Synthesis and reactions of 2-[1-Methyl-1-(pyrrolidin-2-yl)ethyl]-1H-pyrrole and some derivatives with aldehydes: Chiral structures combining a secondary-amine group with an 1H-pyrrole moiety as excellent H-bond donor

Article abstract of DOI:10.1002/hlca.201200459

The synthesis of compound 2 and its derivatives 6 and 8 combining a pyrrolidine ring with an 1H-pyrrole unit is described (Scheme 2). Their attempted usability as organocatalysts was not successful. Reacting these simple pyrrolidine derivatives with cinnamaldehyde led to the tricyclic products 3b, 9b, and 10b first (Scheme 1, Fig. 2). The final, major products were the pyrrolo-indolizidine tricycles 3a, 9a, and 10a obtained via the iminium ion reacting intramolecularly with the nucleophilic β-position of the 1H-pyrrole moiety (cf. Scheme 1).

Full text of DOI:10.1002/hlca.201200459

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Synthesis and Reactions of 2-[1-Methyl-1-(pyrrolidin-2-yl)ethyl]-1H-pyrrole
and Some Derivatives with Aldehydes: Chiral Structures Combining a
Secondary-Amine Group with an 1H-Pyrrole Moiety as Excellent H-Bond
Donor
by Anca Pordeaa)1), Helen Stoeckli-Evansb), Claudio Dalvitc), Reinhard Neier*a)
a
´
ˆ
ˆ
) Institut de chimie, Universite de Neuchatel, Avenue Bellevaux 51, CH-2000 Neuchatel
(phone: þ 41(0)327182428; fax þ 41(0)327182511; e-mail: Reinhard.Neier@unine.ch)
b
´
ˆ
ˆ
) Institut de physique, Universite de Neuchatel, Avenue Bellevaux 51, CH-2000 Neuchatel
(phone: þ 41(0)327182426; e-mail: Helen.Stoeckli-Evans@unine.ch)
c
´
ˆ
ˆ
) Service analytique facultaire, Universite de Neuchatel, Avenue Bellevaux 51, CH-2000 Neuchatel
(phone: þ 41(0)327182435; e-mail: Claudio.Dalvit@unine.ch)
Dedicated to Professor Dieter Seebach on the occasion of his 75th birthday for his remarkable
contributions to chemistry
The synthesis of compound 2 and its derivatives 6 and 8 combining a pyrrolidine ring with an 1H-
pyrrole unit is described (Scheme 2). Their attempted usability as organocatalysts was not successful.
Reacting these simple pyrrolidine derivatives with cinnamaldehyde led to the tricyclic products 3b, 9b,
and 10b first (Scheme 1, Fig. 2). The final, major products were the pyrrolo-indolizidine tricycles 3a, 9a,
and 10a obtained via the iminium ion reacting intramolecularly with the nucleophilic b-position of the
1H-pyrrole moiety (cf. Scheme 1).
1. Introduction. – The re-discovery of the HajosꢀParrishꢀEderꢀSauerꢀWiechert
reaction [1] led to the realization that proline is a privileged skeleton for the synthesis
of chiral organocatalysts [2], capable of combining high selectivities with broad
applicability [3]. Proline, historically the first successful organocatalyst, displays a
simple design combining the pyrrolidine ring carrying a chiral center with an acidic or at
least strongly H-bond donating substituent. After the initial reports of the efficient use
of proline as chiral catalyst by two industrial laboratories [4], substantial efforts were
made to modify the structure of proline with the goal to obtain more selective catalysts
and to deepen our knowledge [5]. Combining an oversimplified, certainly incomplete,
mechanistic picture [3a][3e][6] with the ease with which the proline structure can be
tuned [6d][7] and then tested by a screening approach [8] has led to an ꢀexplosive
growth in this area since the year 2000ꢁ [6b][7b]. An essential part of the operationally
useful mechanistic picture is the inclusion of H-bonds as an important factor for
obtaining good enantioselectivities [3e][6a][6n][6o].
1
)
New address since 1 August, 2012: Department of Chemical & Environmental Engineering,
University of Nottingham, University Park, Nottingham NG72RD, UK (phone: þ 44(0)1159514640;
e-mail: Anca.Pordea@nottingham.ac.uk)
ꢂ 2012 Verlag Helvetica Chimica Acta AG, Zꢃrich

