Pyrroles and indolizidines from deprotonated α-(alkylideneamino) nitriles

Article abstract of DOI:10.1055/s-0030-1260415

Their ready availability from simple starting materials in only two synthetic steps and their versatility as building blocks for the construction of highly substituted amines and N-heterocycles renders α-(alkylideneamino) nitriles useful synthetic intermediates. Herein, short syntheses of tri- and tetrasubstituted pyrroles including the northern half of the HMG-CoA reductase inhibitor atorvastatin as well as an access to 3-substituted indolizidines will be described. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260415

FEATURE ARTICLE
1691
Pyrroles and Indolizidines from Deprotonated a-(Alkylideneamino)nitriles
S
ynthesi
n
s
of Pyrroles
e
and Indoliz
s
idines Schäfer,a,b Till Opatz*b
a
Department of Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Institute of Organic Chemistry, University of Mainz, Duesbergweg 10–14, 55128 Mainz, Germany
Fax +49(6131)3922338; E-mail: opatz@uni-mainz.de
b
Received 10 March 2011; revised 5 April 2011
Dedicated to Professor Dieter Enders on the occasion of his 65th birthday
g-amino acids and pyrrolidines,16,17 the latter process is a
key step in a modular synthesis of tetrasubstituted pyr-
roles.18
Abstract: Their ready availability from simple starting materials in
only two synthetic steps and their versatility as building blocks for
the construction of highly substituted amines and N-heterocycles
renders a-(alkylideneamino)nitriles useful synthetic intermediates.
Herein, short syntheses of tri- and tetrasubstituted pyrroles includ-
ing the northern half of the HMG-CoA reductase inhibitor atorva-
statin as well as an access to 3-substituted indolizidines will be
described.
Results and Discussion
Pyrroles belong to the most abundant aromatic N-hetero-
cycles and new methods for their preparation are constant-
ly being developed.19–27 As demonstrated by Tsuge and
Ueno, the thermal reaction of a-(alkylideneamino)nitriles
1 with acetylenedicarboxylates furnishes pyrrole-3,4-di-
carboxylates 2 via the intermediate formation of N-proto-
nated azomethine ylides in a prototropic shift.28 The
anionic variant of this reaction provides the same products
in even higher yield if cesium carbonate as a base is com-
bined with microwave irradiation of the reaction mixture
(Table 1).
Key words: heterocycles, carbanions, pyrroles, Umpolung,
Michael addition
Introduction
The powerful anion-stabilizing capacity of the cyano
group allows Strecker products derived from aromatic or
heteroaromatic aldehydes and secondary amines to be
deprotonated under relatively mild conditions.1–4 More
surprisingly, even those a-aminonitriles derived from pri-
mary amines or ammonia can be a-deprotonated without
inducing the impending retro-Strecker reaction, i.e. base-
induced dehydrocyanation, if the correct base, such as po-
tassium hexamethyldisilazanide, is employed at low tem-
peratures.4–6 The resulting keteniminates can serve as
stabilized a-aminocarbanion equivalents in one-pot syn-
theses of highly substituted a-branched amines,7 pyrro-
lidines,8 1,2-diamines,9 b-amino alcohols,10 or g-amino
acids.11 After reaction with a suitable electrophile, the ni-
trile substituent can be removed under mild conditions as
delocalization of the amine nitrogen lone pair into the s*-
orbital of the C–CN bond leads to its scission with forma-
tion of an iminium ion which can subsequently be trapped
by suitable nucleophiles.12
Table 1 Pyrroles from Acetylenedicarboxylates
t-BuO2C
CO2t-Bu
t-BuO2C
CO2t-Bu
R2
Cs2CO3, DMF
100 °C
+
CN
R1
microwave
irradiation
N
R1
N
R2
H
1
2
Imine
R1
R2
Pyrrole
Yield (%)
1a
1b
1c
1d
1e
1f
Me
Bn
Bn
Ph
Cy
Cy
2-naphthyl
2a
2b
2c
2d
2e
2f
67
51
56
62
55
86
2-naphthyl
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
2-naphthyl
The more effective charge delocalization in the resulting
carbanions confers an increased CH acidity to a-(alkyli-
deneamino)nitriles, which can even be deprotonated with
cesium carbonate or amidine bases like DBU or 1,1,3,3-
tetramethylguanidine (TMG).13–15 The products obtained
by alkylation or vinylogous addition of these stabilized 2-
azaallyl anions are not susceptible to spontaneous elimi-
nation of cyanide, nevertheless, decyanation can be ef-
fected after removal of the C=N bond, e.g. by reduction or
ring closure. The former option permits the preparation of
4-O2NC6H4
Moreover, alkynes with a single acceptor group turned out
to be sufficiently reactive substrates under identical con-
ditions. The products are formed in regioselective fashion
and we chose the pyrrole portion of the top-selling antihy-
perlipidemic agent atorvastatin (Lipitor®, Sortis®, sales in
2008: 12.4 billion US$) as a test case.29,30
The pronucleophile was prepared by Strecker reaction of
4-fluorobenzaldehyde with ammonium chloride. The re-
sulting aminonitrile 3 was condensed with isobutyralde-
hyde to furnish the a-(alkylideneamino)nitrile 4. Reaction
SYNTHESIS 2011, No. 11, pp 1691–1704
Advanced online publication: 29.04.2011
DOI: 10.1055/s-0030-1260415; Art ID: Z26111SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1

1692
I. Schäfer, T. Opatz
FEATURE ARTICLE
CN
CN
CHO
CHO
NH4Cl, KCN
78%
N
NH2
CH2Cl2, AcOH, MgSO4
79%
F
F
F
3
4
O
1) SOCl2
2)
CO2H
HN
NH2
Cs2CO3, DMF
5
52%
microwave
65 °C → 90 °C
71%
O
0 °C → 40 °C
40%
NH
N
H
F
O
NH
6
N
N
H
F
H
N
F
F
7
8
OH
9:1 mixture
CO2H
HO
atorvatstatin (Sortis®, Lipitor®)
Scheme 1 Synthesis of the pyrrole portion of atorvastatin
of phenylpropiolic acid chloride with aniline gave the un- 8 in 71% combined yield. The mechanism of their forma-
symmetrical electrophile 5, the reaction of which with 4 tion presumably involves the initial formation of pyrrole-
surprisingly gave the highest yield of the target pyrrole 6 carboxanilide 6 and its regioisomer which eliminate
when the temperature of the reaction with cesium carbon- phenyl isocyanate in a retro-Friedel–Crafts reaction
ate in N,N-dimethylformamide was low. In contrast, the (Scheme 1).
conditions optimized for the reaction with acetylenedicar-
boxylates resulted in the formation of a 9:1 isomeric mix-
ture of the decarbamoylated trisubstituted pyrroles 7 and
For the formation of pyrrole 6 from 4 and 5, two mecha-
nistic alternatives may be discussed. One (path A) in-
Biographical Sketches
Ines Schäfer (née Bergner) degree in 2005. She per- 2009. Her research projects
was born 1975 in Pritzwalk, formed her graduate studies focused on 1,4-additions of
Germany. After profession- at the University of Mainz deprotonated
a-aminoni-
al training as a laboratory and at the University of triles and a-(alkylideneami-
assistant, she studied chem- Hamburg under the supervi- no)nitriles. Currently, she is
istry at the University of sion of Professor Till Opatz employed at Merck KGaA,
Mainz to earn her diploma and received her Ph.D. in Darmstadt.
Till Opatz was born in 1973 M. J. Liskamp in Utrecht, burg, and accepted an offer
in Bad Homburg v. d. Höhe, The Netherlands, he com- of chair at the University of
Germany. He received his pleted his habilitation under Mainz in 2010. His research
diploma in chemistry at the the supervision of Prof. interests are the chemistry
University of Frankfurt/M. Horst Kunz in 2006. In of natural products and the
and his Ph.D. at the Univer- 2007, he was appointed Pro- development of new syn-
sity of Mainz. After a post- fessor in Organic Chemistry thetic methods.
doctoral stay with Prof. Rob at the University of Ham-
Synthesis 2011, No. 11, 1691–1704 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Pyrroles and Indolizidines
1693
R2 CN
volves the intermediate formation of an N-metalated
azomethine ylide 9 which adds to alkyne 5 in a 1,3-dipolar
cycloaddition. Alternatively (path B), the anion of 4 reacts
in a Michael addition with 5 and the resulting enolate 12
cyclizes to anion 13, from which cyanide is eliminated,
followed by tautomerization to the thermodynamically fa-
vored 1H-pyrrole.31–34 Since the same reaction can be ef-
fected by amidine and guanidine bases, path B appears
most likely and intermediates of the 1,4-addition derived
from similar electrophiles have been characterized.35
This, however, would mean that the 5-endo-trig cycliza-
tion involved in the latter process is proceeding efficiently
(Scheme 2).
CN
R2
R3
R4
base
R4
+
R1
N
R1
N
R3
H
O
O
1
14
15
O
–
AcOH
R3
R1
R3
R3
tautom.
base
R2
CN
R4
R2
R2
R4
R4
– HCN
N
N
N
H
18
17
16
Scheme 3 Preparation of pyrroles by 1,4-addition and cyclization
Cyanopyrrolines of type 16 can alternatively be obtained
by condensation of enones with N-unsubstituted aminoni-
triles and subsequent base-induced electrocyclization of
their conjugate anions. This procedure has already been
employed by us for the synthesis of di- to tetrasubstituted
pyrroles but turned out to be limited to products with an
aromatic 5-substituent.38 In contrast, the hydrolysis/cy-
clization sequence presented here readily provides 2,5-di-
alkyl-substituted pyrrolines 16. Unfortunately, their
dehydrocyanation is much less efficient than their forma-
tion and the yields of pyrroles 18 over three steps from a-
(alkylideneamino)nitriles 1 are in the 20–40% range. For
the removal of the aldehyde liberated in the cyclization
step, Girard’s reagent T39 in combination with an aqueous
extraction proved useful and was at least equally effective
as a the chromatographic purification of intermediates 16.
For example, 2-methyl-3,5-diphenyl-3,4-dihydro-2H-
pyrrole-2-carbonitrile (16a) could be obtained as a single
diastereomer in 99% yield over two steps using the extrac-
tive procedure without any additional purification
(Scheme 4). In contrast, the presence of the aldehyde in
the dehydrocyanation led to the formation of addition
products and diminished the overall yield. The obtained
results are summarized in Table 2.
CN
CN
Cs2CO3
path A
N
N
Cs
F
F
4
9
Cs2CO3 path B
5
[4π+2π]
CN
N
O
NH
F
11
N
5
1,4-addition
NC
H
F
Cs
10
1) – CsCN
2) tautom.
HN
O
O
NH
N
CN
12
F
N
H
F
6
O
O
NH
1) – CN
CH3
CN
14a
2) tautom.
N
NC
13
H
F
N
TMG
THF, 25 °C
1a
Scheme 2 1,4-Addition (path B) versus 1,3-dipolar cycloaddition
(path A)
NC CH3
N
1) AcOH, THF–H2O
O
Vinylogous additions of a-(alkylideneamino)nitriles to
enones may proceed very cleanly when amidine or guani-
dine bases are used in tetrahydrofuran at ambient temper-
ature.15 The addition products 15 represent imines of g-
aminocarbonyl compounds and should be prone to cy-
clization in acidic medium.36 Indeed, the action of aque-
ous acetic acid liberates aldehydes from compounds 15
and leads to the entropy-driven formation of 3,4-dihydro-
2H-pyrrole-2-carbonitriles 16, which can in turn be dehy-
drocyanated to pyrroles 18 upon treatment with potassium
tert-butoxide (Scheme 3).37
O
2)
H2N
NMe3
Cl
(Girard's reagent T)
15a (not isolated)
N
H
CN
N
CH3
99% from 1a
16a
(single diastereomer)
Scheme 4 Synthesis of the cyanopyrroline 16a
Synthesis 2011, No. 11, 1691–1704 © Thieme Stuttgart · New York

1694
I. Schäfer, T. Opatz
FEATURE ARTICLE
Table 2 Pyrroles from a-(Alkylideneamino)nitriles and Enones
R3
R2 CN
CN
R2
1) AcOH, THF–H2O
2) KOt-Bu
R3
R4
DBU
R4
R1
N
+
R4
R2
R1
N
or TMG
N
R3
O
O
H
1
14
15
18
a-(Alkylideneamino)nitrile 1
Enone 14
Pyrrole 18
Yield (%)
30a
O
1a
14a
18a
N
CN
N
H
36b
28c
O
1c
1c
14b
14c
18b
18c
MeO
MeO
N
CN
N
H
O
30a
MeO
MeO
N
CN
CN
N
H
Cl
O
1a
14d
18d
18a
N
Cl
H3C
N
H
a Girard’s reagent T was used to remove the aldehyde after cyclization.
b Chromatographic purification of the cyanopyrroline intermediate.
c Crude cyanopyrroline was used.
