
127.2, 127.5, 128.0, 128.2, 128.4, 128.5, 133.6, 137.2, 143.4,
138.8, 154.0, 168.4 ppm. IR (neat): ν = 2980, 2935, 2900, 1738,
144.5 ppm. 168.7. IR (neat): ν = 2979, 2934, 2899, 1746, 1450,
˜
˜
1514, 1241, 1120, 1083, 756, 702 cm–1. HRMS (EI): calcd. for
C25H32N2O5 [M]+ 440.2311; found 440.2306.
1252, 1194, 1124, 1088, 758, 700 cm–1. HRMS (EI): calcd. for
C34H39NO6 [M]+ 557.2777; found 557.2770.
Ethyl 5-Cyano-2,2-diethoxy-5-(4-methoxyphenylamino)-3-methyl-
pentanoate (7b): Yellow oil. H NMR (CDCl3): δ = 1.03 (dd, J =
7.0, 22.0 Hz, 3 H, CH3), 1.22–1.34 (m, 9 H, CH3), 1.70 (dt, J =
Ethyl
5-(Ethoxycarbonyldiethoxymethyl)-1-[4-(dimethylamino)-
1
phenyl]-3-phenyl-4,5-dihydro-1H-pyrrole-2-carboxylate (8d): Yellow
oil (34.4 mg, 100% yield). 1H NMR (CDCl3): δ = 0.90 (t, J =
6.6, 7.6 Hz, 1 H, CHH), 2,29–2.49 (m, 2 H), 3.43–3.61 (m, 4 H, 7.0 Hz, 3 H, CH3), 1.12 (t, J = 7.0 Hz, 3 H, CH3), 1.22 (t, J =
CH2), 3.76 (s, 3 H, OCH3), 4.21–4.30 (m, 2 H, CH2), 4.32–4.50 (m,
1 H, NCH), 6.69–6.71 (m, 2 H, Ar), 6.82–6.84 (m, 2 H, Ar) ppm.
13C NMR (CDCl3): δ = 14.3, 15.1, 34.5, 46.3, 55.6, 56.9, 59.2, 61.4,
7.0 Hz, 3 H, CH3), 2.90 [s, 6 H, N(CH3)2], 3.37–3.43 (m, 3 H),
3.48–3.56 (m, 2 H), 3.60–3.61 (m, 1 H), 3.90–4.00 (m, 2 H, CH2),
4.04 (dd, J = 7.9, 10.4 Hz, 1 H, NCH), 4.20–4.27 (m, 2 H, CH2),
6.62–6.65 (m, 2 H, Ar), 7.17–7.20 (m, 1 H, Ar), 7.26–7.30 (m, 4 H,
Ar), 7.37–7.38 (m, 2 H, Ar) ppm. 13C NMR (CDCl3): δ = 13.6,
14.1, 15.1, 15.1, 36.4, 41.0, 58.1, 58.6, 60.4, 61.4, 68.6, 103.2, 112.7,
123.5, 126.6, 127.1, 127.2, 127.9, 135.0, 136.8, 138.1, 148.7, 163.8,
103.8, 114.9, 115.9, 120.4, 139.1, 153.7, 168.0 ppm. IR (neat): ν =
˜
2979, 1739, 1389, 1241, 1181, 1120, 1062 cm–1. HRMS (EI): calcd.
for C20H30N2O5 [M]+ 378.2156; found 378.2138.
Typical Procedure for the Cyclization of Esters 3, 6 and 7 to Dihy-
dro-1H-pyrroles 8–10. Synthesis of Ethyl 5-(tert-Butylthiocarbon-
ylmethyl)-1-(4-methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrrole-2-
carboxylate (9a): Sulfuric acid (H2SO4/H2O = 3:1, 4.0 mL) was
added to ethyl 6-tert-butylthiocarbonyl-2,2-diethoxy-5-(4-methoxy-
phenylamino)-3-phenylhexanoate (6a; 38.4 mg, 0.07 mmol) at 0 °C
and the mixture was stirred for 1.5 h. The mixture was then grad-
ually warmed to room temperature over 1.5 h. The mixture was
extracted with ethyl acetate (5 mLϫ3) and the combined extracts
were dried with Na2SO4 and concentrated in vacuo to give a crude
product. Purification by TLC on silica gel (n-hexane/ethyl acetate
= 1:1) gave 9a (23.3 mg, 73%).
168.1 ppm. IR (neat): ν = 2979, 2932, 2896, 1727, 1616, 1518, 1267,
˜
1154, 1123, 1090, 1056, 823, 783, 759 cm–1. HRMS (EI): calcd. for
C29H38N2O6 [M]+ 510.2730; found 510.2739.