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H-Bonding interactions play a key role in various enzymatic mechanisms, by
participating both in electrophile activation and in substrate recognition [9]. Chemists
have also discovered that small organic H-bond-donor motifs can catalyze organic
transformations, in association or not with other functional groups [2b][10]. Urea and
thiourea derivatives have been successfully used as catalysts for the activation of imine
or carbonyl functionalities, via bidentate H-bonding interaction [2b][7e][7f][7-
h][10a – 10d][11]. Proline acts as a multifunctional catalyst: the secondary-amine
moiety activates the carbonyl group through nucleophilic enamine formation, while the
H-donating carboxylic acid group orients and activates the electrophile
[6a][6n][6o][10b]. The understanding of the simplified, empirically useful mechanism
of proline-catalyzed reactions was the starting point for the development of novel
organocatalysts bearing H-donor moieties. In addition, since the publications of
Barbas, List, MacMillan, and their co-workers on enantioselective organocatalysis
based on iminium and enamine formation [1a][1c], the pyrrolidine motif has been
widely used as a carbonyl activating organocatalyst, via iminium or enamine formation
[3e][12]. Structures containing a pyrrolidine moiety in conjunction with moieties
involved in H-bonding, such as 1H-imidazole, 1H-tetrazoles [13], pyridineamines, etc.,
have been proposed [14]. However, 1H-pyrroleꢀpyrrolidine structures have not yet
been envisaged.
Prompted by the results described in [15] and given the interesting H-bonding
properties observed with these structures [16], we decided to study the synthesis and
properties of simple pyrrolidine derivatives containing an 1H-pyrrole ring as potential
H-bond donor. The 1H-pyrrole has been included in the design of chiral catalysts by the
Jacobsen group fulfilling a structural role exclusively [10d][17]. To the best of our
knowledge, 1H-pyrroles have not been reported to be used as H-bond donors in the
design of organocatalysts.
During a project directed towards the understanding of N-containing macrocycles,
our group became interested in studying the hydrogenation of calix[4]pyrroles
[15a][15b]. The purpose of these efforts was to obtain fully saturated N-macrocycles
with a rigid skeleton and to test the properties of their metal complexes [18]. The
nontrivial hydrogenation of calix[4]pyrrole initiated a long lasting study of different
hydrogenation conditions and catalysts to optimize the formation and isolation of the
fully reduced calix[4]pyrrolidine. During the hydrogenation process, we observed the
formation of partially reduced macrocycles 1 containing alternating 1H-pyrro-
leꢀpyrrolidine structures, which to our surprise could not be further hydrogenated to
the completely saturated structure [15c]. Upon examination of the reactivity and of the

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X-Ray structure of the major stereoisomer of 1, we concluded that this partially
reduced macrocycle was characterized by an extraordinary tight intramolecular H-
bonding network, connecting the 1H-pyrrole NꢀH with the lone pair of the neighboring
pyrrolidine N-atom [15b]. We hypothesized that this network might be responsible for
the unusually low reactivity of the pyrrolidine unit, observed in preliminary studies
[19].
2. Results and Discussion. – Reaction of 2 with (E)-Cinnamaldehyde. The starting
point of this study is compound 2, which can be easily obtained by condensation of two
1H-pyrrole rings with one molecule of acetone, followed by heterogeneous hydro-
genation on Pd/C [16b]. In contrast to the calix[2]pyrrole[2]pyrrolidine macrocycle 1,
this structure only contains one stereogenic center and can be more easily modified at
the 1H-pyrrole ring, thus giving access to a family of molecules with modulated
properties. We intended to test the potential of the unmodified compound 2 to function
as organocatalyst in a series of well studied transformations, which have been
demonstrated to be successfully catalyzed by proline. We also planned to modify 2 in
the a-position of the 1H-pyrrole moiety thereby modifying the electronic properties of
the 1H-pyrrole ring.
We tested 1 first. As expected, 1 did not show any reactivity towards iminium
formation under the conditions tested by us. This is certainly due to the low reactivity of
the pyrrolidine moiety buried inside the macrocycle and ꢀprotectedꢁ by the H-bond
network [15c]. This result is in accordance with the partial or even total protection of
the pyrrolidine rings in the macrocycle 1 against many acylation conditions [15c][19].
When we tested compound 2 as organocatalyst for the Michael addition of
nitromethane or dimethyl malonate to (E)-cinnamaldehyde (¼(2E)-3-phenylprop-2-
enal), preliminary results showed no trace of product formation [20]. The DielsꢀAlder
reaction between (E)-cinnamaldehyde and cyclopentadiene in the presence of 2 was
also unsuccessful. Therefore, we concentrated our efforts on studying the reactivity of
the 1H-pyrroleꢀpyrrolidine system towards iminium formation. We chose (E)-
cinnamaldehyde as reagent for the condensation reaction, so as to minimize the risk
of aldol condensation during our studies. To our surprise, we observed the formation of
one major product, which was identified by NMR spectroscopy as the pyrroloindo-
lizidine tricycle 3a, when mixing 2 and (E)-cinnamaldehyde in stoichiometric amounts
in anhydrous toluene at room temperature (Scheme 1). Molecular sieves were used to
remove H2O formed during the reaction and to ensure complete transformation. Upon
careful investigation of the literature, we found one report of a similar intramolecular
cyclization reaction, starting from a 1H-pyrroleꢀoxazolidinone system [21]. The
reactivity of 1H-pyrrole towards iminium ions or enamines is known; however,
reactions taking place at the a-position of the 1H-pyrrole seem to be generally
preferred according to the published results [20][22]. Similarly to the results published
by Sisti and co-workers [21], also our cyclization reaction was diastereoselective, with
the protons HꢀC(7) and HꢀC(1’) being cis2). The 2D-ROESY technique was used to
determine the relative configuration of compound 3a. We suggest that the diaster-
eoselectivity of the reaction is probably due to the conformationally preferred
2
)
Arbitrary atom numbering; for systematic names, see Exper. Part.