The introduction of alkyl substituents to positions 2 and/ and 18% yield, respectively, after chromatographic sepa-
or 5 of the intermediates 16 provides the opportunity to ration. The minor diastereomer could be crystallized as its
prepare fused bicyclic systems such as indolizidines from picrate salt; its crystal structure is shown in Figure 1. At-
bifunctional electrophiles. 7-Bromohept-1-en-3-one (19), tempts to isolate the intermediate of type 16 were unsuc-
prepared from 5-bromopentanoic acid via the acid chlo- cessful and dinitrile 22 and pyrrole 23 turned out to be the
ride and reaction with trimethyl(vinyl)silane,40 was react- major isolated products when the reduction step was omit-
ed with a-(alkylideneamino)nitrile 1d in the presence of ted (Scheme 5).
DBU. The addition product 20 was obtained in 97% yield
and was cyclized in acid medium followed by reduction
with sodium cyanoborohydride without isolation of the
intermediate cyanopyrroline. The resulting diastereomer-
When the same method was applied to a-(alkylidene-
amino)nitrile 1b, the diastereomeric indolizidines 24a and
24b could be isolated in 14 and 11% yield (over 3 steps
from 1b) after chromatographic separation. Unfortunate-
ly, NOESY data did not help to assign their relative con-
ic 3-phenylindolizidines 21a and 21b were obtained in 24
figuration and attempts to prepare crystalline salts were
unsuccessful.
Solvents were dried and distilled before use: THF and benzene (K/
benzophenone), CH2Cl2 (CaH2), and EtOAc (K2CO3), and petro-
leum ether (bp 40–70 °C, PE) (CaH2). The preparation of 1a–d is
described elsewhere.8,17 All other solvents and reagents were pur-
chased from commercial suppliers and were used without further
purification. TLC was performed on TLC aluminum sheets (silica
gel 60 F254, KGaA Merck). Flash chromatography was carried out
on silica gel (35–70 mm, Acros). 1H and 13C NMR spectra were re-
Figure 1 Crystal structure of the picrate of 21b
Synthesis 2011, No. 11, 1691–1704 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Pyrroles and Indolizidines
1695
(Lit.43 44–45 °C); Rf = 0.17 (cyclohexane–EtOAc, 1:1 + 1%
Me2NEt), ninhydrin.
1) (COCl)2
PhH, 50 °C
Br
HO
Br
SiMe3
AlCl3, CH2Cl2
2)
IR (ATR): 3338 (m), 2924 (s), 2851 (m), 2223 (w, CN), 1624 (m),
1453 (m), 971 (s), 949 (m), 916 (m), 887 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 3.51 (d, J = 5.9 Hz, 1 H, CHCN),
1.94–1.43 (m, 8 H, CH2, NH2), 1.36–1.00 (m, 5 H, CH2).
13C NMR (75.5 MHz, CDCl3): d = 121.4 (CN), 49.0 (CHCN), 42.0
(C1Cy), 29.2, 28.2, 25.9, 25.6, 25.5 (CCy).
19
57%
O
O
–20 °C
CN
MeO
MeO
N
DBU, THF
25 °C
97%
1d
MS (EI): m/z (%) = 138 (4) [M]+, 112 (11) [M – CN]+, 83 (7) [cy-
clohexyl]+, 56 (100) [M – cyclohexyl]+, 41 (22).
CN
1) AcOH, THF–H2O
2) NaCNBH3
Anal. Calcd for C8H14N2: C, 69.52; H, 10.21; N, 20.27. Found: C,
69.74; H, 10.22; N, 20.34.
MeO
MeO
Br
N
EtOH, 25 °C
20
NC
N
O
2-Cyclohexyl-2-[(2-naphthylmethylene)amino]acetonitrile(1e);
Typical Procedure
H
N
H
AcOH
2-Amino-2-cyclohexylacetonitrile (2.00 g, 14.5 mmol) was dis-
solved in anhyd CHCl2. 2-Naphthaldehyde (2.49 g, 15.9 mmol),
MgSO4 (5.20 g, 43.2 mmol), and AcOH (4.15 mL, 72.5 mmol) were
added. The mixture was stirred for 6 h at r.t. under an argon atmo-
sphere. The MgSO4 was filtered off and was washed with CH2Cl2.
The filtrate was washed with sat. aq NaHCO3, dried (Na2SO4), and
concentrated in vacuo. The crude product (3.68 g) was recrystal-
lized (Et2O) to furnish colorless crystals (1.99 g, 7.20 mmol, 50%);
the mother liquor yielded a further crop (0.94 g, 3.40 mmol, 23%).
Product as colorless crystals: total yield: 2.93 g (10.6 mmol, 73%);
mp 89–90 °C; Rf = 0.72 (cyclohexane–EtOAc, 4:1).
THF–H2O
34%
N
+
CN
6%
22
21a
21b
single diastereomer
24% over 2 steps
18% over 2 steps
Br
N
H
23
H
IR (ATR): 2925 (m), 2853 (m), 1646 (m), 1453 (w), 1343 (w), 1122
(w), 1014 (w), 974 (m), 890 (w), 869 (m), 835 (s), 750 (s), 484
cm–1 (m).
1) 19, DBU
THF, 25 °C
N
2) AcOH, THF–H2O
CN
N
1H NMR (400 MHz, CDCl3): d = 8.62 (d, J = 1.4 Hz, 1 H, HC=N),
8.13 (s, 1 H, H1Naphthyl), 8.01 (dd, J = 8.6, 1.6 Hz, 1 H, HNaphthyl),
7.95–7.91 (m, 1 H, HNaphthyl), 7.90–7.85 (m, 2 H, HNaphthyl), 7.60–
7.51 (m, 2 H, HNaphthyl), 4.57 (dd, J = 5.6, 1.4 Hz, 1 H, HCCN),
2.04–1.66 (m, 6 H, HCy), 1.39–1.15 (m, 5 H, HCy).
3) NaCNBH3
EtOH, 25 °C
24a (14%)
+ 24b (11%)
1b
Scheme 5 Preparation of indolizidines
13C NMR (100.6 MHz, CDCl3): d = 162.9 (CH=N), 135.3 (Cq),
133.2 (Cq), 133.0 (Cq), 131.5, 129.0, 128.9, 128.1, 127.9, 126.9,
123.9, 117.5 (CN), 64.6 (CHCN), 42.2 (C1Cy), 30.0, 28.9, 26.2,
26.1, 25.9.
MS (EI): m/z (%) = 276 (100) [M]+, 194 (98), 167 (96), 155 (43).
HRMS (ESI): m/z [M + H]+ calcd for C19H21N2: 277.1705; found:
corded on a Bruker AC 300, AV 400, AMX 400, or DMX 500 in-
strument. Chemical shifts were referenced to the residual solvent
signal (CDCl3: dH = 7.26, dC = 77.0; CD3OD: dH = 3.31, dC = 49.0;
DMSO-d6: dH = 2.70, dC = 39.5).41 IR spectra were recorded on a
Perkin-Elmer 1760X FTIR spectrophotometer or a Bruker Alpha-P
FTIR spectrophotometer. Melting points were measured on a Dr.
Tottoli apparatus and are uncorrected. MS spectra were recorded on
a Finnigan MAT 95 (FD-MS), VG70S (FAB-MS and FAB-HRMS)
or a Varian MAT 311A (EI-MS). ESI-HRMS spectra were recorded
on a Waters Q-ToF-Ultima 3-Instrument. Elemental analyses were
performed on a VarioMicro Cube (Elementar) or a CHN-O-Rapid
(Heraeus).
277.1707.
Anal. Calcd for C19H20N2: C, 82.57; H, 7.29; N, 10.14. Found: C,
82.53; H, 7.29; N, 9.86.
2-Cyclohexyl-2-(4-nitrobenzylideneamino)acetonitrile (1f)
Following the typical procedure for 1e using 2-amino-2-cyclohexyl-
acetonitrile (2.00 g, 14.5 mmol), and anhyd CH2Cl2, 4-nitrobenzal-
dehyde (2.20 g, 14.6 mmol), MgSO4 (5.24 g, 43.5 mmol), and
AcOH (5 drops). The MgSO4 was filtered off and was washed with
CH2Cl2. The filtrate was washed with sat. aq NaHCO3, dried
(Na2SO4), and concentrated in vacuo. Recrystallization (Et2O) gave
colorless crystals (3.26 g, 12.0 mmol, 83%); the mother liquor
yielded further crystals (0.29 g, 1.1 mmol, 7%). Product as colorless
crystals; total yield: 3.55 g (13.1 mmol, 90%); mp 76–77 °C;
Rf = 0.70 (cyclohexane–EtOAc, 2:1).
Crystal data of 21b picrate were obtained on a Siemens/Bruker
AXS Smart diffractometer. CCDC-818238 contains the supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or
from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44(1223)336033; e-mail:
deposit@ccdc.cam.ac.uk.
2-Amino-2-cyclohexylacetonitrile
According to a modified protocol by Taillades et al.,42 the title com-
pound was prepared by addition of a soln of cyclohexanecarbalde-
hyde (12.00 g, 0.107 mol) in EtOH (40 mL) to a soln of KCN (8.52
g, 0.131 mol) and NH4Cl (11.35 g, 0.212 mol) in 25% NH3 (150
mL). After stirring at r.t. for 1.5 h, the mixture was extracted with
Et2O (2 × 100 mL). The combined organic layers were concentrated
in vacuo to furnish a colorless oil. The crude product (14.86 g) was
filtered over silica gel (cyclohexane–EtOAc, 4:1) to yield the prod-
uct (9.33 g, 0.068 mol, 63%) as colorless crystals; mp 42–43 °C
IR (ATR): 2929 (m), 1650 (m), 1522 (s), 1345 (s), 1292 (m), 1012
(m), 850 (s), 827 (m), 745 (m), 676 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 8.56 (d, J = 1.7 Hz, 1 H, HC=N),
8.30 (AA¢-part of AA¢BB¢-system, 2 H, H3Ar, H5Ar), 7.97 (BB¢-part
of AA¢BB¢-system, 2 H, H2Ar, H6Ar), 4.60 (dd, J = 5.5, 1.7 Hz, 1 H,
CH), 2.07–1.66 (m, 6 H, HCy), 1.39–1.12 (m, 5 H, HCy).
Synthesis 2011, No. 11, 1691–1704 © Thieme Stuttgart · New York

1696
I. Schäfer, T. Opatz
FEATURE ARTICLE
13C NMR (100.6 MHz, CDCl3): d = 160.5 (HC=N), 149.8 (C4Ar),
140.5 (C1Ar), 129.6 (2 C, C2Ar, C6Ar), 124.2 (2 C, C3Ar, C5Ar), 116.8
(CN), 64.5 (CH), 42.1 (C1Cy), 30.0, 28.8, 26.1, 25.99, 25.9 (CCy).
13C NMR (125.8 MHz, DMSO-d6): d = 164.8 (C=O), 163. 4 (C=O),
139.5 (Cq), 135.8 (Cq), 132.6 (Cq), 132.1 (Cq), 130.4 (Cq), 128.7
(Cq), 128.3 (2 C, Ph), 128.1 (2 C, Ph), 127.7, 127.7, 127.6, 126.6,
126.2, 126.1, 125.8, 125.7, 116.3 (Cq), 113.9 (Cq), 79.9 [C(CH3)3],
79.5 [C(CH3)3], 31.7 (CH2), 27.9 [C(CH3)3], 27.7 [C(CH3)3].
MS (ESI): m/z (%) = 484.4 (65) [M + H]+, 372.2 (100), 354.2 (52),
260.2 (40).
MS (EI): m/z (%) = 271 (8) [M]+, 189 (100), 83 (34), 55 (49).
Anal. Calcd for C15H17N3O2: C, 66.40; H, 6.32; N, 15.49. Found: C,
66.39; H, 6.42; N, 15.39.
Pyrroles 2 from a-(Alkylideneamino)nitriles and Di-tert-butyl
Acetylenedicarboxylate; General Procedure
HRMS (ESI): m/z [M + H]+ calcd for C31H34NO4: 484.2488; found:
484.2494.
To an argon-flushed microwave reaction vessel was added a mix-
ture of imine 1, di-tert-butyl acetylenedicarboxylate (1–1.2 equiv),
and Cs2CO3 (2 equiv) in DMF (20 mL/mmol). The mixture was
heated to 100 °C for 1 min by irradiation with microwaves (CEM
Discover, air cooling, IR-temperature control, maximum power 100
W). After pressure equilibration, the mixture was diluted with sat.
aq NaHCO3 (5 mL/100 mg imine) and the mixture was extracted
with EtOAc (3 × 5 mL/100 mg imine). The combined organic layers
were washed with H2O (10 mL/100 mg imine) and brine (10 mL/
100 mg imine) and dried (Na2SO4). After removal of the solvent in
vacuo, the crude product was purified by column chromatography.