Ethyl
5-(tert-Butylthiocarbonylmethyl)-1-(4-methoxyphenyl)-3-
phenyl-4,5-dihydro-1H-pyrrole-2-carboxylate (9a): Yellow oil
1
(23.3 mg, 73%). H NMR (CDCl3): δ = 0.93 (t, J = 7.1 Hz, 3 H,
CH3), 1.42 (s, 9 H, tBu), 2.75 (dd, J = 8.8, 15.9 Hz, 1 H, CHH),
2.85 (dd, J = 9.5, 15.3 Hz, 1 H, CHH), 2.97 (dd, J = 4.3, 15.3 Hz,
1 H, CHH), 3.41 (dd, J = 9.8, 15.9 Hz, 1 H, CHH), 3.78 (s, 3 H,
OCH3), 3.95–4.10 (m, 3 H), 6.84–6.85 (m, 2 H, Ar), 7.04–7.05 (m,
2 H, Ar), 7.26–7.34 (m, 5 H, Ar) ppm. 13C NMR (CDCl3): δ =
13.6, 29.7, 40.0, 48.3, 49.2, 55.4, 60.9, 63.7, 114.5, 123.3, 125.9,
126.9, 127.2, 128.0, 134.9, 136.8, 139.3, 157.3, 163.7, 198.0 ppm.
Ethyl
5-(Ethoxycarbonyldiethoxymethyl)-1-(4-methoxyphenyl)-3-
phenyl-4,5-dihydro-1H-pyrrole-2-carboxylate (8a): Yellow oil
IR (neat): ν = 2962, 1678, 1510, 1459, 1367, 1247, 1179, 1034, 834,
˜
1
(8.5 mg, 88% yield). H NMR (CDCl3): δ = 0.89 (t, J = 7.0 Hz, 3
758 cm–1. HRMS (EI): calcd. for C26H31NO4S [M]+ 453.1974;
found 453.1990.
H, CH3), 1.11 (t, J = 7.0 Hz, 3 H, CH3), 1.22 (t, J = 7.0 Hz, 3 H,
CH3), 1.23 (t, J = 7.0 Hz, 3 H, CH3), 3.36–3.44 (m, 3 H), 3.48–
3.55 (m, 2 H, CH2), 3.62–3.65 (m, 1 H), 3.77 (s, 3 H, OCH3), 3.89–
3.98 (m, 2 H, CH2), 4.02–4.06 (m, 1 H, NCH), 4.12–4.23 (m, 2 H,
Ethyl 5-(tert-Butylthiocarbonylmethyl)-1-[4-(dimethylamino)phenyl]-
3-phenyl-4,5-dihydro-1H-pyrrole-2-carboxylate (9b): Yellow oil
1
CH2), 6.79–6.81 (m, 2 H, Ar), 7.19–7.22 (m, 1 H, Ar), 7.26–7.34 (21.9 mg, 67% yield). H NMR (CDCl3): δ = 0.93 (t, J = 7.0 Hz,
(m, 4 H, Ar) 7.37–7.39 (m, 2 H, Ar) ppm. 13C NMR (CDCl3): δ = 3 H, CH3), 1.42 (s, 9 H, tBu), 2.75 (dd, J = 9.4, 16.5 Hz, 1 H,
13.6, 14.1, 15.1, 36.6, 55.4, 58.2, 58.7, 60.5, 61.5, 103.1, 113.7,
CHH), 2.84 (dd, J = 9.8, 15.3 Hz, 1 H, CHH), 2.92 [s, 6 H,
124.9, 126.8, 127.3, 127.9, 134.9, 136.3, 141.6, 157.3, 163.5, N(CH3)2], 2.98 (dd, J = 4.3, 15.3 Hz, 1 H, CHH), 3.39 (dd, J =
168.1 ppm. IR (neat): ν = 2979, 2934, 2900, 1727, 1628, 1510, 1247,
9.8, 16.5 Hz, 1 H, CHH), 3.94–4.13 (m, 4 H, CH2), 6.65–6.68 (m,
2 H, Ar), 7.18–7.20 (m, 1 H, Ar), 7.22–7.32 (m, 2 H, Ar), 7.36–
7.39 (m, 2 H, Ar) ppm. 13C NMR (CDCl3): δ = 13.6, 29.7, 39.7,
40.8, 48.2, 49.1, 60.8, 63.9, 113.1, 126.1, 121.8, 126.1, 126.6, 127.0,
˜
1181, 1123, 1091, 837, 757 cm–1. HRMS (EI): calcd. for
C28H35NO7 [M]+ 497.2414; found 497.2390.
Ethyl
5-(Ethoxycarbonyldiethoxymethyl)-1-(4-methoxyphenyl)-3-
128.0, 135.0, 135.5, 137.6, 148.8, 163.9, 198.0 ppm. IR (neat): ν =
˜
methyl-4,5-dihydro-1H-pyrrole-2-carboxylate (8b): Clear oil
2923, 1725, 1678, 1518, 1346, 1273, 1170, 821, 756 cm–1. HRMS
(EI): calcd. for C27H34N2O3S [M]+ 466.2290; found 466.2276.