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Scheme 1. Reaction between 2 and (E)-Cinnamaldehyde, Leading to the Formation of the Cyclized
Products 3a and 3b
equatorial arrangement of both the 1-methyl-1-(1H-pyrrol-2-yl)ethyl and the phenyl-
ethenyl moiety.
It is likely that 3a is obtained by intramolecular electrophilic substitution by the
iminium ion intermediate at the electron-rich 1H-pyrrole system. The product can be
tentatively interpreted as a hint for the occurrence of the iminium ion followed by the
reaction with the electron rich heterocycle. Unfortunately the intramolecular reaction
with the electrophilic 1H-pyrrole ring seems to be faster than the intended
intermolecular transformations needed for the organocatalytic cycle.
Following the course of the reaction in deuterated benzene at room temperature in
the NMR tube, no 1H-NMR signal corresponding to the iminium ion could be observed
(expected at d(H) ca. 8 ppm), thus suggesting that the cyclization reaction is too fast to
be observed by NMR under these conditions. On the other hand, the time-dependent
NMR experiment showed the formation of a second cyclization product, which we
identified as the regioisomer 3b in which the substitution is located at the N-atom of the
1H-pyrrole (Fig. 1). The reaction reached equilibrium after 3.5 h. After this time, the
conversion reached 96%, with formation of compound 3a in 85% yield and of its
regioisomer 3b in 6% yield, and of an additional, not yet completely identified minor
compound in 5% yield (see Supporting Information3)). In our hands, separation of the
three reaction products by column chromatography (neutral alumina) proved to be
very difficult, and we characterized the mixture by 1D and 2D 1H-NMR spectroscopy.
3
)
Supporting Information is available from the corresponding author.

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Fig. 1. Comparison of the reactions between 2 and (E)-cinnamaldehyde, in the presence and in the absence
1
of CF3COOH. The reaction time course was followed by H-NMR in C6D6 at r.t.
GC/MS Analysis of the mixture showed the presence of two products with identical
molecular mass and nearly the same retention time, corresponding to isomers 3a and
3b, as well as of the additional by-product with a different retention time.
In the published report by Sisti and co-workers, trifluoroacetic acid (CF3COOH)
was shown to promote intramolecular cyclization between an oxazolidinone and a N-
methyl substituted 1H-pyrrole [21]. In our case, addition of 1 equiv. of CF3COOH
slightly increased the initial reaction rate and allowed the reaction to reach completion.
The rate of the reaction became slower after the first 1.5 h. Most importantly, the
reaction in the presence of CF3COOH proved to be completely regioselective. Only the
presence of the pyrroloindolizine 3a arising from cyclization at the b-position of the 1H-
pyrrole could be observed during the reaction (Fig. 1).
Acceleration of the condensation reaction in the presence of CF3COOH could be
explained by acid-promoted iminium formation. In our case, the 1H-pyrrole NH of 2
could be responsible for this activation, which could explain the relatively small
influence of CF3COOH on the reaction. When (E)-cinnamaldehyde was treated with
pyrrolidine in C6D6 at room temperature, in the absence of CF3COOH, no iminium
signal was detected by NMR, and the reaction proceeded to an equilibrium, with
formation of the hemiaminal intermediate in a 1:1 ratio with the starting material.
Addition of 1 equiv. of 1H-pyrrole had no influence on this equilibrium. Normally it is
assumed that iminium formation between the pyrrolidine ring and (E)-cinnamalde-
hyde should occur under acid catalysis. Since the reaction between (E)-cinnamalde-
hyde and the 1H-pyrroleꢀpyrrolidine compound 2 proceeds smoothly, it is likely that

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the NH of the 1H-pyrrole moiety provides the acidic protons necessary to for iminium
formation.
Synthesis and Reactivity of the Deactivated 1H-Pyrrole Compounds 6 and 8. To
reduce the nucleophilicity of the 1H-pyrrole ring, we synthesized substituted 1H-
pyrroleꢀpyrrolidine structures bearing electron-attracting substituents at position 5 on
the 1H-pyrrole ring and tested their reactivity in the reaction with (E)-cinnamalde-
hyde. During our studies, we became aware of the work of Thompson and co-workers
[23], who tested different conditions for the synthesis of substituted dimethyldipyrro-
methane (¼2,2’-(1-methylethylidene)bis[1H-pyrrole] derivatives; an unusual cycliza-
tion reaction took place during the condensation of 1H-pyrrole rings with methyl
ketone electrophiles, during which the N-atom of the 1H-pyrrole underwent alkylation
with an electrophilic intermediate. In this study it was reported that 1H-pyrroles
deactivated by conjugation with an electron withdrawing ester group did not undergo
such an unusual cyclization [23]. Therefore, we proceeded to a-substitution at the 1H-
pyrrole moiety of 2 with electron-withdrawing groups, with the purpose of slowing
down the cyclization process and of promoting nucleophilic attack of the iminium
intermediate by other nucleophiles present in the system, thereby hopefully creating
compounds suitable for organocatalysis. Moreover, we hypothesized that an electron-
withdrawing group might enhance the acidity of the 1H-pyrrole NH, and therefore its
H-bonding capacity [24].
We first proceeded to the introduction of a trifluoromethyl substitution at the a-
position of the 1H-pyrrole moiety of 2 by a method developed by Togni and co-workers
(Scheme 2) [25]. Pyrrolidine protection (!4) and deprotection steps were necessary,
and the benzyl group was chosen for this purpose, due to the ease of removal at the end
of the reaction (5 ! 6). The corresponding trifluoromethyl-substituted ꢀdimethylpyrro-
pyrrolidinylmethaneꢁ (¼2-[1-methyl-1-(pyrrolidin-2-yl)ethyl]-1H-pyrrol) 6 could be
analyzed by X-Ray diffraction, showing tight packing due to H-bonding between the
1H-pyrrole and the pyrrolidine units, as already reported for 2 (see Exper. Part) [16b].
Treatment of the CF3-substituted 1H-pyrrole 6 with (E)-cinnamaldehyde in
toluene afforded the cyclized regio- and diastereoiosomer 9a almost exclusively.
1
Following the reaction course by H-NMR in C6D6 at room temperature showed first
the formation of the N-cyclized regioisomer 9b, which then equilibrated to the C-
cyclized regioisomer 9a (Fig. 2). This suggests that the N-cyclization is under kinetic
control, while the C-cyclized product is thermodynamically favored. The starting
material 6 was completely consumed at the end of the reaction, while 9a was obtained
in 95% yield, as determined by 1H-NMR. A third product, which could not be
1
completely identified by H-NMR, was formed in 5% yield, while no trace of the N-
cyclized 9b could be observed at the end of the reaction. Addition of CF3COOH
disfavored the N-cyclized product, which formed in a smaller amount and disappeared
faster than in the absence of CF3COOH. Moreover, the reaction proceeded slower in
the presence of CF3COOH.
Introduction of the electron withdrawing CF3 substituent at the a-position of the
1H-pyrrole (!6) showed no significant effect on the total reaction rate. However, the
regioselectivity of the reaction was enhanced in the presence of the CF3-substituent,
and the reaction proceeded to complete consumption of the starting material as
compared to the unsubstituted 2.

Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 2. Synthesis of Compounds 6 and 8
2255
We then tested the effect of a carboxylate ester substitution at the a-position of the
1H-pyrrole moiety of 2, which deactivates the 1H-pyrrole by conjugation and
introduces at the same time a supplementary H-bond acceptor [26]. Compound 7
was prepared by a known procedure, involving introduction of a trichloroacetyl
substituent, followed by substitution of the CCl3 group by MeO (Scheme 2) [27].
Removal of the benzyl protecting group afforded compound 8. When 8 was treated
with (E)-cinnamaldehyde in C6D6 at room temperature, the reaction proceeded much
slower than in the case of 2 and 6, with initial formation of the N-cyclized regioisomer
10b in up to 46% yield in the first 5 h, followed by its decrease over the next 56 h and its
equilibration into the C-cyclized regioisomer 10a. After 56 h we stopped following the
reaction. The transformation was not complete, and the equilibrium was not reached:
only 74% of the starting material 8 was transformed. The reaction was less
diastereoselective in this case, and the C-cyclized diastereoisomer 10c was formed in
20% yield only. Addition of 1 equiv. CF3COOH greatly decreased the reaction rate of
the formation of all three compounds 10a – 10c (Fig. 3). This result was encouraging,
because it established that the cyclization preference could be reversed, due to

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Fig. 2. Time course for the formation of compounds 3a and 3b, 9a and 9b, and 10a, 10b, and 10c followed
by 1H-NMR
deactivating substitutions at position 5 of the 1H-pyrrole ring of 2. However, an
attempt to use compound 8 as organocatalyst in the reaction between (E)-
cinnamaldehyde and dimethyl malonate or nitromethane did not afford the desired
Michael addition product neither.
3. Conclusions. – The present study describes an easy access to three compounds of
a novel structural type combining a basic pyrrolidine ring with 1H-pyrrole as good H-
bond donor linked by a quaternary C-center. Our 1H-NMR studies showed that these
compounds 2, 6, and 8 react with (E)-cinnamaldehyde in an intramolecular fashion.
The reaction products 3b, 9b and 10b formed first retained the oxidation state of the
aldehyde C-atom and, therefore, resemble the oxazolidinones isolated from the

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Fig. 3. Time course for the formation of compounds 10a – 10c in the absence and in the presence of
CF3COOH
reaction between the doubly silylated proline and pivaldehyde [6e]. Depending on the
substituent at the 5 position of the 1H-pyrrole, these products were then irreversibly
transformed into the thermodynamically more stable products 3a, 9a, and 10a by an
intramolecular Mannich-type reaction with the electrophilic 3 position of their 1H-
pyrrole moiety. This intramolecular reaction of the iminium C-atom from cinnamalde-
hyde with the electrophilic C(3)-atom of the 1H-pyrrole moiety corresponds to one of
the reaction types observed intermolecularly in organocatalytic transformations. The
formation of the products 3a, 9a, and 10a was diastereoselective and thermodynami-
cally controlled. The structure of the minor products 3c, 9c and 10c was attributed
tentatively to the other diastereoisomer. The presence of the strong acid CF3COOH
accelerated the transformation of compound 2, whereas the transformation of 6 and 8
was slowed down by CF3COOH.
The diversity of reaction pathways opened up by the activation of C¼O compounds
by secondary-amine moieties such as typically in proline or imidazolidinone derivatives
is overwhelming. The mechanistic intricacies are slowly deciphered and show a much
more complex picture than the mechanistic rules of thumb, which have been used
successfully to optimize the screening process used for the development of many of the
reactions published in the literature. The success of organocatalysis is a testimony to the
utility of simplified mechanistic proposals and to the efficiency of effective analytical
screening methods. For our new structures 2, 6, and 8, we identified the reactivity
needed for a catalytic process; a parasitic intramolecular reaction between the iminium