Di-tert-butyl 5-Benzyl-2-(3,4-dimethoxyphenyl)-1H-pyrrole-
3,4-dicarboxylate (2c)
According to the general procedure using 1c (100.5 mg, 0.341
mmol), di-tert-butyl acetylenedicarboxylate (77.9 mg, 0.344
mmol), and Cs2CO3 (222.9 mg, 0.684 mmol) in DMF (0.71 mL). A
part (151.0 mg) of the crude product (160.8 mg) was purified by col-
umn chromatography (silica gel, PE–EtOAc, 4:1) to furnish 2c
(89.0 mg, 0.180 mmol, 56%) as light-yellow foam; Rf = 0.26 (PE–
EtOAc, 4:1).
IR (KBr): 3316 (m), 2976 (m), 1703 (vs), 1505 (s), 1457 (m), 1367
(m), 1252 (s), 1228 (s), 1166 (s), 1122 (m), 1090 (m), 1026 (m), 848
cm–1 (m).
1H NMR (300 MHz, DMSO-d6): d = 11.64 (br s, 1 H, NH), 7.33–
7.15 (m, 5 H), 7.09 (d, J = 1.6 Hz, 1 H), 7.05–6.99 (m, 2 H), 4.15 (s,
2 H, CH2Ph), 3.77 (6 H, 2 OCH3), 1.40 [s, 9 H, C(CH3)3], 1.39 [s, 9
H, C(CH3)3].
13C NMR (75.5 MHz, DMSO-d6): d = 165.0 (C=O), 163.3 (C=O),
148.4 (COCH3), 148.2 (COCH3), 139.5 (Cq), 134.6 (Cq), 130.7
(Cq), 128.2 (2 C, Ph), 127.9 (2 C, Ph), 126.0, 123.8 (Cq), 119.9,
115.0 (Cq), 113.7 (Cq), 111.5, 111.3, 79.5 [C(CH3)3], 79.2
[C(CH3)3], 55.5 (OCH3), 55.4 (OCH3), 31.6 (CH2Ph), 27.8 [3 C,
C(CH3)3], 27.6 [3 C, C(CH3)3].
Di-tert-butyl 5-Methyl-2-(2-naphthyl)-1H-pyrrole-3,4-dicar-
boxylate (2a)
According to the general procedure using 1a (100.1 mg, 0.481
mmol), di-tert-butyl acetylenedicarboxylate (130.1 mg, 0.575
mmol), and Cs2CO3 (311.9 mg, 0.957 mmol) in DMF (1.5 mL). A
portion (238.6 mg) of the crude product (251.8 mg) was purified by
column chromatography (silica gel, PE–EtOAc, 5:1) to furnish 2a
(123.9 mg, 0.304 mmol, 67%) as a yellow foam; Rf = 0.26 (PE–
EtOAc, 4.5:1).
IR (KBr): 3290 (m), 2977 (m), 1698 (vs), 1478 (m), 1429 (m), 1392
(m), 1230 (m), 1170 (s), 1139 (m), 1117 (s), 1099 (s), 848 (m), 747
cm–1 (m).
1H NMR (300 MHz, DMSO-d6): d = 11.75 (br s, 1 H, NH), 7.99–
7.85 (m, 4 H, HNaphthyl), 7.62 (dd, J = 8.6, 1.7 Hz, 1 H, HNaphthyl), 7.53
(mc, 2 H, HNaphthyl), 2.41 (s, 3 H, CH3), 1.50 [s, 9 H, C(CH3)3], 1.40
[s, 9 H, C(CH3)3].
MS (ESI): m/z (%) = 494.3 (87) [M + H]+, 382.2 (100), 364.2 (68).
HRMS (ESI): m/z [M + H]+ calcd for C29H36NO6: 494.2543; found:
494.2560.
13C NMR (75.5 MHz, DMSO-d6): d = 165.0 (C=O), 163.2 (C=O),
134.0 (Cq), 132.6 (Cq), 131.9 (Cq), 129.2 (Cq), 128.8 (Cq), 127.7,
127.6, 127.5, 126.6, 126.1, 125.3, 125.2, 116.3 (Cq), 113.3 (Cq),
79.7 [C(CH3)3], 79.1 [C(CH3)3], 28.0 [3 C, C(CH3)3], 27.6 [3 C,
C(CH3)3], 12.5 (CH3).
Di-tert-butyl 2-(3,4-Dimethoxyphenyl)-5-phenyl-1H-pyrrole-
3,4-dicarboxylate (2d)
According to the general procedure using 1d (199.8 mg, 0.713
mmol), di-tert-butyl acetylenedicarboxylate (194.1 mg, 0.858
mmol), and Cs2CO3 (465.1 mg, 1.427 mmol) in DMF (1.49 mL). A
part (361.9 mg) of the crude product (381.9 mg) was purified by col-
umn chromatography (silica gel, PE–EtOAc, 3:1) to obtain pure 2d
(201.3 mg, 0.420 mmol, 62%) as a light-yellow foam; Rf = 0.10
(PE–EtOAc, 4:1).
MS (ESI): m/z (%) = 471.3 (60) [M + CH3CN + Na]+, 430.2 (35) [M
+ Na]+, 408.2 (88) [M + H]+, 352.2 (43), 296.1 (100), 278.1 (63).
HRMS (ESI): m/z [M + H]+ calcd for C25H30NO4: 408.2175; found:
408.2185.
IR (KBr): 3318 (m), 2976 (m), 1704 (vs), 1504 (s), 1455 (m), 1440
(m), 1367 (m), 1250 (s), 1169 (s), 1127 (s), 1058 (m), 1026 (m), 848
(m), 697 cm–1 (m).
1H NMR (300 MHz, DMSO-d6): d = 11.76 (br s, 1 H, NH), 7.55–
7.35 (m, 5 H, Ph), 7.17 (d, J = 1.9 Hz, 1 H, H2), 7.11 (dd, J = 8.4,
1.9 Hz, 1 H, H6), 7.02 (d, J = 8.4 Hz, 1 H, H5), 3.79 (s, 6 H, 2
OCH3), 1.40 [s, 9 H, C(CH3)3], 1.34 [s, 9 H, C(CH3)3].
13C NMR, PENDANT (100.6 MHz, DMSO-d6): d = 164.3 (C=O),
163.8 (C=O), 148.5 (COCH3), 148.1 (COCH3), 132.9 (2 Cq), 141.4
(Cq), 128.6 (2 C), 127.8 (2 C), 127.7, 123.7 (Cq), 120.8, 115.3 (Cq),
115.0 (Cq), 112.1, 111.3, 79.5 [C(CH3)3], 79.5 [C(CH3)3], 55.5
(OCH3), 55.4 (OCH3), 27.6 [3 C, C(CH3)3], 27.5 [3 C, C(CH3)3].
Di-tert-butyl 5-Benzyl-2-(2-naphthyl)-1H-pyrrole-3,4-dicar-
boxylate (2b)
According to the general procedure using 1b (200.4 mg, 0.705
mmol), di-tert-butyl acetylenedicarboxylate (161.4 mg, 0.713
mmol), and Cs2CO3 (460.4 mg, 1.413 mmol) in DMF (1.46 mL). A
part (382.4 mg) of the crude product (393.5 mg) was purified by col-
umn chromatography (silica gel, PE–EtOAc, 5:1) to furnish 2b
(167.6 mg, 0.347 mmol, 51%) as a light-brown foam; Rf = 0.42
(PE–EtOAc, 4.5:1).
IR (KBr): 2976 (m), 1698 (vs), 1455 (m), 1427 (m), 1367 (s), 1230
(m), 1167 (s), 1139 (m), 1118 (m), 1091 (s), 847 cm–1 (m).
MS (ESI): m/z (%) = 480.4 (97) [M + H]+, 368.2 (100), 350.1 (68).
HRMS (ESI): m/z [M + H]+ calcd for C28H34NO6: 480.2386; found:
1H NMR (500 MHz, DMSO-d6): d = 11.95 (br s, 1 H, NH), 8.00–
7.86 (m, 4 H, HNaphthyl), 7.62 (dd, J = 8.5, 1.7 Hz, 1 H, HNaphthyl), 7.53
(mc, 2 H, HNaphthyl), 7.32–7.25 (m, 4 H, Ph), 7.22–7.16 (m, 1 H,
H4Ph), 4.20 (s, 2 H, CH2Ph), 1.42 [s, 9 H, C(CH3)3], 1.39 [s, 9 H,
C(CH3)3].
480.2393.
Synthesis 2011, No. 11, 1691–1704 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Pyrroles and Indolizidines
1697
Di-tert-butyl 5-Cyclohexyl-2-(2-naphthyl)-1H-pyrrole-3,4-di-
carboxylate (2e)
colorless crystals; combined yield: 7.63 g (50.8 mmol, 78%); mp
72–73.5 °C; Rf = 0.38 (PE–EtOAc, 1:1).
According to the general procedure using 1e (200 mg, 0.724 mmol),
di-tert-butyl acetylenedicarboxylate (164.0 mg, 0.725 mmol), and
Cs2CO3 (471.0 mg, 1.446 mmol) in DMF (1.5 mL). The crude prod-
uct (434 mg) was purified by column chromatography (silica gel,
PE–EtOAc, 8:1) to furnish 2e (188 mg, 0.395 mmol, 55%) as a yel-
low foam; Rf = 0.19 (PE–EtOAc, 8:1).
IR (KBr): 3334 (m), 3274 (m), 3185 (m), 2227 (m, CN), 1607 (m),
1516 (s), 1247 (s), 1160 (m), 1084 (m), 979 (m), 962 (s), 936 (m),
881 (m), 835 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 7.56–7.48 (m, 2 H, H2Ar, H6Ar),
7.15–7.06 (m, 2 H, H3Ar, H5Ar), 4.90 (t, J = 7.5 Hz, 1 H, CH), 1.95
(br s, 2 H, NH2).
IR (KBr): 2927 (m), 1693 (s), 1450 (m), 1365 (m), 1223 (m), 1166
(s), 1130 (s), 1116 (m), 1082 (m), 746 cm–1 (m).
1
13C NMR (75.5 MHz, CDCl3): d = 162.9 (d, J = 247.5 Hz, 1 C,
C4Ar), 132.1 (d, 4J = 3.4 Hz, 1 C, C1Ar), 128.4 (d, 3J = 9.1 Hz, 2 C,
1H NMR (300 MHz, DMSO-d6): d = 11.39 (br s, 1 H, NH), 8.00–
7.86 (m, 4 H, HNaphthyl), 7.63–7.48 (m, 3 H, HNaphthyl), 3.20 (pseudo-
t, Japp ≈ 11.5 Hz, 1 H, CHCy), 1.91–1.61 (m, 7 H, HCy), 1.61–1.12
{m, 21 H, contained in this multiplet: 1.50 [s, 9 H, C(CH3)3], 1.35
[s, 9 H, C(CH3)3]}.
13C NMR (75.5 MHz, DMSO-d6): d = 164.7 (C=O), 163.5 (C=O),
142.1 (Cq), 132.5 (Cq), 132.0 (Cq), 130.5 (Cq), 128.8 (Cq), 127.6,
127.5, 127.2, 126.4, 126.3 (2 C), 126.0, 115.7 (Cq), 112.5 (Cq),
79.5 [C(CH3)3], 79.2 [C(CH3)3], 35.5 (CCy), 31.6 (2 C, CCy), 27.9 [3
C, C(CH3)3], 27.5 [3 C, C(CH3)3], 26.3 (2 C, CCy)), 25.4 (CCy).
MS (EI): m/z (%) = 475 (39) [M]+, 346 (55), 345 (100), 249 (30), 56
(32).
HRMS (ESI): m/z [M + H]+ calcd for C30H38NO4: 476.2801; found:
476.2810.
2
C2Ar, C6Ar), 120.7 (CN), 116.0 (d, J = 21.4 Hz, 2 C, C3Ar, C5Ar),
46.6 (CH).
MS (FD): m/z (%) = 150.1 (100) [M]+.
Anal. Calcd for C8H7FN2: C, 63.99; H, 4.70; N, 18.66. Found: C,
64.01; H, 4.58; N, 18.87.
2-(4-Fluorophenyl)-2-[(2-methylpropylidene)amino]acetoni-
trile (4)
To a stirred soln of 3 (2.00 g, 13.32 mmol) in anhyd CH2Cl2 (5 mL)
were added MgSO4, (2.4 g, 20.0 mmol), isobutyraldehyde (1.34
mL, 14.65 mmol), and AcOH (10 drops) under an argon atmo-
sphere. The mixture was stirred for 17 h at r.t. Due to incomplete
conversion, further AcOH (12 drops) was added and stirring was
continued for 4 h. After addition of further AcOH (12 drops), the
mixture was heated to reflux for 4 h and stirred overnight at r.t. The
MgSO4 was filtered off and washed with CH2Cl2. The combined fil-
trates were washed with sat. aq NaHCO3 (20 mL) and brine (20
mL), dried (MgSO4), and concentrated in vacuo to furnish a light-
yellow oil (2.15 g, 10.5 mmol, 79%), which was sufficiently pure
for the next synthetic transformation; Rf = 0.69 (PE–EtOAc, 2:1).