1
(12.6 mg, 69% yield). H NMR (CDCl3): δ = 0.97 (t, J = 7.1 Hz,
3 H, CH3), 1.18 (t, J = 7.2 Hz, 3 H, CH3), 1.12–1.26 (m, 9 H,
CH3), 2.07 (s, 3 H, CH3), 2.94–2.97 (m, 2 H, CH2), 3.43–3.51 (m, Ethyl 5-(tert-Butylthiocarbonylmethyl)-1-(2,4-dimethoxyphenyl)-3-
4 H, CH2), 3.76 (s, 3 H, OCH3), 3.80–3.89 (m, 1 H), 3.90–3.98 (m, phenyl-4,5-dihydro-1H-pyrrole-2-carboxylate (9c): Yellow oil
1
1 H), 4.01–4.08 (m, 1 H, NCH), 4.11–4.29 (m, 2 H, CH2), 6.75– (11.4 mg, 79% yield). H NMR (CDCl3): δ = 0.89 (t, J = 7.0 Hz,
6.78 (m, 2 H, Ar), 7.18–7.21 (m, 2 H, Ar) ppm. 13C NMR (CDCl3): 3 H, CH3), 1.41 (s, 9 H, tBu), 2.79 (dd, J = 9.2, 16.5 Hz, 1 H,
δ = 13.9, 14.0, 15.1, 15.2, 38.3, 55.4, 58.4, 59.8, 61.2, 69.4, 103.1,
113.5, 125.2, 131.8, 134.0, 144.0, 156.2, 162.6, 168.0 ppm. IR
CHH), 2.83 (dd, J = 9.5, 15.3 Hz, 1 H, CHH), 2.93 (dd, J = 4.0,
14.7 Hz, 1 H, CHH), 3.35 (dd, J = 10.5, 16.5 Hz, 1 H, CHH), 3.78
(neat): ν = 2979, 2933, 1713, 1510, 1444, 1372, 1335, 1277, 1245, (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.89–4.04 (m, 2 H, CH2),
˜
1178, 1123, 1073, 836, 756 cm–1. HRMS (EI): calcd. for
C23H33NO7 [M]+ 435.2257; found 435.2239.
4.11–4.17 (m, 1 H, NCH), 6.39–6.46 (m, 2 H, Ar), 7.02–7.04 (m, 1
H, Ar), 7.24–7.37 (m, 5 H, Ar) ppm. 13C NMR (CDCl3): δ = 13.5,
29.7, 39.9, 48.1, 48.9, 55.4, 55.5, 60.5, 99.4, 104.0, 126.5, 127.2,
Ethyl
5-(Ethoxycarbonyldiethoxymethyl)-1-(diphenylmethyl)-3-
127.9, 135.6, 156.7, 158.9, 163.5, 198.3 ppm. IR (neat): ν = 2926,
˜
phenyl-4,5-dihydro-1H-pyrrole-2-carboxylate (8c): Yellow oil
1724, 1678, 1610, 1509, 1459, 1258, 1209, 1159, 1034, 756 cm–1.
HRMS (EI): calcd. for C27H33NO5S [M]+ 483.2079; found
483.2092.