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ion formed from cinnamaldehyde and these pyrrolidine compounds blocked catalytic
conversions. Modification of the electronic properties of the 1H-pyrrole moiety
influenced the path of the reaction in a way predicted by the electronic properties of the
substituents. We did not yet discover reaction conditions or substituent patterns
allowing the use of our type of molecules in organocatalysis, despite the fact that the
inherent reactivity needed for a catalytic cycle was demonstrated.
ˆ
The authors thank Dr. Armelle Vallat, University of Neuchatel, for recording mass spectra and Fredy
Nydegger, University of Fribourg, for recording HR-MS. This work was financially supported by the
ˆ
Swiss National Science Foundation (grant 200020_124696) and the University of Neuchatel.
Experimental Part
General. All the reagents were purchased from commercial sources and used as such, unless specified
in the literature describing their syntheses. Solvents for extraction and chromatography were of anal.
grade. Column chromatography (CC): 63 – 200 mesh SiO2 (Brunschwig). Anal. TLC: SiO2 plates with
QF-254 indicator (Merck); detection by UV light (254 nm) and/or after treatment with phosphomolybdic
acid. M.p.: Gallenkamp apparatus; uncorrected. IR Spectra: Fourier-transform spectrophotometer
Perkin Elmer Spectrum One, version B; in cmꢀ1 1H- and 13C-NMR Spectra: DPX-400-Bruker
.
spectrometer at r.t. for 1D plots and Avance-400-Bruker spectrometer at 238 with typically a mixing
time of 300 or 400 ms for ROESY; d in ppm rel. to SiMe4, J in Hz. ESI-MS: Finnigan-LCQ mass
spectrometer; in m/z (rel %). Anal. GC-MS: Polaris-Q-Trace GC instrument (Finnigan) fitted with a
flame-ionization detector (H2 carrier gas, 1 ml minꢀ1, detector temp. 3008) and a ZB-5MS column
(30 m ꢁ 0.25 mm ꢁ 0.25 mm), and MS acquired in EI mode (70 eV); in m/z (rel %).
2-[1-Methyl-1-(pyrrolidin-2-yl)ethyl)-1H-pyrrole (2) [16b]. In an autoclave vessel were introduced
2,2’-(1-methylethylidene)bis[1H-pyrrole] [16a] (2 g, 11.5 mmol, 1 equiv.), 10% Pd/C (524 mg,
0.043 equiv. Pd), and MeOH/AcOH 4 :1 (v/v; 100 ml). The suspension was stirred for 20 h at r.t. under
65 bar H2. Then the Pd/C was filtered on Celite, the Celite pad washed with CH2Cl2 (3ꢁ), and the
combined filtrate concentrated to give a yellow slurry to which 2m NaOH (175 ml) and CH2Cl2 (100 ml)
were added. The aq. phase was extracted with CH2Cl2 (3ꢁ), the combined org. phase dried (K2CO3) and
concentrated, and the resulting residue purified by CC(SiO2; AcOEt/MeOH/Et3N 95 :5 :1: 1.665 g (81%)
of 2. Colorless crystals. M.p. 758. IR (KBr): 3413w, 3150.4m, 3081.5m, 2966.4s, 2872.3s, 1618.4w, 1566.8m,
1452.5w, 1423.4s, 1070.2s, 946.2s, 880.1m, 725.7s, 714.4s. 1H-NMR (CDCl3): 10.3 (br. s, HꢀN(1));
6.69 – 6.66 (m, HꢀC(5)); 6.14 – 6.09 (m, HꢀC(4)); 5.96 – 5.92 (m, HꢀC(3)); 3.11 (t, J ¼ 8.1, HꢀC(2’’));
2.91 – 2.88 (m, CH2(5’’)); 2.04 (br. s, HꢀN(1’’)); 1.78 – 1.72 (m, CH2(3’’)); 1.66 – 1.56 (m, CH2(4’’)); 1.33 (s,
Me); 1.25 (s, Me); 1.23 – 1.17 (m, 1 H, CH2)3’’)). 13C-NMR (CDCl3): 139.4 (C(2)); 116.0 (C(5)); 106.4
(C(4)); 103.8 (C(3)); 68.9 (C(2’’)); 46.7 (C(5’’)); 37.2 (Me2C(1’)); 29.4 (Me); 26.9 (C(3’’)); 25.8 (C(4’’));
24.8 (Me). ESI-MS: 217.2 (30, [M þ K]þ), 207.2 (20), 201.2 (50, [M þ Na]þ), 179.2 (100, [M þ H]þ). HR-
ESI-MS: 179.1544 (C11H18Nþ2 , [M þ H]þ; calc. 178.1470).
2-{1-Methyl-1-[1-(phenylmethyl)pyrrolidin-2-yl]ethyl}-1H-pyrrole (4). To a soln. of 2 (3.175 g,
17.8 mmol, 1 equiv.) in EtOH (42 ml) was added K2CO3 (5.17 g, 35.6 mmol, 2.1 equiv.) and benzyl
bromide (2.12 ml, 17.8 mmol, 1 equiv.), and the soln. was stirred overnight. The EtOH was evaporated,
and AcOEt and H2O were added. The aq. phase was extracted twice with AcOEt (2ꢁ), the combined
org. phase dried (Na2SO4) and concentrated, and the crude product purified by CC(SiO2, cyclohexane/
AcOEt 95 :5): 4 (4.04 g, 85%). Yellow oil. IR (KBr): 3397.6s (br.), 3061.9w, 3027.8w, 2964.8s, 2868.2s,
2799.5m, 1556.9m, 1494.8w, 1452.7m, 1381.7w, 1334.2w, 1107.9m, 1070.2m, 1030.5m, 785.6m, 718.9s,
699.2s. 1H-NMR (CDCl3): 9.76 (br. s, HꢀN(1)); 7.48 – 7.41 (m, 4 H, Ph); 7.37 – 7.35 (m, 1 H, Ph);
6.73 – 6.72 (m, HꢀC(5)); 6.16 – 6.15 (m, HꢀC(4)); 6.00 – 5.98 (m, HꢀC(3)); 4.17 (d, J ¼ 13.1, 1 H, PhCH2);
3.54 (d, J ¼ 13.1, 1 H, PhCH2); 2.86 (dd, J ¼ 8.85, 5.5, HꢀC(2’’)); 2.79 – 2.73 (m, 1 H, CH2(5’’)); 2.47 – 2.41
(m, 1 H, CH2(5’’)); 1.97 – 1.88 (m, 1 H, CH2(3’’)); 1.62 – 1.53 (m, 1 H, CH2(4’’)); 1.52 – 1.45 (m, 1 H,
CH2(3’’)); 1.55 (s, Me); 1.34 (s, Me); 1.16 – 1.08 (m, 1 H, CH2(4’’)). 13C-NMR (CDCl3): 140.7 (Cipso); 138.9