Di-tert-butyl 5-Cyclohexyl-2-(4-nitrophenyl)-1H-pyrrole-3,4-
dicarboxylate (2f)
According to the general procedure using 1f (200.0 mg, 0.737
mmol), di-tert-butyl acetylenedicarboxylate (200.2 mg, 0.885
mmol), and Cs2CO3 (480.0 mg, 1.47 mmol) in DMF (1.54 mL). A
part (440.0 mg) of the crude product (450.0 mg) was purified by col-
umn chromatography (silica gel, PE–EtOAc, 11:2) to furnish 2f
(298.0 mg, 0.633 mmol, 86%) as a yellow foam; Rf = 0.27 (PE–
EtOAc, 8:1).
IR (film): 2970 (s), 2933 (m), 2875 (m), 2244 (w, CN), 1662 (s),
1606 (s), 1510 (s), 1468 (m), 1234 (s), 1160 (m), 837 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 7.97 (dd, J = 4.7, 1.6 Hz, 1 H,
HC=N), 7.42–7.36 (m, 2 H, H2Ar, H6Ar), 7.14–7.06 (m, 2 H, H3Ar,
H5Ar), 5.52 (br s, 1 H, HCCN), 2.60 [mc, 1 H, CH(CH3)2], 1.14 [d,
J = 6.9 Hz, 6 H, CH(CH3)2].
IR (KBr): 1698 (s), 1518 (m), 1451 (m), 1366 (m), 1230 (m), 1161
(s), 1120 (s), 1109 (m), 1084 (m), 847 cm–1 (m).
1H NMR (300 MHz, DMSO-d6): d = 11.52 (br s, 1 H, NH), 8.29
(AA¢-part of AA¢BB¢-system, Japp ≈ 8.8 Hz, 2 H, H3, H5), 7.72
(BB¢-part of AA¢BB¢-system, Japp ≈ 8.8 Hz, 2 H, H2, H6), 3.18 (tt,
J = 11.9, 3.4 Hz, 1 H, CHCy), 1.87–1.57 (m, 7 H, HCy), 1.50 [s, 9 H,
C(CH3)3], 1.40 [s, 9 H, C(CH3)3], 1.35–1.19 (m, 3 H, HCy).
13C NMR (75.5 MHz, DMSO-d6): d = 164.4 (C=O), 163.2 (C=O),
146.0 (COCH3), 143.4 (COCH3), 137.5 (Cq), 128.3 (2 C), 127.8
(Cq), 123.3 (2 C), 117.6 (Cq), 113.3 (Cq), 80.2 [C(CH3)3], 79.5
[C(CH3)3], 35.6 (CCy), 31.5 (2 C, CCy), 27.9 [3 C, C(CH3)3], 27.5 [3
C, C(CH3)3], 26.2 (2 C, CCy), 25.4 (CCy).
13C NMR (75.5 MHz, CDCl3): d = 172.9 (HC=N), 161.1 (d, 1JC-F
=
248.4 Hz, 1 C, C4Ar), 130.7 (d, 4JC-F = 3.3 Hz, 1 C, C1Ar), 128.9 (d,
3JC-F = 8.5 Hz, 2 C, C2Ar, C6Ar), 116.8 (CN), 115.7 (d, 2JC-F = 22.0
Hz, 2 C, C3Ar, C5Ar), 60.8 (CH), 34.3 [CH(CH3)2], 18.9 [2 C,
CH(CH3)2].
MS (FD): m/z (%) = 256.1 (100), 204.2 (90) [M]+.
Anal. Calcd for C12H13FN2: C, 70.57; H, 6.42; N, 13.72. Found: C,
70.21; H, 6.49; N, 13.45.
N,3-Diphenylpropiolamide (5)
HRMS (ESI): m/z [M + H]+ calcd for C26H35N2O6: 471.2495; found:
A suspension of phenylpropiolic acid (2.50 g, 17.1 mmol) and
SOCl2 (1.49 mL, 20.5 mmol) in anhyd benzene (9 mL) was stirred
for 3 h at 70 °C. After 30 min, a clear soln resulted. Excess SOCl2
and benzene were removed in vacuo. The oily residue was dissolved
in anhyd benzene (9 mL) and cooled to 0 °C. A soln of aniline (3.19
g, 34.2 mmol) in anhyd benzene (9 mL) was added over 10 min. The
ice bath was removed and the mixture was stirred for 80 min at r.t.
The beige and turbid mixture was poured into ice-cold water (40
mL), the organic layer was separated, and the aqueous layer was ex-
tracted with EtOAc (3 × 20 mL). The combined organic layers were
washed with 5% HCl, H2O, 5% aq Na2CO3, and again with H2O (30
mL each) After drying (Na2SO4), the solvent was removed in vacuo
and the crude product (2.68 g, light beige solid) was recrystallized
(EtOH, 10 mL) to obtain a colorless solid (1.16 g, 5.24 mmol, 31%);
the mother liquor gave a further crop of colorless crystals (0.80 g,
3.62 mmol, 21%). Product 5 was obtained as colorless crystals;
471.2498.
Anal. Calcd for C26H34N2O6: C, 66.36; H, 7.28; N, 5.95. Found: C,
66.34; H, 7.26; N, 5.81.
2-Amino-2-(4-fluorophenyl)acetonitrile (3)
To a soln of KCN (5.04 g, 77.35 mmol) and NH4Cl (6.90 g, 0.129
mol) in 25% aq NH3 (95 mL) was added a soln of 4-fluorobenzal-
dehyde (8.12 g, 65.4 mmol) in EtOH (25 mL) over 10 min. After
105 min stirring at r.t., the slightly yellow soln was extracted with
Et2O (3 × 100 mL). The combined organic layers were washed with
half-sat. brine, dried (Na2SO4), and the solvent was removed in vac-
uo. The crude product (9.83 g) still contained minor impurities and
was recrystallized (EtOH) to give colorless crystals (5.31 g, 35.4
mmol, 54%); a further crop of crystals could be obtained from the
mother liquor (2.32 g, 15.5 mmol, 24%). Product 3 was obtained as
Synthesis 2011, No. 11, 1691–1704 © Thieme Stuttgart · New York

1698
I. Schäfer, T. Opatz
FEATURE ARTICLE
combined yield: 1.96 g (8.89 mmol, 52%); mp 124–125 °C (Lit.44
125–126 °C); Rf = 0.45 (PE–EtOAc, 2:1).
2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-1H-pyrrole (7) and
5-(4-Fluorophenyl)-2-isopropyl-3-phenyl-1H-pyrrole (8)
An argon-flushed microwave reaction vessel was charged with 4
(300.3 mg, 1.47 mmol), 5 (357.7 mg, 1.62 mmol), and Cs2CO3
(962.1 mg, 2.95 mmol). After addition of anhyd DMF (3.0 mL), the
mixture was heated under stirring to 65 °C for 2 min (CEM Discov-
er, air cooling, IR temperature control, maximum power 100 W)
and then to 90 °C for 2 min (maximum power 150 W). After pres-
sure equilibration, sat. aq NaHCO3 (15 mL) and EtOAc (15 mL)
were added. The aqueous layer was extracted with EtOAc (3 × 15
mL), the combined organic layers were washed with H2O and brine
(30 mL each) and dried (Na2SO4). After removal of the solvent in
vacuo, a part (621.2 mg) of the crude product (664.5 mg) was puri-
fied by column chromatography (silica gel, PE–EtOAc, 4:1) to fur-
nish a 9:1 isomeric mixture of 7 and 8 as a light-brown oil (273.9
mg, 0.98 mmol, 71%) which crystallized later to give a light-brown
solid; Rf = 0.56 (PE–EtOAc, 4:1).
IR (KBr): 2212 (m), 1625 (m), 1604 (m), 1593 (m), 1542 (s), 1497
(m), 1487 (m), 1441 (s), 1327 (m), 1319 (m), 1249 (m), 751 (s), 720
(m), 687 (s), 508 cm–1 (m).
1H NMR (300 MHz, DMSO-d6): d = 10.87 (br s, 1 H, NH), 7.77–
7.62 (m, 4 H, Ph), 7.58–7.44 (m, 3 H, Ph), 7.34 (pseudo-t, Japp ≈ 7.4
Hz, 2 H, Ph), 7.17 (pseudo-t, Japp ≈ 6.9 Hz, 1 H, Ph).
13C NMR (75.5 MHz, CDCl3): d = 151.1 (C=O), 137.4 (C1¢), 132.6
(2 C), 130.3, 129.1 (2 C), 128.6 (2 C), 124.9, 120.0 (2 C), 119.9
(C1¢¢), 85.8 (C3), 83.4 (C2).
MS (FAB): m/z (%) = 222.1 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C15H12NO: 222.0919; found:
222.0922.
5-(4-Fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-car-
boxanilide (6)
IR (KBr): 3420 (m), 2966 (m), 1603 (m), 1525 (m), 1510 (s), 1220
(m), 835 (s), 803 (m), 770 (s), 705 cm–1 (m).
To a soln of 4 (53.0 mg, 0.259 mmol) and 5 (63.2 mg, 0.285 mmol)
in DMF (490 mL) was added, under an argon atmosphere, Cs2CO3
(169.1 mg, 0.519 mmol). The mixture was stirred for 135 min at 0
°C, for 170 min at r.t. and for 75 min at 40 °C. TLC indicated com-
plete consumption of 4. The mixture was partitioned between sat. aq
NaHCO3 (5 mL) and EtOAc (5 mL). The aqueous phase was ex-
tracted with EtOAc (3 × 5 mL) and the combined organic layers
were washed with H2O and brine (10 mL each) and dried (Na2SO4),
and the solvent was removed in vacuo. A part (108.7 mg) of the vis-
cous yellow material (125.7 mg) was purified by column chroma-
tography (silica gel, toluene) to furnish 6 (35.4 mg, 0.089 mmol,
40%) as a slightly yellowish solid; mp 199–200.5 °C. The starting
material 5 (28.3 mg, 0.128 mmol, 57%) was also recovered;
Rf = 0.47 (PE–EtOAc, 4:1); Rf = 0.13 (toluene).
MS (FD): m/z (%) = 279.2 (100) [M]+.
HRMS (FAB): m/z [M]+ calcd for C19H18FN: 279.1423; found:
279.1425.
Compound 7
1H NMR, COSY, HMBC (400 MHz, 100.6 MHz, DMSO-d6):
d = 10.83 (br s, 1 H, NH), 7.36–7.28 (m, 2 H, H2¢, H6¢), 7.28–7.14
(m, 4 H, H2¢¢, H6¢¢, H3¢¢, H5¢¢), 7.16–7.10 (m, 3 H, H3¢, H5¢, H4¢¢),
5.94 (dd, J = 2.7, 0.6 Hz, 1 H, =CH), 2.90 (sept, J = 6.9 Hz, 1 H,
CH), 1.25 [d, J = 6.9 Hz, 6 H, CH(CH3)2].
13C NMR, HMBC, HSQC (100.6 MHz, 400 MHz, DMSO-d6):
d = 160.7 (d, 1JC-F = 243.1 Hz, 1 C, C4¢), 139.6 (C5), 137.2 (C1¢¢),
130.1 (d, 4JC-F = 3.0 Hz, 1 C, C1¢), 129.3 (d, 3JC-F = 7.9 Hz, 2 C, C2¢,
C6¢), 128.3, 127.8 (2 × 2 C, C2¢¢, C6¢¢; C3¢¢, C5¢¢), 125.2 (C4¢¢),
IR (KBr): 3407 (m), 3249 (m), 1639 (s), 1597 (m), 1510 (s), 1439
(m), 1221 (m), 750 (m), 691 cm–1 (m).
2
125.1 (C2), 120.4 (C3), 115.1 (d, JC-F = 21.4 Hz, 2 C, C3¢, C5¢),
1H NMR, COSY, HMBC (400 MHz, 100.6 MHz, DMSO-d6):
d = 11.14 (br s, 1 H, NH), 9.21 (br s, 1 H, NHCO), 7.44–7.38 (m, 2
H, H2¢¢Ar, H6¢¢Ar), 7.27–7.16 (m, 9 H), 7.15–7.08 (m, 2 H, H3¢Ar,
H5¢Ar), 6.96 (pseudo-t, Japp ≈ 7.3 Hz, 1 H, H4¢¢Ar), 3.33 (sept, J = 7.0
Hz, 1 H, CH, partly buried under the H2O signal), 1.32 [d, J = 7.0
Hz, 6 H, CH(CH3)2].
105.0 (=CH), 26.6 (CH), 22.7 [2 C, CH(CH3)2].
Compound 8
Characteristic NMR shifts.
1H NMR (400 MHz, DMSO-d6): d = 10.8 (br s, 1 H, NH), 6.49 (d,
J = 2.8 Hz, 1 H, =CH), 3.20 (sept, J = 7.0 Hz, 1 H, CH), 1.31 [d,
J = 7.0 Hz, 6 H, CH(CH3)2].