1
(19.6 mg, 96% yield). H NMR (CDCl3): δ = 0.95 (t, J = 7.2 Hz,
3 H, CH3), 1.12–1.33 (m, 9 H, CH3), 2.91 (dd, J = 4.3, 16.5 Hz, 1
H), 3.16–3.20 (m, 1 H), 3.26 (dd, J = 5.6, 16.5 Hz, 1 H), 3.44–3.70
(m, 4 H, CH2), 3.87–3.92 (m, 2 H, CH2), 4.14–4.30 (m, 2 H, CH2), Ethyl
5-(tert-Butylthiocarbonylmethyl)-1-(4-methoxyphenyl)-3-
5.83 (s, 1 H, Ph2CH), 7.10–7.29 (m, 9 H, Ar), 7.32–7.43 (m, 4 H, methyl-4,5-dihydro-1H-pyrrole-2-carboxylate (9d): Yellow oil
Eur. J. Org. Chem. 2010, 191–200
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
197

A. Takahashi, S. Kawai, I. Hachiya, M. Shimizu
FULL PAPER
1
(19.8 mg, 86% yield). H NMR (CDCl3): δ = 1.00 (t, J = 6.9 Hz, 3.82 (s, 3 H, OCH3), 3.91 (q, J = 7.1 Hz, 2 H, CH2), 4.05 (q, J =
3 H, CH3), 1.43 (s, 9 H, tBu), 2.07 (s, 3 H, CH3), 2.30 (dd, J = 7.6,
7.1 Hz, 2 H, CH2), 6.51 (s, 1 H, Ar), 6.82–6.85 (m, 2 H, Ar), 7.01–
17.4 Hz, 1 H, CHH), 2.75 (dd, J = 9.5, 15.0 Hz, 1 H, CHH), 2.96 7.05 (m, 2 H, Ar) ppm. 13C NMR (CDCl3): δ = 14.3, 14.4, 14.5,
(dd, J = 4.5, 15.0 Hz, 1 H, CHH), 2.98 (dd, J = 2.4, 3.4 Hz, 1 H, 15.4, 55.8, 58.6, 60.0, 62.1, 97.5, 113.3, 114.1, 123.4, 129.1, 130.1,
CHH), 3.77 (s, 3 H, OCH3), 3.79–3.84 (m, 1 H), 3.94–4.00 (m, 1
H, NCH), 4.09–4.15 (m, 2 H, CH2), 6.76–6.80 (m, 2 H, Ar), 6.81–
6.94 (m, 2 H, Ar) ppm. 13C NMR (CDCl3): δ = 13.8, 14.2, 29.7,
29.7, 41.8, 48.2, 50.1, 55.4, 60.1, 64.4, 114.2, 124.2, 130.0, 134.7,
131.9, 136.3, 159.7, 161.8, 167.2 ppm. IR (neat): ν = 2979, 2933,
˜
1756, 1701, 1513, 1442, 1374, 1341, 1297, 1248, 1190, 1094, 1065,
832, 755, 665 cm–1. HRMS (EI): calcd. for C23H31NO7 [M]+
433.2101; found 433.2094.
142.3, 156.5, 162.9, 198.1 ppm. IR (neat): ν = 2963, 1679, 1512,
˜
Ethyl
5-(Ethoxycarbonyldiethoxymethyl)-1-(diphenylmethyl)-3-
1247, 1164, 1091, 1034 cm–1. HRMS (EI): calcd. for C21H29NO4S
[M]+ 391.1817; found 391.1823.
phenyl-1H-pyrrole-2-carboxylate (11c): Yellow oil (9.8 mg, 100%
yield). 1H NMR (CDCl3): δ = 0.68 (t, J = 7.0 Hz, 3 H, CH3), 1.07–
1.13 (m, 9 H, CH3), 3.38–3.50 (m, 6 H, CH2), 3.66 (q, J = 7.0 Hz,
2 H, CH2), 6.77 (s, 1 H, Ph2CH), 7.15–7.32 (m, 14 H, Ar), 7.38–
7.41 (m, 2 H, Ar) ppm. 13C NMR (CDCl3): δ = 13.4, 14.0, 14.6,
58.5, 60.4, 61.9, 63.8, 97.8, 111.9, 123.3, 126.3, 127.0, 127.5, 127.8,
Ethyl 5-Cyano-1-(4-methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyr-
role-2-carboxylate (10a): Yellow oil (41.8 mg, 100% yield). 1H
NMR (CDCl3): δ = 0.94 (t, J = 7.1 Hz, 3 H, CH3), 3.32 (dd, J =
8.3, 16.2 Hz, 1 H, CHH), 3.52 (dd, J = 10.9, 16.2 Hz, 1 H, CHH),
3.80 (s, 3 H, OCH3), 3.98–4.07 (m, 2 H, CH2), 4.50 (dd, J = 8.3, 128.4, 128.6, 128.9, 133.0, 135.5, 138.9, 162.6, 167.7 ppm. IR
10.9 Hz, 1 H, NCH), 6.88–6.91 (m, 2 H, Ar), 7.16–7.20 (m, 2 H, (neat): ν = 3062, 2980, 2935, 2898, 1718, 1497, 1451, 1392, 1349,
˜
Ar), 7.26–7.40 (m, 5 H, Ar) ppm. 13C NMR (CDCl3): δ = 13.5,
39.1, 55.4, 55.9, 61.2, 114.8, 118.7, 122.7, 125.5, 127.4, 127.7, 128.2,
1301, 1255, 1194, 1127, 1089, 856, 828, 758, 699, 668 cm–1. HRMS
(EI): calcd. for C34H37NO6 [M]+ 555.2621; found 555.2628.