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(C(2)); 128.5 (CH(Ph)); 128.45 (CH(Ph)); 127.0 (CH)Ph)); 116.5 (C(5)); 106.8 (C(4)); 104.2 (C(3));
74.8 (C(2’’)); 63.6 (PhCH2); 54.9 (C(5’’)); 39.0 (Me2C(1’)); 29.7 (Me); 28.9 (C(3’’)); 25.2 (Me); 24.2
(C(4’’)). EI-MS: 269.13 (10, [M þ H]þ), 267.12 (10, [M ꢀ H]þ), 160.1 (25, [M ꢀ C4H3NHC(Me)2]þ), 91.12
(100, PhCHþ2 ). HR-ESI-MS: 269.2013 (C18H25Nþ2 , [M þ H]þ; calc. 269.2012).
2-{1-Methyl-1-[(phenylmethyl)pyrrolidin-2-yl]ethyl}-5-(trifluoromethyl)-1H-pyrrole (5). According
to [25]: A suspension of 4 (413 mg, 1.54 mmol, 1 equiv.) and 1-(trifluoromethyl)-1,2-benziodoxol-3(1H)-
one (730 mg, 2.3 mmol, 1.5 equiv.) in anh. MeCN (5 ml) was stirred under N2 at 408 for 18 h. The brown-
red soln. was concentrated and CH2Cl2 (20 ml) added. The org. phase was washed successively with sat.
NaHCO3 and NaCl solns. (20 ml of each), dried (Na2SO4), and concentrated and the resulting crude
product purified by CC(SiO2, cyclohexane/AcOEt 98 :2): 5 (290 mg, 56%). Yellow oil. IR (KBr): 3294.1s
(br.), 3025.2m, 2969.9s, 2868.3m, 2806.7w, 1608.4w, 1577.6w, 1504.8s, 1451.7m, 1321.7s, 1236.7m, 1149.7s,
1102.5s, 1037.8w, 943.6m, 783.1s, 732.9m, 699.8m. 1H-NMR (CDCl3): 10.9 (br. s, HꢀN(1)); 7.41 – 7.38 (m,
4 H, Ph); 7.33 – 7.30 (m, 1 H, Ph); 6.45 (s, HꢀC(4)); 5.95 (s, HꢀC(3)); 4.24 (d, J ¼ 13, 1 H, PhCH2); 3.58 (d,
J ¼ 13, 1 H, PhCH2); 2.86 (dd, J ¼ 8.6, 6.2, HꢀC(2’’)); 2.74 (dt, J ¼ 10.5, 6.1, 1 H, CH2(5’’)); 2.45 (dt, J ¼
10.5, 6.7, 1 H, CH2(5’’)); 1.97 – 1.88 (m, 1 H, CH2(3’’)); 1.61 – 1.51 (m, 1 H, CH2(4’’)); 1.49 (s, Me); 1.40 –
1.32 (m, 1 H, CH2(4’’)); 1.29 (s, Me); 1.17 – 1.07 (m, 1 H, CH2(3’’)). 13C-NMR (CDCl3): 142.2 (C(2));
140.2 (Cipso); 128.6 (CH(Ph)); 127.9 (CH(Ph)); 127.1 (CH(Ph)); 121.7 (q, J ¼ 266, CF3); 118.9 (q, J ¼ 39,
C(5)); 108.5 (q, J ¼ 2.9, C(4)); 105.2 (C(3)); 74.8 (C(2’’)); 63.4 (PhCH2); 54.8 (C(5’’)); 38.8 (Me2C(1’));
30.4 (Me); 29.0 (C(3’’)); 24.9 (Me); 24.1 (C(4’’)). EI-MS: 337.18 (12, [M þ H]þ), 250.22 (12), 160.1 (100,
[M ꢀ CF3C4H2NHC(Me)2]þ), 91.6 (29, PhCH2þ ). HR-ESI-MS: 337.1882 (C19H24F3Nþ2 , [M þ H]þ; calc.
337.1886).
2-[1-Methyl-1-(pyrrolidin-2-yl)ethyl]-5(trifluoromethyl)-1H-pyrrole (6). To a soln. of 5 (851 mg,
2.53 mmol, 1 equiv.) in EtOH (50 ml) was added 10% Pd/C (134 mg, 0.05 equiv. Pd), and the suspension
was shaken under 2 bar H2 at r.t. overnight. The mixture was then filtered on Celite, the Celite pad
thoroughly washed with EtOH, the solvent evaporated, and the crude product purified by CC (basic
alumina, 0.5% MeOH/CH2Cl2): 192 mg (31%) of 6. Colorless-yellowish crystals. M.p. 508. IR (KBr):
3280w, 3137.4w, 3100m, 2967.6s, 2877.4s, 1700.1w, 1595.2w, 1501.1s, 1366.3m, 1349.3s, 1254m, 1174.9m,
1155.9s, 1112.6s, 945.5s, 853.3m, 768.2m. 1H-NMR (CDCl3): 11.2 (br. s, HꢀN(1)); 6.40 (s, HꢀC(4)); 5.9 (s,
HꢀC(3)); 3.13 (t, J ¼ 8.0, HꢀC(2’’)); 2.94 – 2.88 (m, CH2(5’’)); 2.1 (br. s, HꢀN(1’’)); 1.85 – 1.71 (m, 1 H,
CH2(3’’)); 1.71 – 1.47 (m, CH2(4’’)); 1.32 (s, Me); 1.23 (s, Me); 1.17 – 1.03 (m, 1 H, CH2(3’’)). 13C-NMR
(CDCl3): 142.8 (C(2)); 121.7 (q, J ¼ 266, CF3); 118.4 (q, J ¼ 39, C(5)); 108.3 (q, J ¼ 2.9, C(4)); 104.9
(C(3)); 68.6 (C(2’’)); 46.5 (C(5’’)); 37.2 (Me2C(1’)); 29.7 (Me); 27.0 (C(3’’)); 25.8 (C(4’’)); 24.6 (Me). ESI-
MS: 247.1 (100, [M þ H]þ), 227.2 (10, [M ꢀ F]þ). HR-ESI-MS: 247.1414 (C12H17F3Nþ2 , [M þ H]þ; calc.
246.1344).
Crystal Structure Analysis of 64) (Figs. 4 and 5). Suitable crystals of 6 were obtained as colorless rods
by slow evaporation of a soln. of 6 in pentane. The intensity data were collected at 173K (ꢀ1008) with a
Stoe-Mark-II image plate diffraction system [28] equiped with a two-circle goniometer and with MoKa
graphite-monochromated radiation (l 0.71073 ꢄ). Image plate distance 130 mm, w rotation scans 0 –
1808 at f 08, and 0 – 1688 at f ¼ 908, step Dw ¼ 1.08, exposures of 3 min per image, 2q range 1.76 –
52.598, dmin – dmax ¼ 23.107 – 0.802 ꢄ. The structure was solved by direct methods with the programme
SHELXS-97 [29]. The refinement and all further calculations were carried out with SHELXL-97 [29].
The NH H-atoms were located in a difference Fourier map and were freely refined. The C-bound H-
atoms were included in calculated positions and treated as riding atoms: CꢀH ¼ 0.95, 0.99, 0.98, and
1.00 ꢄ for CH(arom), CH2, Me, and CH(methine), resp., with Uiso(H) ¼ k · Ueq (parent C-atom), where
k ¼ 1.5 for Me H-atoms and k ¼ 1.2 for all other H-atoms. The non-H atoms were refined anisotropically,
with weighted full-matrix least-squares on F2. A semi-empirical absorption correction was applied with
the MULscanABS routine in PLATON [30].
Methyl 5-{1-Methyl-1-[1-(phenylmethyl)pyrrolidin-2-yl]ethyl}-1H-pyrrole-2-carboxylate (7). Ac-
cording to [27a] for the trichloroacetylation of the 1H-pyrrole moiety [27a] and to [27b] for the ester
formation: A soln. of 4 (218 mg, 0.8 mmol, 1 equiv.) in anh. THF (1.5 ml) was slowly added to a soln. of
4
)
CCDC-907947 contains the supplementary crystallographic data for this paper. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif.