13C NMR (100.7 MHz, DMSO-d6): d = 105.7 (HC=), 25.2 (CH),
22.9 [2 C, CH(CH3)2].
13C NMR, HMBC, HSQC (100.6 MHz, 400 MHz, DMSO-d6):
d = 164.8 (C=O), 159.1 (d, 1JC-F = 243.7 Hz, 1 C, C4¢), 139.4 (C1¢¢),
3
139.2 (C2), 135.2 (C1¢¢¢Ar), 130.0 (2 C, Ar¢¢¢), 129.4 (d, JC-F = 8.0
Hz, 2 C, C2¢, C6¢), 129.0 (d, 4JC-F = 3.2 Hz, 1 C, C1¢), 128.5 (2 C,
C3¢¢Ar, C5¢¢Ar), 128.1 (2 C, Ar¢¢¢), 126.2 (C4¢¢¢Ar), 125.7 (C4), 122.8
(C4¢¢Ar), 119.3 (C3), 119.0 (2 C, C2¢¢Ar, C6¢¢Ar), 117.2 (C5), 114.8 (d,
2JC-F = 21.4 Hz, 2 C, C3¢, C5¢), 25.9 (CH), 22.4 [2 C, CH(CH3)2].
2-Methyl-2-[(2-naphthylmethylene)amino]-5-oxo-3,5-diphenyl-
pentanenitrile (15a)
Under an argon atmosphere, 1a (249.7 mg, 2.00 mmol) was dis-
solved in anhyd THF (2 mL). After addition of TMG (158 mL, 1.26
mmol), the mixture was stirred for 1 min at r.t. A soln of chalcone
(14a, 250.4 mg, 1.20 mmol) in anhyd THF (0.5 mL) was added and
the mixture was stirred for 3.5 h at r.t. The mixture was washed with
sat. aq NaHCO3 (2 × 5 mL) and the combined aqueous phases were
re-extracted with EtOAc (2 × 5 mL). The combined organic layers
were dried (Na2SO4) and the solvent was removed in vacuo to yield
a light-yellow oil (541.2 mg, quant.) which was used without further
purification for the next synthetic step; Rf = 0.66 (PE–EtOAc, 1:1);
bright-orange color after ninhydrin treatment.
Transient NOE: Irradiation on d = 1.32 [CH(CH3)2] enhances the
signals at d = 11.14 (NH, 1.4%), 9.21 (NHCO, 0.2%), and 3.33 (CH,
4.3%); irradiation on d = 3.33 (CH) enhances the signals at
d = 11.14 (NH, 0.1%), 9.21 (NHCO, 0.1%), and 1.32 [CH(CH3)2,
0.7%]; irradiation on d = 9.21 (NHCO) enhances the signals at d =
7.44–7.38 (H2¢¢Ar, H6¢¢Ar, 10.4%), 7.27–7.16 (1.6%), 3.33 (CH,
0.2%), and 1.32 [CH(CH3)2, 0.3%]; irradiation on d = 11.14 (NH)
enhances the signals at d = 7.27–7.16 (H2¢Ar, H6¢Ar, 11.6%), 3.33
(CH, 0.2%), and 1.32 [CH(CH3)2, 5.8%].
MS (ESI): m/z (%) = 399.31 (100) [M + H]+, 355.33 (21) [M – i-Pr
+ H]+.
2-Methyl-3,5-diphenyl-3,4-dihydro-2H-pyrrole-2-carbonitrile
(16a)
HRMS (ESI): m/z [M + H]+ calcd for C26H24FN2O: 399.1873;
found: 399.1874.
Under an argon atmosphere, crude 15a (515.6 mg) was dissolved in
THF (1.5 mL). H2O (1.5 mL) and AcOH (412 mL, 7.20 mmol) were
added and the mixture was stirred for 17.5 h at r.t. The mixture was
partitioned between sat. aq NaHCO3 (10 mL) and EtOAc (5 mL).
The aqueous layer was extracted with EtOAc (2 × 5 mL), the com-
Synthesis 2011, No. 11, 1691–1704 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Pyrroles and Indolizidines
1699
bined organic layers were washed H2O and brine (10 mL each) and
dried (Na2SO4), and the solvent was removed in vacuo to furnish a
light-brown oil (409.7 mg). A portion (394 mg) of the crude product
was dissolved in EtOH (5 mL), Girard’s reagent T (317.2 mg, 1.89
mmol) and AcOH (5 drops) were added. The mixture was stirred for
20 h under an argon atmosphere. After partitioning between sat. aq
NaHCO3 (15 mL) and EtOAc (10 mL), the aqueous phase was ex-
tracted with EtOAc (2 × 10 mL). The combined organic layers were
washed with H2O (4 × 10 mL) and brine (10 mL) and dried
(Na2SO4), and the solvent was removed in vacuo. The resulting res-
idue was dissolved in EtOAc (10 mL), washed with H2O (4 × 10
mL), and dried (Na2SO4), and the solvent was removed in vacuo to
furnish 16a (282.3 mg, 1.08 mmol, 99% over 2 steps) as a yellow
oil that gave yellow crystals; mp 96–98 °C; Rf = 0.43 (PE–EtOAc,
5:1).
2-Benzyl-2-[(3,4-dimethoxybenzylidene)amino]-5-oxohexane-
nitrile (15b)
Under an argon atmosphere, 1c (1.008 g, 3.43 mmol) was dissolved
in anhyd THF (10 mL). After the addition of DBU (533 mL, 3.57
mmol), the mixture was stirred for 1 min at r.t. Methyl vinyl ketone
(14b, 283 mL, 3.40 mmol) was added and the mixture was stirred for
a further 135 min. The organic layer was washed with sat. aq
NaHCO3 (2 × 10 mL). The combined aqueous layers were re-ex-
tracted with EtOAc (2 × 10 mL), the combined organic layers were
dried (Na2SO4), and the solvent was removed in vacuo to furnish a
viscous yellow oil (1.22 g, 3.35 mmol, 99%), which was used with-
out further purification; Rf = 0.45 (PE–EtOAc, 1:1).
IR (NaCl): 1716 (m), 1642 (m), 1601 (m), 1586 (m), 1514 (s), 1455
(m), 1422 (m), 1269 (s), 1241 (m), 1164 (m), 1141 (m), 1025 cm–1
(m).
IR (ATR): 1606 (m), 1572 (w), 1446 (m), 1339 (m), 1179 (w), 1121
(w), 762 (s), 692 (s), 669 (w), 566 (w), 495 (w), 477 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 7.98–7.90 (m, 2 H, H2¢Ph, H6¢Ph),
7.58–7.44 (m, 3 H, Ph), 7.41–7.28 (m, 5 H, Ph), 4.11 (t, J = 8.6 Hz,
1 H, CH), 3.49 (dq, Jq = 17.1, Jd = 8.6 Hz, 2 H, CH2), 1.23 (s, 3 H,
CH3).
13C NMR (75.5 MHz, CDCl3): d = 175.3 (C=N), 136.6 (Cq), 132.9
(Cq), 131.8, 128.8 (2 C), 128.7 (2 C), 128.1 (2 C), 127.9 (3 C), 122.7
(CN), 71.8 (CCN), 52.1 (CH2), 39.6 (CH), 22.0 (CH3).
1H NMR (300 MHz, CDCl3): d = 7.97 (s, 1 H, HC=N), 7.38 (d,
J = 1.8 Hz, 1 H, H2¢), 7.25–7.14 (m, 6 H, HBn, H6¢), 6.89 (d, J = 8.3
Hz, 1 H, H5¢), 3.96 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 3.16 (AB-
system, J = 13.6 Hz, 2 H, CH2Ph), 2.64–2.22 (m, 4 H, 2 CH2), 2.12
(s, 3 H, CH3).
13C NMR (75.5 MHz, CDCl3): d = 206.7 (C=O), 160.6 (HC=N),
152.1, 149.3 (C3¢/C4¢), 134.0 (Cq), 130.9 (2 C, CBn), 128.1 (2 C,
CBn), 127.8 (Cq), 127.4, 123.9 (C6¢), 118.4 (CN), 110.5, 109.2 (C2¢/
C6¢), 67.8 (CCN), 56.0 (2 C, 2 OCH3), 46.5 (CH2Ph), 38.8, 33.9,
30.1.
Transient NOE: Irradiation at d = 4.11 (CH) enhances the signals at
d = 7.31 (C6H5, 3.3%), 3.49 (CH2, 2.6%), and 1.23 (CH3, 0.4%); ir-
radiation at d = 1.23 (CH3) enhances the signals at d = 7.94 (C6H5,
0.2%), 7.31 (C6H5, 0.8%), 4.11 (CH, 0.4%), and 3.49 (CH2, 0.8%).
HRMS (ESI): m/z [M + Na]+ calcd for C22H24NaN2O3: 387.1685;
found: 387.1682.
2-Benzyl-5-methyl-3,4-dihydro-2H-pyrrole-2-carbonitrile
(16b)
MS (FAB): m/z (%) = 261.2 (33) [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C18H17N2: 261.1391; found:
Under an argon atmosphere, 15b (1.015 g, 2.78 mmol) was dis-
solved in THF (5 mL) and after the addition of H2O (5 mL) and
AcOH (956 mL, 16.70 mmol), the mixture was stirred for 21 h at r.t.
The mixture was partitioned between sat. aq NaHCO3 (10 mL) and
EtOAc (10 mL). The aqueous layer was extracted with EtOAc
(2 × 10 mL), the combined organic layers were washed with H2O
(10 mL) and dried (Na2SO4), and the solvent was removed in vacuo
to furnish a light-brown oil (878.4 mg). A portion (868.4 mg) of the
crude product was purified by column chromatography (silica gel,
PE–EtOAc, 3:1) to furnish 16b as a yellow oil which solidified later
to give a yellow solid; yield: 345.2 mg (1.74 mmol, 63%); mp 61–
62 °C; Rf = 0.32 (PE–EtOAc, 1:1), brown spot (ninhydrin).
261.1394.
2-Methyl-3,5-diphenyl-1H-pyrrole (18a)
Under an argon atmosphere, 16a (199.2 mg, 0.765 mmol) was dis-
solved in anhyd THF (2 mL), KOt-Bu (90.2 mg, 0.803 mmol) was
added and the mixture was stirred for 125 min at r.t. Since TLC in-
dicated incomplete conversion, another portion of KOt-Bu (45.1
mg, 0.402 mmol) was added and the mixture was stirred for 19 h at
r.t. After addition of further KOt-Bu (45.3 mg, 0.404 mmol) stirring
was continued for 3 h. The brown mixture was partitioned between
sat. aq NaHCO3 (10 mL) and EtOAc (5 mL). The aqueous layer was
extracted with EtOAc (3 × 5 mL), the combined organic layers were
washed with H2O (3 × 5 mL) and dried (Na2SO4), and the solvent
was removed in vacuo to furnish a light-brown oil (179.0 mg). A
portion (167.7 mg) of the crude product was purified by column
chromatography (silica gel, PE–EtOAc, 5:1) to furnish 18a as a
light-yellow oil; yield: 50.1 mg (0.215 mmol, 30%); yield over 3
steps: 30%; Rf = 0.44 (CH2Cl2–PE–EtOAc, 3:3:0.1).
IR (film/NaCl): 3030 (m), 2922 (m), 2237 (w, CN), 1643 (s), 1497
(m), 1456 (m), 1430 (m), 1380 (m), 1322 (m), 1032 (m), 740 (m),
704 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 7.33–7.23 (m, 5 H, Ph), 3.23 (d,
J = 13.5 Hz, 1 H, PhCH2-Ha), 3.12 (d, J = 13.5 Hz, 1 H, PhCH2-
Hb), 2.63–2.49 (m, 1 H), 2.32–2.07 (m, 3 H), 2.05 (s, 3 H, CH3).
IR (ATR): 1604 (m), 1495 (m), 1449 (m), 1439 (m), 1152 (m), 753
(s), 733 (m), 690 (s), 669 (m), 647 (m), 527 (m), 491 cm–1 (m).
1H NMR (300 MHz, DMSO-d6): d = 11.14 (br s, 1 H, NH), 7.64
(pseudo-d, Japp ≈ 8.2 Hz, 2 H, Ph), 7.47–7.41 (m, 2 H, Ph), 7.39–
7.30 (m, 4 H, Ph), 7.20–7.09 (m, 2 H, Ph), 6.71 (d, J = 2.6 Hz, 1 H,
=CH), 2.41 (s, 3 H, CH3).
13C NMR (75.5 MHz, CDCl3): d = 179.7 (C=N), 134.3 (C1Ph),
130.5 (2 C, Ph), 128.3 (2 C, Ph), 127.4 (C4Ph), 121.7 (CN), 73.5
(CCN), 44.9 (CH2Ph), 39.3, 33.1, 19.5 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C13H14NaN2: 221.1055;
found: 221.1051.