133.3, 138.1, 158.1, 162.0 ppm. IR (neat): ν = 2922, 2853, 2227,
˜
Ethyl
2-(Ethoxycarbonyldiethoxymethyl)-1-[4-(dimethylamino)-
1718, 1512, 1461, 1254, 1181, 804, 763 cm–1. HRMS (EI): calcd.
for C21H20N2O3 [M]+ 348.1474; found 348.1477.
phenyl]-3-phenyl-1H-pyrrole-2-carboxylate (11d): Yellow oil
(5.9 mg, 66% yield). H NMR (CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3
1
Ethyl 5-Cyano-1-(4-methoxyphenyl)-3-methyl-4,5-dihydro-1H-pyr-
role-2-carboxylate (10b): Yellow oil (30.0 mg, 86% yield). 1H NMR
(CDCl3): δ = 1.02 (t, J = 7.1 Hz, 3 H, CH3), 2.08 (s, 3 H, CH3),
2.87 (dd, J = 7.8, 17.0 Hz, 1 H, CHH), 3.15 (dd, J = 10.9, 17.2 Hz,
1 H, CHH), 3.78 (s, 3 H, OCH3), 3.99–4.14 (m, 2 H, CH2), 4.26
(dd, J = 7.7, 10.7 Hz, 1 H, NCH), 6.83–6.86 (m, 2 H, Ar), 7.05–
7.02 (m, 2 H, Ar) ppm. 13C NMR (CDCl3): δ = 13.7, 40.8, 55.4,
H, CH3), 1.17 (t, J = 7.0 Hz, 3 H, CH3), 1.22 (t, J = 7.0 Hz, 6 H,
CH3), 2.97 [s, 6 H, N(CH3)2], 3.37–3.43 (m, 2 H, CH2), 3.47–3.53
(m, 2 H, CH2), 3.91–3.96 (m, 4 H, CH2), 6.62–6.65 (m, 2 H, Ar),
6.73 (s, 1 H, Ar), 7.00–7.05 (m, 2 H, Ar), 7.26–7.30 (m, 1 H, Ar),
7.33–3.36 (m, 2 H, Ar), 7.49–7.51 (m, 2 H, Ar) ppm. 13C NMR
(CDCl3): δ = 13.5, 14.0, 14.9, 40.4, 58.1, 59.9, 61.6, 97.0, 110.9,
112.6, 126.6, 127.6, 129.1, 129.3, 131.2, 135.9, 136.1, 150.2, 161.3,
56.0, 60.6, 114.5, 119.3, 124.3, 127.3, 134.3, 140.6, 157.4, 166.6 ppm. IR (neat): ν = 2979, 2933, 2894, 1757, 1710, 1612, 1523,
˜
161.8 ppm. IR (neat): ν = 2981, 1716, 1509, 1374, 1247, 1178, 1141,
1477, 1447, 1373, 1341, 1259, 1191, 1097, 1062, 820, 764, 730 cm–1.
HRMS (EI): calcd. for C29H36N2O6 [M]+ 508.2573; found
508.2580.
˜
1033, 832 cm–1. HRMS (EI): calcd. for C16H18N2O3 [M]+ 286.1317;
found 286.1321.
Typical Procedure for the Oxidation of Dihydro-1H-pyrroles 8–10
to -1H-pyrroles 11–13. Synthesis of Ethyl 5-(tert-Butylthiocarbon-
ylmethyl)-1-(4-methoxyphenyl)-3-phenyl-1H-pyrrole-2-carboxylate
(12a): Under argon, a solution of 9a (20.4 mg, 0.045 mmol) in 1,4-
dioxane (1.0 mL) was added to a solution of 2,3-dichloro-5,6-dicy-
ano-1,4-benzoquinone (DDQ; 10.5 mg, 0.04 mmol) in 1,4-dioxane
Ethyl
5-(tert-Butylthiocarbonylmethyl)-1-(4-methoxyphenyl)-3-
phenyl-1H-pyrrole-2-carboxylate (12a): Yellow oil (12.5 mg, 62%
yield). H NMR (CDCl3): δ = 0.88 (t, J = 7.1 Hz, 3 H, CH3), 1.40
1
(s, 9 H, tBu), 3.53 (s, 2 H, CH2), 3.87 (s, 3 H, OCH3), 3.94 (q, J =
7.1 Hz, 2 H, CH2), 6.30 (s, 1 H, Ar), 6.92–6.95 (m, 2 H, Ar), 7.18–
7.22 (m, 2 H, Ar), 7.31–7.38 (m, 3 H, Ar), 7.48–7.51 (m, 2 H,
(1.0 mL) at room temperature. The mixture was stirred for 12.5 h Ar) ppm. 13C NMR (CDCl3): δ = 13.5, 29.6, 42.2, 48.2, 55.4, 59.7,
at room temperature. Saturated aqueous 10% NaHSO3 (5.0 mL)
was added to quench the reaction. The mixture was extracted with
ethyl acetate (10 mLϫ3) and the combined extracts were dried
with Na2SO4 and concentrated in vacuo to give a crude product.
Purification by TLC on silica gel (n-hexane/ethyl acetate = 1:1) gave
12a (12.5 mg, 62%).