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Helvetica Chimica Acta – Vol. 95 (2012)
Fig. 4. The molecular structure and crystallo-
graphic numbering scheme of the compound
6. Displacement ellipsoids at the 50% prob-
ability level.
Fig. 5. Crystal packing of compound 6, viewed along the b-axis
showing the formation of the NꢀH ··· N H-bonded square formed
by two inversion-related molecules. H-bonds are shown as dashed
cyan lines; the C-bound H-atoms are omitted for clarity.
trichloroacetyl chloride (0.1 ml, 0.9 mmol, 1.1 equiv.) in anh. THF (1 ml) and the resulting yellow-brown
soln. was stirred at r.t. under N2. After 10 min, a precipitate formed, and the mixture was stirred for a
total of 1.5 h at r.t.. Then the precipitate was collected by filtration, washed with cold Et2O (4ꢁ) and
dried under vacuum, to afford 304 mg (92%) of a white solid, which was used without further
purification. The solid (265 mg, 0.64 mmol) was dissolved in anh. MeOH, MeONa (90 mg, 1.66 mmol,
2.6 equiv.) was added in two portions (initially and after 3 h), and the mixture was stirred for 5 h at r.t.
under N2. Then additional MeONa (45 mg, 0.83 mmol, 1.3 equiv.) was added, and the mixture was stirred
at 408 for 18 h. The solvent was evaporated, and H2O (20 ml) and AcOEt (20 ml) were added. The aq.
phase was extracted with AcOEt (3ꢁ), the combined org. phase dried (Na2SO4), and the solvent
evaporated: 7 (140 mg, 59% over 2 steps). Yellow oil, which was used for the next step without further
purification. IR (KBr): 3338.9s (br.), 2965.2s, 2868.3m, 2806.7w, 1694.7s, 1560.8m, 1488.5m, 1314.7m,
1244.8m, 1194.4m, 1155.2m, 1104.9m, 1034.8m, 1004.3m, 929.3m, 791.3s, 763.0s, 698.9s. 1H-NMR
(CDCl3): 10.75 (br. s, HꢀN(1)); 7.48 – 7.37 (m, 4 H (Ph)); 7.26 – 7.32 (m, 1 H (Ph)); 6.84 – 6.83 (m,
HꢀC(3)); 6.02 – 6.01 (m, HꢀC(4)); 4.16 (d, J ¼ 13.7, 1 H, PhCH2); 3.82 (s, COOMe); 3.57 (d, J ¼ 13.7, 1 H,
PhCH2); 2.85 (dd, J ¼ 8.6, 5.9, HꢀC(2’’)); 2.81 (m, 1 H, CH2(5’’)); 2.41 (dt, J ¼ 10.4, 6.8, 1 H, CH2(5’’));
1.96 – 1.85 (m, 1 H, CH2)3’’)); 1.58 – 1.49 (m, 1 H, CH2(4’’)); 1.45 (s, Me); 1.42 – 1.34 (m, 1 H, CH2(3’’));
1.29 (s, Me); 1.18 – 1.08 (m, 1 H, CH2(4’’)). 13C-NMR (CDCl3): 161.5 (COOMe); 144.6 (C(5)); 140.3
(Cipso); 128.5 (CH(Ph)); 128.0 (CH(Ph)); 126.9 (CH(Ph)); 121.2 (C(2)); 114.7 (C(3)); 107.1 (C(4)); 74.6
(C(2’’)); 63.4 (PhCH2); 54.9 (C(5’’)); 51.1 (COOMe); 39.2 (Me2C(1’)); 29.6 (Me); 29.0 (C(3’’)); 24.7
(Me); 24.2 (C(4’’)). ESI-MS: 363.3 (10), 349.2 (50, [M þ Na]þ), 327.3 (100, [M þ H]þ). HR-ESI-MS:
327.2069 (C20H27N2O2þ, [M þ H]þ; calc. 327.2067).
Methyl 5-[1-Methyl-1-(pyrrolidin-2-yl)ethyl]-1H-pyrrole-2-carboxylate (8). To a soln. of 7 (140 mg,
0.43 mmol, 1 equiv.) in EtOH (20 ml) was added 10% Pd/C (45 mg, 0.1 equiv. Pd), and the suspension
was shaken under 2 bar H2 at r.t. overnight. The mixture was then filtered on Celite, the Celite pad
thoroughly washed with CH2Cl2, the solvent evaporated, and the crude product purified by CC (neutral
alumina gel, 0.5% MeOH/CH2Cl2): 72 mg (72%) of 8. Yellow paste. IR (KBr): 3342.5s (br.), 2966.6s,