2-Benzyl-5-methyl-1H-pyrrole (18b)
13C NMR (100.6 MHz, DMSO-d6): d = 136.9 (Cq), 132.7 (Cq),
129.3 (Cq), 128.6 (2 C), 128.4 (2 C), 126.6 (2 C), 125.9 (Cq), 125.2,
124.7, 123.0 (2 C), 121.2 (Cq), 105.3 (=CH), 12.7 (CH3).
HRMS (ESI): m/z [M]+ calcd for C17H15N: 233.1204; found:
233.1215.
Under an argon atmosphere, 16b (5.0 mg, 0.025 mmol) was dis-
solved in anhyd THF (50 mL), KOt-Bu (3.2 mg, 0.029 mmol) was
added and the mixture was stirred for 17.5 h at 45 °C. The dark
brown mixture was partitioned between sat. aq NaHCO3 (2 mL) and
EtOAc (2 mL). The organic layer was dried (Na2SO4) and the sol-
vent was removed in vacuo to furnish 18b (2.5 mg, 0.015 mmol,
58%) as a brown oil; yield over 3 steps: 36%; Rf = 0.44 (PE–EtOAc,
5:1), spot turned pink in air.
Synthesis 2011, No. 11, 1691–1704 © Thieme Stuttgart · New York

1700
I. Schäfer, T. Opatz
FEATURE ARTICLE
IR (film/NaCl): 3421 (m), 3367 (m), 2923 (m), 2854 (m), 1494 (m),
1454 (m), 1036 (m), 769 (s), 715 (m), 696 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.47 (br s, 1 H, NH), 7.34–7.29
(m, 2 H, Ph), 7.25–7.21 (m, 3 H, Ph), 5.86 (t, J = 2.8 Hz, 1 H, =CH),
5.79 (t, J = 2.8 Hz, 1 H, =CH), 3.94 (s, 2 H, CH2Ph), 2.21 (s, 3 H,
CH3).
13C NMR (75.5 MHz, CDCl3): d = 139.8 (C1Ph), 129.2 (C2), 128.7
(2 C, Ph), 128.6 (2 C, Ph), 127.0 (C5), 126.3 (C4Ph), 106.5 (=CH),
105.8 (=CH), 34.2 (CH2), 13.0 (CH3).
1H NMR (300 MHz, DMSO-d6): d = 10.6 (br s, 1 H, NH), 7.31–7.22
(m, 6 H, Ph), 7.20–7.06 (m, 4 H, Ph), 5.92 (d, J = 2.4 Hz, 1 H, =CH),
4.00 (s, 2 H, CH2Ph), 2.17 (s, 3 H, CH3).
13C NMR (75.5 MHz, DMSO-d6): d = 140.8 (C1Bn), 137.3 (C1Ph),
128.3 (2 C), 128.3 (2 C), 127.9 (2 C), 126.6 (2 C), 126.1 (Cq), 125.8,
124.5, 124.4 (Cq), 120.5 (Cq), 105.5 (=CH), 31.9 (CH2Ph), 12.7
(CH3).
MS (ESI): m/z (%) = 248.2 (60) [M + H]+, 247.17 (63) [M]·+, 246.15
(100) [M – H]+.
MS (ESI): m/z (%) = 341.24 (90) [2 M – H]+, 250.18 (63), 170.07
HRMS (ESI): m/z [M]+ calcd for C18H17N: 247.1361; found:
247.1357.
(100) [M – H]+.
HRMS (ESI): m/z [M]+ calcd for C12H13N: 171.1048; found:
171.1051.
(E)-1-(4-Chlorophenyl)-4,4-dimethylpent-1-en-3-one (14d)
Pinacolone (8.00 g, 79.9 mmol) and 4-chlorobenzaldehyde (12.52
g, 89.1 mmol) were dissolved in EtOH (30 mL) and H2O (10 mL)
and 10% aq NaOH (8 mL) were added. The mixture was stirred
overnight at r.t. The light-yellow crystals were removed by filtra-
tion, washed with 50% EtOH and dried in vacuo (14.82 g, 66.5
mmol, 83%); from the mother liquor, another crop (0.92 g, 4.1
mmol, 5%) of crystals was obtained. The product was obtained as
light-yellow crystals; combined yield: 15.74 g (70.7 mmol, 88%);
mp 85–86 °C (Lit.45 85–85.5 °C); Rf = 0.60 (PE–EtOAc, 5:1).
2-Benzyl-2-[(3,4-dimethoxybenzylidene)amino]-5-oxo-3-phe-
nylhexanenitrile (15c)
Under an argon atmosphere, 1c (250.3 mg, 0.850 mmol) was dis-
solved in anhyd THF (2.0 mL). After addition of DBU (133 mL,
0.892 mmol), the mixture was stirred for 1 min at r.t. Benzylidene-
acetone (14c, 124.4 mg, 0.851 mmol) in anhyd THF (0.5 mL) was
added and the mixture was stirred for 20 h at r.t. The mixture was
washed with sat. aq NaHCO3 (2 × 5 mL) and the combined aqueous
phases were extracted with EtOAc (2 × 5 mL). The combined or-
ganic layers were dried (Na2SO4) and the solvent was removed in
vacuo to furnish a viscous orange oil (418.9 mg, quant.) which was
subjected to the next step without further purification; Rf = 0.17
(PE–EtOAc, 4:1).
IR (ATR): 1678 (m), 1608 (m), 1487 (m), 1075 (s), 1004 (m), 983
(s), 815 (s), 776 (m), 524 (m), 488 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.59 (d, Jtrans = 15.6 Hz, 1 H, H1),
7.47 (AA¢-part of AA¢BB¢-system, 2 H, H2Ph, H6Ph), 7.32 (BB¢-part
of AA¢BB¢-system, 2 H, H3Ph, H5Ph), 7.07 (d, Jtrans = 15.6 Hz, 1 H,
H2), 1.20 [s, 9 H, C(CH3)3].
13C NMR, PENDANT (125.8 MHz, CDCl3): d = 203.9 (C=O),
141.4 (=CHAr), 136.0 (Cq), 133.4 (Cq), 129.4 (2 C), 129.1 (2 C),
121.1 (=CHCO), 43.3 [Cq, C(CH3)3], 26.2 [3 C, C(CH3)3].
2-Benzyl-5-methyl-3-phenyl-3,4-dihydro-2H-pyrrole-2-carbo-
nitrile (16c)
Under an argon atmosphere, crude 15c (402.7 mg) was dissolved in
THF (1.5 mL), H2O (1.5 mL) and AcOH (583 mL, 10.2 mmol) were
added and the mixture was stirred for 21.5 h at r.t. The mixture was
partitioned between sat. aq NaHCO3 (15 mL) and EtOAc (10 mL),
the aqueous layer was extracted with EtOAc (2 × 5 mL), the com-
bined organic layers were washed with H2O (10 mL) and dried
(Na2SO4), and the solvent was removed in vacuo to furnish a vis-
cous orange oil (351.2 mg). A portion (338.4 mg) of the crude prod-
uct was dissolved in EtOH (5 mL), Girard’s reagent T (257.6 mg,
1.536 mmol) and AcOH (5 drops) were added. After stirring for 22
h under an argon atmosphere at r.t., the mixture was partitioned be-
tween sat. aq NaHCO3 (15 mL) and EtOAc (10 mL). The aqueous
layer was extracted with EtOAc (2 × 5 mL) and the combined or-
ganic layers were washed with H2O (5 × 5 mL) and brine (10 mL)
and dried (Na2SO4), and the solvent was removed in vacuo to fur-
nish a viscous orange material (245.2 mg), which partially crystal-
lized and was subjected to the subsequent reaction without further
purification; Rf = 0.35 (PE–EtOAc, 2:1), ochre color (ninhydrin).
MS (FAB): m/z (%) = 223.2 (100) [M + H]+.
Anal. Calcd for C13H15ClO: C, 70.11; H, 6.79. Found: C, 70.26; H,
6.92.
3-(4-Chlorophenyl)-2,6,6-trimethyl-2-[(2-naphthylmethyl-
ene)amino]-5-oxoheptanenitrile (15d)
Under an argon atmosphere, 1a (249.0 mg, 1.12 mmol) was dis-
solved in anhyd THF (2 mL). After addition of TMG (158 mL, 1.26
mmol), the mixture was stirred for 1 min at r.t. A soln of 14d (267.1
mg, 1.2 mmol) in anhyd THF (0.5 mL) was quickly added and the
mixture was stirred for 6 h at r.t. The mixture was washed with sat.
aq NaHCO3 (5 mL), the combined aqueous layers were re-extracted
with EtOAc (2 × 5 mL). The combined organic layers were dried
(Na2SO4) and the solvent was removed in vacuo to furnish a light-
yellow oil (541.2 mg, quant.) which was subjected to the subsequent
reaction without further purification; yield: 541.2 mg (quant.);
Rf = 0.43 (PE–EtOAc, 5:1).
2-Benzyl-5-methyl-3-phenyl-1H-pyrrole (18c)
Under an argon atmosphere, crude 16c (217.6 mg, 0.793 mmol) was
dissolved in anhyd THF (2.0 mL) and KOt-Bu (93.5 mg, 0.833
mmol) was added. The mixture was stirred for 1.5 h at r.t. The dark
brown mixture was partitioned between sat. aq NaHCO3 (10 mL)
and EtOAc (5 mL) and the aqueous layer was extracted with EtOAc
(3 × 5 mL), the combined organic layers were washed with H2O
(4 × 5 mL) and dried (Na2SO4), and the solvent was removed in vac-
uo to furnish a light-brown foam (164.5 mg). A portion (153 mg) of
the crude product was purified by column chromatography (silica
gel, cyclohexane–EtOAc, 5:1) to furnish 18c (48.3 mg, 0.195
mmol) as a red-brown resin; yield over 3 steps: 30%; Rf = 0.45 (PE–
EtOAc, 5:1), spot turns pink in air.
5-tert-Butyl-3-(4-chlorophenyl)-2-methyl-3,4-dihydro-2H-pyr-
role-2-carbonitrile (16d)
Under an argon atmosphere, crude 15d (517.1 mg, 1.20 mmol) was
dissolved in THF (1.5 mL), H2O (1.5 mL) and AcOH (412 mL, 7.20
mmol) were added and the mixture was stirred for 16.5 h at r.t. The
mixture was partitioned between sat. aq NaHCO3 (10 mL) and
EtOAc (5 mL). The aqueous layer was extracted with EtOAc (2 × 5
mL), the combined organic layers were washed with H2O and brine
(10 mL each) and dried (Na2SO4), and the solvent was removed in
vacuo to furnish a yellow oil (428.8 mg). A portion (412.2 mg) of
the crude product was dissolved in EtOH (5 mL), Girard’s reagent
T (320.7 mg, 1.91 mmol) and AcOH (5 drops) were added and the
mixture was stirred for 18 h at r.t. The mixture was partitioned be-
tween sat. aq NaHCO3 (15 mL) and EtOAc (10 mL), the aqueous
layer was extracted with EtOAc (2 × 10 mL), the combined organic
IR (ATR): 1599 (m), 1492 (m), 1451 (m), 1439 (m), 760 (s), 730
(m), 695 (s), 648 (m), 525 (m), 459 cm–1 (m).
Synthesis 2011, No. 11, 1691–1704 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Pyrroles and Indolizidines
1701
layers were washed with H2O (4 × 10 mL) and brine (10 mL) and
dried (Na2SO4), and the solvent was removed in vacuo to furnish a
yellow oil (286.0 mg); Rf = 0.31 (PE–EtOAc, 5:1), pink color (nin-
hydrin).
15.44 mmol, 57%) as a light-yellow liquid. A small quantity of hy-
droquinone was added before concentration in vacuo. The product
was stored at –18 °C to prevent polymerization; Rf = 0.45 (PE–Et2O,
1:1).
1H NMR (300 MHz, CDCl3): d = 7.33 (AA¢-part of AA¢BB¢-sys-
tem, 2 H, H3Ph, H5Ph), 7.19 (BB¢-part of AA¢BB¢-system, 2 H, H2Ph,
H6Ph), 3.86 (t, J = 8.8 Hz, 1 H, CH), 3.11 (dd, J = 17.2, 8.6 Hz, 1 H,
CH2-Ha), 2.92 (dd, J = 17.2, 9.1 Hz, 1 H, CH2-Hb), 1.24 [s, 9 H,
C(CH3)3], 1.09 (s, 3 H, CH3).
IR (ATR): 1698 (m), 1678 (s), 1614 (m), 1401 (m), 1251 (m), 1201
(m), 984 (m), 963 (s), 559 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 6.35 (dd, J = 17.7, 10.5 Hz, 1 H,
H2), 6.22 (dd, J = 17.7, 1.2 Hz, 1 H, =CH2-Htrans), 5.83 (dd, J = 10.5
Hz, 1.2 Hz, 1 H, =CH2-Hcis), 3.41 (t, J = 6.6 Hz, 2 H, CH2Br), 2.63
(t, J = 7.1 Hz, 2 H, CH2CO), 1.93–1.84 (m, 2 H, CH2-6), 1.82–1.73
(m, 2 H, CH2-5).