112.4, 113.9, 121.2, 126.7, 127.5, 129.1, 129.5, 131.6, 131.9, 133.1,
136.0, 159.3, 161.0, 196.1 ppm. IR (neat): ν = 2962, 1701, 1607,
˜
1511, 1467, 1250, 1178, 1036, 978, 833, 759, 699 cm–1. HRMS (EI):
calcd. for C26H29NO4S [M]+ 451.1817; found 451.1822.
Ethyl 5-(tert-Butylthiocarbonylmethyl)-1-[4-(dimethylamino)phenyl]-
3-phenyl-1H-pyrrole-2-carboxylate (12b): Yellow oil (8.2 mg, 93%
1
Ethyl
5-(Ethoxycarbonyldiethoxymethyl)-1-(4-methoxyphenyl)-3-
yield). H NMR (CDCl3): δ = 1.26 (t, J = 7.1 Hz, 3 H), 1.41 (s, 9
phenyl-1H-pyrrole-2-carboxylate (11a): Yellow oil (138.7 mg, 100%
yield). 1H NMR (CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H, CH3), 1.16–
1.26 (m, 9 H, CH3), 3.36–3.42 (m, 2 H, CH2), 3.46–3.52 (m, 2 H,
H, tBu), 3.00 [s, 6 H, N(CH3)2], 3.54 (s, 2 H, CH2), 3.95 (q, J =
7.1 Hz, 2 H, CH2), 6.28 (s, 1 H, Ar), 6.69–6.72 (m, 2 H, Ar), 7.10–
7.13 (m, 2 H, Ar), 7.30–7.50 (m, 5 H, Ar) ppm. 13C NMR (CDCl3):
CH2), 3.84 (s, 3 H, OCH3), 3.93 (q, J = 7.0 Hz, 4 H, OCH2), 6.74 δ = 13.6, 29.7, 40.5, 42.4, 48.2, 59.7, 111.8, 112.0, 121.2, 126.6,
(s, 1 H, CH), 6.87–6.89 (m, 2 H, Ar), 7.12–7.14 (m, 2 H, Ar), 7.27–
7.30 (m, 1 H, Ar), 7.37–7.34 (m, 2 H), 7.49–7.51 (m, 2 H) ppm.
13C NMR (CDCl3): δ = 13.5, 14.0, 14.9, 55.3, 58.2, 60.0, 61.8, 97.0,
113.0, 122.7, 126.7, 127.6, 129.3, 129.7, 130.9, 131.6, 135.7, 135.8,
127.5, 128.6, 129.6, 132.2, 132.8, 136.4, 150.1, 161.2, 196.4 ppm.
IR (neat): ν = 2919, 1701, 1610, 1522, 1344, 1158, 1034, 760 cm–1.
˜
HRMS (EI): calcd. for C27H32N2O3S [M]+ 464.2134; found
464.2122.
159.5, 161.2, 166.7 ppm. IR (neat): ν = 3018, 2981, 2929, 1754,
˜
Ethyl 5-(tert-Butylthiocarbonylmethyl)-1-(2,4-dimethoxyphenyl)-3-
phenyl-1H-pyrrole-2-carboxylate (12c): Yellow oil (12.2 mg, 97%
yield). H NMR (CDCl3): δ = 0.89 (t, J = 7.1 Hz, 3 H, CH3), 1.39
1698, 1611, 1513, 1297, 1250, 1216, 1191, 1096, 1065, 756 cm–1.
HRMS (EI): calcd. for C28H33NO7 [M]+ 495.2257; found 495.2271.
1
Ethyl
5-(Ethoxycarbonyldiethoxymethyl)-1-(4-methoxyphenyl)-3-
(s, 9 H, tBu), 3.42 (d, J = 16.5 Hz, 1 H, CHH) 3.58 (d, J = 16.5 Hz,
1 H, CHH), 3.74 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.95 (q, J
= 7.1 Hz, 2 H, CH2), 6.31 (s, 1 H, Ar), 6.53–6.55 (m, 2 H, Ar),
methyl-1H-pyrrole-2-carboxylate (11b): Yellow oil (7.3 mg, 95%
yield). 1H NMR (CDCl3): δ = 1.08 (t, J = 7.1 Hz, 3 H, CH3), 1.13–
1.25 (m, 9 H, CH3), 2.38 (s, 3 H, CH3), 3.30–3.48 (m, 4 H, CH2), 7.12–7.15 (m, 2 H, Ar), 7.29–7.37 (m, 3 H, Ar), 7.49–7.53 (m, 2 H,
198
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 191–200

Multisubstituted Pyrroles from α,β-Unsaturated Imines
Ar) ppm. 13C NMR (CDCl3): δ = 13.6, 29.6, 42.2, 48, 55.5, 55.7,
59.5, 99.1, 103.9, 112.3, 121, 126.5, 127.4, 129.6, 130.1, 131.9,
1513, 1252, 1166, 1119, 758 cm–1. HRMS (EI): calcd. for
C16H32N2O3 [M]+ 372.2260; found 372.2259.
133.0, 136, 157, 160.8, 196 ppm. IR (neat): ν = 2962, 1700, 1514,
˜
Procedure for the Synthesis of Ethyl 5-Cyano-3-methyl-1H-pyrrole-
2-carboxylate (18): Under argon, CH3SO3H (1.0 mL) in acetoni-
trile (1.2 mL) was added to 16 (41.1 mg, 0.11 mmol) at 0 °C and
the mixture was stirred for 1.5 h. This mixture was added to a solu-
tion of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
(31.4 mg, 0.11 mmol) in acetonitrile (2.4 mL) at room temperature
and the mixture was stirred for 2.5 h at room temperature. The
layers were separated and the organic layer was washed with a 10%
aq. Na2SO3 (5 mL). The aqueous layer was made basic by the ad-
dition of 10% aq. Na2CO3 (pH = 12) and extracted with AcOEt
(3 mLϫ3). The combined organic layers were washed with 10%
aq. Na2CO3 (3 mLϫ3) and with brine (3 mLϫ3), dried with
Na2SO4 and concentrated. The product was purified by TLC on
buffered silica gel (n-hexane/ethyl acetate = 2:1) to give 18 (18.1 mg,
92%). White crystals; m.p. 115–117 °C. 1H NMR (CDCl3): δ = 1.40
(t, J = 7.3 Hz, 3 H, CH3), 2.33 (s, 3 H, CH3), 4.42 (q, J = 7.3 Hz,
2 H, CH2), 6.64 (s, 1 H, Ar), 10.0 (br. s, 1 H, NH) ppm. 13C NMR
(CDCl3): δ = 12.5, 14.3, 61.5, 103.9, 113.0, 121.5, 123.8, 127.5,
1457, 1309, 1210, 1161, 1033, 760 cm–1. HRMS (EI): calcd. for
C27H31NO5S [M]+ 481.1923; found 481.1926.
Ethyl
5-(tert-Butylthiocarbonylmethyl)-1-(4-methoxyphenyl)-3-
methyl-1H-pyrrole-2-carboxylate (12d): Yellow oil (21.7 mg, 69%
1
yield). H NMR (CDCl3): δ = 1.10 (t, J = 7.1 Hz, 3 H, CH3), 1.40
(s, 9 H, tBu), 2.39 (s, 3 H, CH3), 3.46 (s, 2 H, CH2), 3.84 (s, 3 H,
OCH3), 4.07 (q, J = 7.1 Hz, 4 H, CH2), 6.08 (s, 1 H, Ar), 6.91–
6.92 (m, 2 H, Ar), 7.09–7.10 (m, 2 H, Ar) ppm. 13C NMR (CDCl3):
δ = 14.0, 14.1, 29.6, 42.2, 48.2, 55.4, 59.3, 113.0, 113.7, 121.9, 129.2,
129.8, 131.9, 132.0, 159.2, 161.2, 196.3 ppm. IR (neat): ν = 2923,
˜
1693, 1513, 1248, 1197, 1091, 1035 cm–1. HRMS (EI): calcd. for
C21H27NO4S [M]+ 389.1661; found 389.1656.
Ethyl
5-Cyano-1-(4-methoxyphenyl)-3-phenyl-1H-pyrrole-2-carb-
1
oxylate (13a): Yellow oil (71.8 mg, 74% yield). H NMR (CDCl3):
δ = 0.91 (t, J = 7.1 Hz, 3 H, CH3), 3.87 (s, 3 H, OCH3), 4.00 (q, J
= 7.1 Hz, 2 H, CH2), 6.93 (s, 1 H, Ar), 6.98–7.01 (m, 2 H, Ar),
7.29–7.45 (m, 7 H, Ar) ppm. 13C NMR (CDCl3) δ = 13.5, 55.5,
61.0, 110.0, 112.4, 114.2, 120.2, 125.6, 127.7, 127.9, 128.0, 129.2,
161.0 ppm. IR (neat): ν = 3253, 2989, 2226, 1688, 1487, 1285, 819,
˜
717 cm–1. HRMS (EI): calcd. for C9H10N2O2 [M]+ 178.0742; found
178.0745.
130.3, 132.0, 133.8, 160.0, 160.1 ppm. IR (neat): ν = 2930, 2845,
˜
2226, 1718, 1513, 1461, 1382, 1299, 1254, 1182, 1110, 1033, 835,
767, 699 cm–1. HRMS (EI): calcd. for C21H18N2O3 [M]+ 346.1317;
found 346.1332.