13C NMR, PENDANT (100.7 MHz, CDCl3): d = 200.0 (C=O),
136.4 (=CH), 128.2 (=CH2), 38.4 (C4), 33.2 (C7), 32.1 (C6), 22.4
(C5).
5-tert-Butyl-3-(4-chlorophenyl)-2-methyl-1H-pyrrole (18d)
Under an argon atmosphere, crude 16d (205.1 mg, 0.746 mmol)
was dissolved in anhyd THF (2 mL), KOt-Bu (89.1 mg, 0.794
mmol) was added and the mixture was stirred for 50 min at r.t. The
brown mixture was partitioned between sat. aq NaHCO3 (10 mL)
and EtOAc (5 mL) and the aqueous layer was extracted with EtOAc
(3 × 5 mL). The combined organic layers were washed with H2O
(3 × 5 mL) and dried (Na2SO4), and the solvent was removed in
MS (EI): m/z (%) = 191 (3) [M]+, 111 (29) [M – Br]+, 55 (100)
[C3H5O]+.
1
vacuo to furnish a light-yellow oil (192.3 mg). H NMR indicated
(E)-9-Bromo-2-[(3,4-dimethoxybenzylidene)amino]-5-oxo-2-
phenylnonanenitrile (20)
the presence of unreacted starting material and a portion (177.3 mg)
of the crude product was dissolved in anhyd THF (1.7 mL), KOt-Bu
(87.9 mg, 0.783 mmol) was added and the mixture was stirred for
24 h at r.t. The workup procedure was repeated to furnish a light-
brown and partially crystalline material (148.6 mg), a portion
(139.0 mg) of which was purified by column chromatography (sili-
ca gel, PE–EtOAc, 8:1) to furnish a yellow oil (30.2 mg, 0.122
mmol) which still contained minor impurities; yield: 30.2 mg (0.122
mmol); yield over 3 steps: 18%; Rf = 0.41 (PE–EtOAc, 5:1).
1H NMR (300 MHz, DMSO-d6): d = 10.41 (br s, 1 H, NH), 7.33 (br
s, 4 H, Ph), 5.87 (d, J = 2.7 Hz, 1 H, =CH), 2.30 (s, 3 H, CH3), 1.24
[s, 9 H, C(CH3)3].
13C NMR (75.5 MHz, DMSO-d6): d = 139.7 (C4Ph), 136.6 (Cq),
128.2 (2 C), 127.8 (2 C), 122.9 (Cq), 117.0 (Cq), 101.5 (=CH), 30.9
[C(CH3)3], 30.3 [3 C, C(CH3)3], 12.6 (CH3).
Under an argon atmosphere, 1d (734.7 mg, 2.62 mmol) was dis-
solved in anhyd THF (7.5 mL). After addition of DBU (430 mL,
2.88 mmol), the mixture was stirred for 1 min at r.t. To the deep red
soln was added 19 (502.1 mg, 2.63 mmol) in anhyd THF (2.5 mL)
over 2 min. The orange-colored soln was stirred for 90 min at r.t.
Sat. aq NaHCO3 (50 mL) was added and the mixture was extracted
with EtOAc (4 × 25 mL). The combined organic layers were dried
(Na2SO4) and the solvent was removed in vacuo to furnish a light-
brown resin (1.195 g, 2.53 mmol, 97%) which was subjected to the
next step without further purification; Rf = 0.37 (PE–EtOAc, 2:1).
IR (ATR): 1510 (s), 1448 (m), 1420 (m), 1265 (s), 1239 (s), 1162
(m), 1139 (m), 1021 (s), 761 (m), 698 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 8.53 (s, 1 H, HC=N), 7.65–7.61
(m, 2 H, H2¢¢, H6¢¢), 7.48 (d, J = 1.9 Hz, 1 H, H2¢), 7.44–7.38 (m, 2
H, H3¢¢, H5¢¢), 7.37–7.32 (m, 2 H, H4¢¢, H6¢), 6.93 (d, J = 8.3 Hz, 1
H, H5¢), 3.97 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 3.34 (t, J = 6.6
Hz, 2 H, CH2-9), 2.55–2.48 (m, 4 H), 2.40 (td, J = 7.1, 2.3 Hz, 2 H),
1.82–1.74 (m, 2 H, CH2-8), 1.70–1.61 (m, 2 H, CH2-7).
13C NMR (100.7 MHz, CDCl3): d = 208.0 (C=O), 160.2 (HC=N),
152.4, 149.4 (C3¢/C4¢), 139.7 (C1¢¢), 128.9 (2 C, C3¢¢,5¢¢), 128.7
(C4¢¢), 128.0 (C1¢), 125.9 (2 C, C2¢¢, C6¢¢), 124.2 (C6¢), 118.9 (CN),
110.6 (C2¢), 109.5 (C5¢), 70.0 (CCN), 56.0, 56.0 (2 OCH3), 41.8
(C6), 37.9, 37.6, 33.1, 31.9, 22.1 (C7).
MS (ESI): m/z (%) = 264.15 (100) [M + OH]+, 247.1 (15) [M]+,
207.99 (18).
HRMS (ESI): m/z [M]+ calcd for C15H18ClN: 247.1128; found:
247.1132.
5-Bromopentanoyl Chloride46
In a flame-dried round bottom flask, 5-bromopentanoic acid (5.00
g, 27.6 mmol) was dissolved in anhyd benzene (10 mL) under an ar-
gon atmosphere. The mixture was warmed to 50 °C and oxalyl chlo-
ride (3.44 mL, 40.1 mmol) was added over 150 min. Stirring was
continued for a further 60 min at 50 °C and overnight at r.t. The sol-
vent and excess oxalyl chloride were removed in vacuo and the re-
sulting light-yellow liquid (5.41 g, 27.1 mmol, 98%) was used
without further purification.
MS (FAB): m/z (%) = 471.1 (72) [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C24H2879BrN2O3: 471.1283;
found: 471.1277.
rel-(3R,8aR)-3-Phenyloctahydroindolizine (21a) and
rel-(3R,8aS)-3-Phenyloctahydroindolizine (21b)
7-Bromohept-1-en-3-one (19)47
To a soln of 20 (1.17 g, 2.49 mmol) in THF (2 mL) was added H2O
(1 mL) and AcOH (900 mL, 15.7 mmol) and the mixture was stirred
for 2 h at r.t. EtOH (9.20 mL, 157 mmol) and NaCNBH3 (994.2 mg,
15.8 mmol) were added to the yellow mixture which was stirred for
17.5 h at r.t. Ethanolamine (2 mL) was added to destroy the borane–
amine complexes and stirring was continued for 6 h. The mixture
was partitioned between sat. aq NaHCO3 and EtOAc (80 mL each),
the aqueous layer was extracted with EtOAc (3 × 40 mL), the com-
bined organic layers were washed with half-sat. brine (2 × 80 mL)
and extracted with 1 M HCl (4 × 20 mL). The combined acidic ex-
tracts were made alkaline with sat. aq Na2CO3 (50 mL) and extract-
ed with Et2O (4 × 40 mL). The combined ethereal extracts were
dried (Na2SO4) and the solvent was removed in vacuo to furnish a
light-brown liquid (438.4 mg) which consisted of the diastereomer-
ic products 21a and 21b in a 1.2:1 ratio. Separation of both diaste-
reomers was achieved by column chromatography (silica gel, PE–
The title compound was synthesized according to a modified proce-
dure by Calas et al.,40 the workup was performed according to a pro-
cedure by Andersen et al.48 An argon-flushed flame-dried round-
bottom flask was charged with anhyd CH2Cl2 (32.5 mL) and AlCl3
(3.80 g, 28.5 mmol) The mixture was cooled to –20 °C and a soln
of trimethyl(vinyl)silane (2.72 g, 27.1 mmol) and 5-brompentanoyl
chloride (5.41 g, 27.1 mmol) was added over 45 min. Stirring was
continued for 105 min at –20 °C. The reaction was quenched by
pouring the mixture onto a mixture of ice and NH4Cl (100 g/20 g).
The aqueous phase was extracted with CH2Cl2 (2 × 60 mL) and the
combined organic layers were washed with sat. aq NaHCO3, H2O
and brine (60 mL each) and dried (Na2SO4); after the addition of a
small amount of hydroquinone, the solvent was removed in vacuo
to furnish an orange turbid liquid (5.22 g). Chromatographic purifi-
cation (silica gel, PE–EtOAc, 10:1 to 7:1) furnished 19 (2.95 g,
Synthesis 2011, No. 11, 1691–1704 © Thieme Stuttgart · New York

1702
I. Schäfer, T. Opatz
FEATURE ARTICLE
EtOAc, 5:1 + 1% Me2NEt) to furnish pure 21a (colorless liquid,
116.3 mg, 0.578 mmol, 24% over 2 steps) and pure 21b (colorless
liquid, 89.7 mg, 0.446 mmol, 18% over 2 steps).
1H NMR, COSY, HMBC (400 MHz, 100.6 MHz, CDCl3):
d = 7.58–7.54 (m, 2 H, H2Ph, H6Ph), 7.43–7.33 (m, 3 H, H3Ph, H5Ph,
H4Ph), 2.89 (ddd, J = 13.9, 10.3, 8.7 Hz, 1 H, H2a), 2.80 (td,
J = 11.9, 2.8 Hz, 1 H, H4a), 2.71 (mc, 1 H, H4b), 2.44 (ddd,
J = 12.6, 8.7, 1.9 Hz, 1 H, H1a), 2.27 (mc, 1 H, H7a), 2.19 (ddd,
J = 13.9, 9.8, 1.9 Hz, 1 H, H2b), 1.97 (dt, J = 12.6, 10.3 Hz, 1 H,
H1b), 1.91–1.83 (m, 1 H, H6a), 1.80–1.71 (m, 2 H, H5a, H6b),
1.68–1.60 (m, 1 H, H7b), 1.54–1.42 (m, 1 H, H5b).
13C NMR, HSQC, HMBC (100.7 MHz, 400 MHz, CDCl3):
d = 139.7 (C1¢), 129.0 (2 C, C3¢, C5¢), 128.9 (C4¢), 125.4 (2 C, C2¢,
C6¢), 117.9 (CN), 117.9 (CN), 67.0 (C3), 63.0 (C8a), 43.5 (C4),
39.4 (C2), 36.0 (C7), 35.7 (C1), 24.5 (C5), 20.9 (C6).
MS (EI): m/z (%) = 251 (50) [M]+, 224 (45), 197 (60), 174 (74) [M
– Ph]+, 122 (100), 106 (83), 82 (62), 78 (68), 55 (56), 51 (72), 41
(75).
HRMS (ESI): m/z [M + Na]+ calcd for C16H17NaN3: 274.1320;
found: 274.1331.
Major Diastereomer 21a
Rf = 0.83 (PE–EtOAc, 1:1), greenish color (ninhydrin).
IR (ATR): 2930 (m), 2787 (w), 1450 (w), 1257 (w), 1141 (w), 1120
(w), 1077 (w), 1047 (w), 755 (m), 698 (s), 543 cm–1 (w).
1H NMR, COSY, HMBC (400 MHz, 100.6 MHz, CD3OD):
d = 7.36–7.27 (m, 4 H, H2Ph, H6Ph, H3Ph, H5Ph), 7.25–7.20 (m, 1 H,
H4Ph), 3.12 (t, J = 8.5 Hz, 1 H, H3), 2.75 (pseudo-d, Japp ≈ 10.9 Hz,
1 H, H4a), 2.14–2.00 (m, 2 H, H2a, H8a), 1.94–1.74 (m, 4 H, H1a,
H5a, H7a, H4b), 1.71–1.61 (m, 1 H, H2b), 1.60–1.50 (m, 2 H, H6a,
H1b), 1.49–1.41 (m, 1 H, H5b), 1.40–1.25 (m, 2 H, H6b, H7b).
13C NMR, HSQC, HMBC (100.6 MHz, 400 MHz, CD3OD):
d = 143.8 (C1¢), 129.3 (2 C, C3¢, C5¢), 128.9 (2 C, C2¢, C6¢), 128.2
(C4¢), 71.9 (C3), 66.8 (C8a), 52.5 (C4), 32.8 (C2), 31.9 (C7), 30.4
(C1), 26.2 (C5), 25.4 (C6).
Compound 23
Rf = 0.67 (PE–EtOAc, 2:1).
MS (EI): m/z (%) = 201 (65) [M]+, 200 (76) [M – H]+, 172 (35) [M
– C2H4]+, 124 (100) [M – Ph]+.
1H NMR (400 MHz, MHz, CDCl3): d = 7.43–7.34 (m, 5 H, H2Ph,
H6Ph, H3Ph, H5Ph, NH), 7.28–7.23 (m, 1 H, H4Ph), 6.20 (d, J = 3.5
Hz, 1 H, H4), 5.94 (dt, J = 3.5, 1.1 Hz, 1 H, H3), 3.95 (t, J = 5.9 Hz,
2 H, CH2-4¢), 2.89 (t, J = 6.2 Hz, 2 H, CH2-1¢), 1.95–1.88 (m, 2 H,
CH2-3¢), 1.87–1.80 (m, 2 H, CH2-2¢). The spectrum showed the
presence of impurities.
13C NMR (100.7 MHz, CDCl3): d = 132.7 (Cq), 130.7 (Cq), 128.8
(2 C, Ph), 128.5 (2 C, Ph), 126.5 (C4Ph), 125.7 (Cq), 108.3 (=CH),
104.9 (=CH), 30.6, 24.3, 24.0, 21.2.
HRMS (ESI): m/z [M + 2 H]+ calcd for C14H21N: 203.1674; found:
203.1675.
Minor Diastereomer 21b
Rf = 0.24 (PE–EtOAc, 1:1), greenish color (ninhydrin).
IR (ATR): 2926 (m), 2850 (m), 1686 (w), 1455 (m), 1358 (w), 1306
(w), 1181 (w), 1136 (w), 1109 (w), 1065 (w), 1027 (w), 754 (m),
699 cm–1 (s).
1H NMR, COSY, HMBC (400 MHz, 100.6 MHz, CD3OD):
d = 7.35–7.29 (m, 2 H, H2Ph, H6Ph), 7.28–7.23 (m, 3 H, H3Ph, H5Ph,
H4Ph), 4.20 (dd, J = 8.4, 4.8 Hz, 1 H, H3), 2.83 (mc, 1 H, H8a), 2.70
(pseudo-d, Japp ≈ 12.3 Hz, 1 H, H4a), 2.34 (mc, 1 H, H2a), 2.18 (mc,
1 H, H1a), 2.00 (dt, J = 12.5, 3.2 Hz, 1 H, H4b), 1.96–1.88 (m, 1 H,
H2b), 1.80–1.66 (m, 2 H, H6a, H7a), 1.57 (mc, 2 H, H5a, H1b),
1.42–1.28 (m, 2 H, H5b, H7b), 1.27–1.16 (m, 1 H, H6b).
13C NMR, HSQC, HMBC (100.7 MHz, 400 MHz, CD3OD):
d = 142.6 (C1¢), 129.6 (2 C), 129.2 (2 C), 128.4 (C4¢), 65.6 (C3),
60.8 (C8a), 48.4 (C4), 31.3, 31.2 (C1/C2), 30.9 (C7), 25.3 (C6),
23.6 (C5).
HRMS (ESI): m/z [M]+ calcd for C14H1679BrN: 277.0466; found:
277.0476.
(E)-2-Benzyl-9-bromo-2-[(2-naphthylmethylene)amino]-
5-oxononanenitrile
Under an argon atmosphere, 1b (399.7 mg, 1.41 mmol) was dis-
solved in anhyd THF (4 mL) and DBU (231 mL, 1.55 mmol) was
added. The mixture was stirred for 1 min at r.t. before 19 (269.1 mg,
1.41 mmol) in anhyd THF (2.5 mL) was added over 1 min. Since
TLC revealed only incomplete conversion after 2 h stirring at r.t.,
another portion of 19 (49.0 mg, 0.256 mmol) was added and stirring
was continued for 70 min. To the dark-blue mixture was added sat.
aq NaHCO3 (30 mL) and the mixture was extracted with EtOAc
(4 × 15 mL). The combined organic layers were dried (Na2SO4) and
the solvent was removed in vacuo to furnish a brown resin (709.0
mg, quant.) which was subjected to the next step without further pu-
rification; Rf = 0.27 (PE–EtOAc, 5:1).
MS (EI): m/z (%) = 201 (58) [M]+, 200 (67) [M – H]+, 172 (35) [M
– C2H4]+, 124 (100) [M – Ph]+.
HRMS (ESI): m/z [M]+ calcd for C14H19N: 201.1517; found:
201.1515.
3-Phenyloctahydroindolizine-3,8a-dicarbonitrile (22) and
2-(4-Bromobutyl)-5-phenyl-1H-pyrrole (23)
IR (ATR): 1712 (m), 1638 (m), 1454 (m), 1371 (m), 1269 (m), 1241
(m), 820 (m), 752 (s), 701 (s), 476 cm–1 (s).
To a soln of 20 (137.0 mg, 0.291 mmol) in THF (1 mL) was added
H2O (1 mL) and AcOH (100 mL, 1.75 mmol). The mixture was
stirred for 17 h at r.t. before sat. aq NaHCO3 (10 mL) was added and
the mixture was extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with H2O and brine (10 mL each), dried
(Na2SO4) and the solvent was removed in vacuo. A portion (142.4
mg) of the resulting resin (149.8 mg) was purified by column chro-
matography (silica gel, PE–EtOAc, 4:1) to furnish 23 (5.0 mg,
0.018 mmol, 6%) as a light-yellow oil and 22 (23.5 mg, 0.094
mmol, 34%) as a light-orange oil.
1H NMR (400 MHz, CDCl3): d = 8.21 (s, 1 H, HC=N), 8.02 (br s, 1
H, H1Naphthyl), 7.99 (dd, J = 8.6, 1.6 Hz, 1 H, H3Naphthyl), 7.92–7.86
(m, 3 H, H4Naphthyl, H5Naphthyl, H8Naphthyl), 7.56 (tt, J = 12.6, 3.5 Hz, 2
H, H6Naphthyl, H7Naphthyl), 7.24–7.18 (m, 5 H, Ph), 3.32 (t, J = 6.6 Hz,
2 H, H2–H9), 3.22 (AB-system, J ≈ 13.6 Hz, 2 H, CH2Ph), 2.60–
2.29 (m, 6 H), 1.87–1.73 (m, 2 H), 1.71–1.61 (m, 2 H).
13C NMR, PENDANT (100.7 MHz, CDCl3): d = 208.1 (C=O),
161.5 (HC=N), 135.1 (Cq), 133.9 (Cq), 132.9 (Cq), 132.3 (Cq),
131.4, 130.9 (2 C), 128.8, 128.7, 128.2 (2 C), 127.9, 127.8, 127.5,
126.8, 123.6, 118.3 (CN), 68.2 (CCN), 46.4, 41.8, 37.9, 34.0, 33.1,
32.0, 22.1.
Compound 22
Rf = 0.42 (PE–EtOAc, 2:1); orange/green color (ninhydrin).
MS (FAB): m/z (%) = 475.2 (100) [M]+, 385.2 (45).
HRMS (FAB): m/z [M + H]+ calcd for C27H2879BrN2O: 475.1385;
IR (ATR): 2946 (m), 1447 (m), 1256 (m), 1210 (m), 1150 (m), 1140
(m), 1104 (m), 957 (m), 760 (s), 698 cm–1 (s).
found: 475.1387.
Synthesis 2011, No. 11, 1691–1704 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Pyrroles and Indolizidines
1703
rel-(3R,8aR)-3-Benzyloctahydroindolizine and
rel-(3R,8aS)-3-Benzyloctahydroindolizine (24a, 24b)
HRMS (ESI): m/z [M + H]+ calcd for C15H22N: 216.1752; found:
216.1761.
To a soln of crude (E)-2-benzyl-9-bromo-2-[(2-naphthylmethyl-
ene)amino]-5-oxononanenitrile (657.8 mg, 1.384 mmol) in THF (1
mL) was added H2O (0.5 mL) and AcOH (475 mL, 8.30 mmol) and
the mixture was stirred for 19 h at r.t. EtOH (4.9 mL, 83.5 mmol)
and NaCNBH3 (540.3 mg, 8.60 mmol) were added to the yellow
mixture which was stirred for another 3 h at r.t. Ethanolamine (1
mL) was added to destroy borane complexes and the mixture was
stirred for 75 min. After addition of sat. aq NaHCO3 (40 mL), the
brown mixture was extracted with EtOAc (4 × 20 mL), the com-
bined organic layers were washed with half-sat. brine (2 × 40 mL)
and extracted with 1 M HCl (5 × 15 mL). The combined acidic ex-
tracts were made alkaline by addition of sat. aq Na2CO3 and were
extracted with CH2Cl2 (5 × 20 mL). The combined organic layers
were dried (Na2SO4) and the solvent was removed in vacuo to fur-
nish a brownish liquid (99.6 mg). A portion (97.1 mg) of the crude
product was purified by column chromatography (silica gel, PE–
EtOAc, 6:1 + 1% Me2NEt) to yield 24a (37.5 mg, 0.174 mmol, 14%
over 2 steps) as a colorless liquid and 24b (30.1 mg, 0.140 mmol,
11% over 2 steps) also as a colorless liquid. Care should be taken to
prevent evaporation of the products during removal of solvent and/
or eluent in vacuo. The relative configuration of both products could
not be determined by ROESY experiments and attempts to obtain
single crystals of the salts failed.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft.
We thank I. Nevoigt (University of Hamburg) for the crystallogra-
phic analysis and Dr. S. Franke (late, University of Hamburg) and
Dr. N. Hanold (University of Mainz) for mass spectrometry.
References
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Compound 24a
Rf = 0.35 (PE–EtOAc, 6:1 + 1% Me2NEt), grayish color (ninhy-
drin).
IR (ATR): 2930 (m), 2856 (w), 2787 (w), 1495 (w), 1452 (m), 1362
(w), 1336 (w), 1273 (w), 1206 (s), 1139 (m), 1117 (m), 739 (m), 698
(s), 496 cm–1 (m).
1H NMR, COSY, HMBC (400 MHz, 100.6 MHz, CD3OD):
d = 7.26–7.23 (m, 2 H, H3Ph, H5Ph), 7.19–7.13 (m, 3 H, H2Ph, H6Ph,
H4Ph), 3.26 (mc, 1 H, H4a), 3.09 (dd, J = 11.4, 2.6 Hz, 1 H, PhCH2-
Ha), 2.46–2.35 (m, 2 H, PhCH2-Hb, H3), 2.00–1.90 (m, 2 H, H4b,
H8a), 1.80–1.76 (m, 2 H, H6a, H7a), 1.75–1.68 (m, 2 H, H1a, H6b),
1.66–1.53 (m, 2 H, H2a, H5a), 1.48–1.39 (m, 1 H, H2b), 1.38–1.33
(m, 1 H, H1b), 1.31–1.26 (m, 2 H, H5b, H7b).
13C NMR, HSQC, HMBC (100.7 MHz, 400 MHz, CD3OD):
d = 141.0 (C1¢), 130.1 (2 C, C2¢, C6¢), 129.4 (2 C, C3¢, C5¢), 127.2
(C4¢), 68.4 (C3), 67.2 (C8a), 52.9 (C4), 40.5 (CH2Ph), 31.7 (C7),
29.5 (C1), 29.2 (C2), 26.1 (C5), 25.4 (C6).
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HRMS (ESI): m/z [M + H]+ calcd for C15H22N: 216.1752; found:
216.1761.
(24) Balme, G. Angew. Chem. Int. Ed. 2004, 43, 6238.
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Compound 24b
Rf = 0.11 (PE–EtOAc, 6:1 + 1% Me2NEt), grayish color (ninhy-
drin).
IR (ATR): 2926 (m), 2851 (w), 1496 (w), 1451 (w), 1330 (w), 1196
(w), 1138 (w), 1115 (w), 1085 (w), 735 (m), 698 (s), 505 cm–1 (w).
1H NMR, COSY, HMBC (400 MHz, 100.6 MHz, CD3OD):
d = 7.27–7.23 (m, 2 H, H3Ph, H5Ph), 7.18–7.13 (m, 3 H, H2Ph, H6Ph,
H4Ph), 3.40 (ddd, J = 14.8, 8.2, 4.1 Hz, 1 H, H3), 3.07–2.98 [m, 2 H,
H4a, contained in this multiplet: 3.00 (dd, J = 12.9, 4.1 Hz, 1 H,
PhCH2-Ha)], 2.80 (mc, 1 H, H8a), 2.72–2.65 (m, 1 H, H4b), 2.35
(dd, J = 12.9, 10.7 Hz, 1 H, PhCH2-Hb), 1.94 (mc, 1 H, H7a), 1.81–
1.72 (m, 2 H, H2a, H5a), 1.70–1.65 (m, 1 H, H1a), 1.61–1.48 (m, 3
H, H2b, H5b, H6a), 1.42–1.33 (m, 2 H, H6b, H7b), 1.29–1.22 (m, 1
H, H1b).
13C NMR, HSQC, HMBC (100.7 MHz, 400 MHz, CD3OD):
d = 141.1 (C1¢), 130.3 (2 C, C2¢, C6¢), 129.5 (2 C, C3¢, C5¢), 127.1
(C4¢), 62.8 (C3), 60.9 (C8a), 48.2 (C4), 37.6 (CH2Ph), 31.0 (C1),
30.4 (C7), 28.2 (C2), 25.3 (C5), 24.1 (C6).
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