Procedure for the Synthesis of Ethyl 5-Formyl-3-methyl-1H-pyrrole-
2-carboxylate (14):[8] A mixture of 18 (6.7 mg, 0.037 mmol) and
sodium hypophosphate hydrate (23.1 mg, 0.26 mmol) in water/ace-
tic acid/pyridine (1:1:2, 4.0 mL) was treated with Raney nickel W4
(15 mg) and the mixture was stirred at room temperature for 2.5 h.
The mixture was filtered, the catalyst washed with EtOH and the
extracts added to the filtrate. The remainder of the filtrate was di-
luted with water and extracted with Et2O. The combined organic
layers were washed with 10% aq. Na2CO3 (5 mL), the aqueous
layer was made basic by the addition of 10% aq. Na2CO3 (pH =
12) and extracted with Et2O (3 mLϫ3). The combined organic lay-
ers were washed with 10% aq. Na2CO3 (3 mLϫ3) and then with
brine (3 mLϫ3), dried with Na2SO4 and concentrated. The prod-
uct was purified by TLC on silica gel (dichloromethane/ethyl ace-
tate = 9:1) to give 14 (4.9 mg, 73%). White crystals; m.p. 104–105
Ethyl 5-Cyano-1-(4-methoxyphenyl)-4-methyl-1H-pyrrole-2-carbox-
ylate (13b): Colourless oil (65.5 mg, 82% yield). 1H NMR (CDCl3):
δ = 1.12 (t, J = 7.3 Hz, 3 H, CH3), 2.37 (s, 3 H, CH3), 3.85 (s, 3
H, OCH3), 4.13 (q, J = 7.1 Hz, 2 H, CH2), 6.71 (s, 1 H, Ar), 6.95–
6.97 (m, 2 H, Ar), 7.19–7.20 (m, 2 H, Ar) ppm. 13C NMR (CDCl3):
δ = 13.5, 13.9, 55.5, 60.5, 110.0, 112.6, 114.0, 120.7, 128.1, 128.9,
130.9, 159.9 ppm. IR (neat): ν = 2980, 2224, 1711, 1513, 1440,
˜
1252, 1188, 1095, 833 cm–1. HRMS (EI): calcd. for C16H16N2O3
[M]+ 284.1161; found 284.1168.
Procedure for the Synthesis of Ethyl 5-Cyano-2,2-diethoxy-5-(tert-
butoxycarbonylamino)-3-methylpentanoate (16): Under argon,
PhI(OAc)2 (283.0 mg, 0.88 mmol) was completely dissolved in
MeOH (2.0 mL) and AcOH (0.55 mL). A solution of ethyl 5-cy-
ano-2,2-diethoxy-5-(4-methoxyphenylamino)-3-methylpentanoate
(7b; 86.2 mg, 0.22 mmol) in MeOH (2.0 mL) was slowly added to
the resulting solution at room temperature and the mixture was
stirred for 30 min. A 1.2  HCl solution (2.7 mL) was added to the
mixture, which was stirred for 30 min. A 10% aq. Na2S2O3 solution
(2.7 mL) was added and the mixture was stirred for 30 min. The
reaction mixture was then made basic by the addition of 10% aq.
Na2CO3 (2.7 mL) upon which the solution turned dark-red. A solu-
tion of Boc2O (192.0 mg, 0.88 mmol) in CH2Cl2 (1.0 mL) was
added and the mixture was stirred at room temperature for 13.0 h.
MeOH was distilled off under reduced pressure. The resulting solu-
tion was extracted with CH2Cl2 (5 mLϫ3) and the combined or-
ganic layers were dried with Na2SO4. The solvent was evaporated
under reduced pressure to afford a brown oil, which was purified
by column chromatography on silica gel (n-hexane/ethyl acetate =
4:1). The colourless oil obtained was 16 (68.8 mg, 84%). Colourless
1
°C. H NMR (CDCl3): δ = 1.39 (t, J = 7.1 Hz, 3 H, CH3), 2.37 (s,
3 H, CH3), 4.35 (q, J = 7.1 Hz, 2 H, CH2), 6.76 (s, 1 H, Ar), 9.60
(s, 1 H, CHO) ppm. 13C NMR (CDCl3): δ = 12.5, 14.3, 61.0, 121.2,
125.0, 128.3, 132.5, 160.9, 180.3 ppm. IR (neat): ν = 3270, 1675,
˜
1485, 1324, 1266, 1143, 1017, 820, 724 cm–1. HRMS (EI): calcd.
for C9H11NO3 [M]+ 181.0739; found 181.0733.
Supporting Information (see also the footnote on the first page of
this article): 13C NMR spectra of all new compounds.
Acknowledgments
This work was supported by Grants-in-Aid for Scientific Research
(B) and Priority Areas from the Ministry of Education, Culture,
Sports, Science and Technology and the Japanese Society for the
Promotion of Science.
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Eur. J. Org. Chem. 2010, 191–200
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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