Helvetica Chimica Acta – Vol. 95 (2012)
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2869.4s, 1701.3s, 1559.3m, 1489.9s, 1463.7m, 1317.5m, 1231m, 1160.2m, 1103.5m, 1039.2m, 1002.9m,
929.4m, 791.7m, 764.9s. 1H-NMR (CDCl3): 11.1 (br. s, HꢀN(1)); 6.79 (d, J ¼ 3.7, HꢀC(3)); 5.96 (d, J ¼ 3.7,
HꢀC(4)); 3.81 (s, MeO); 3.11 (t, J ¼ 8.2, HꢀC(2’’)); 2.91 (t, J ¼ 6.7, CH2(5’’)); 1.83 (br. s, HꢀN(1’’)); 1.80 –
1.71 (m, 1 H, CH2)3’’)); 1.68 – 1.50 (m, CH2(4’’)); 1.30 (s, Me); 1.23 (s, Me); 1.16 – 1.06 (m, 1 H, CH2(3’’)).
13C-NMR (CDCl3): 161.8 (COOCH3), 145.3 (C(5)); 120.9 (C(2)); 114.5 (C(3)); 106.8 (C(4)); 68.4
(C(2’’)); 51.0 (MeO); 46.6 (C(5’’)); 37.6 (Me2C(1’)); 29.3 (Me); 27.1 (C(3’’)); 25.9 (C(4’’)); 24.5 (Me). EI-
MS: 237.01 (10, [M þ H]þ), 134.08 (15), 70.1 (100, C4H8Nþ). HR-ESI-MS (pos.): 237.1596 (C13H20N2Oþ2 ,
[M þ H]þ; calc. 236.1525).
Compounds 3a and 3b (racemic). To a soln. of 2 (150 mg, 0.84 mmol, 1 equiv.) in anh. toluene
(0.2 ml) and molecular sieves Fluka 4 ꢄ was added a soln. of (E)-cinnamaldehyde (127 mg, 0.96 mmol,
1.14 equiv.) in toluene (0.65 ml), and the mixture was stirred at r.t. overnight under N2. Then the solvent
was evaporated, the product dissolved in CH2Cl2, and the solvent evaporated (procedure repeated 5 ꢁ ),
to yield a yellow solid (215 mg, 88%) as a mixture of starting materials, 3a, 3b, and a not completely
1
identified by-product (ratio 3a/3b 14 :1 by H-NMR). The crude mixture was purified by CC (neutral
alumina, 1% MeOH/CH2Cl2; then basic alumina, CH2Cl2): 3a (74 mg, 30%). Due to its low ratio in the
crude mixture and to the difficulty of the purification, 3b was characterized only by 1D and 2D 1H-NMR
of the crude mixture.
(4RS,8aSR)-4,6,7,8,8a,9-Hexahydro-9,9-dimethyl-4-[(1E)-2-phenylethenyl]-1H-pyrrolo[3,2-f]indoli-
zine (3a): Orange solid. 1H-NMR (C6D6): 7.29 (d, J ¼ 7.3, 2 Ho); 7.09 (t, J ¼ 7.45, 2 Hm); 7.03 (t, J ¼ 7.1, Hp);
6.75 (br. s, HꢀN(1)); 6.68 (d, J ¼ 15.8, PhCH¼CH); 6.44 (dd, J ¼ 15.8, 8.6, PhCH¼CH); 6.31 (t, J ¼ 2.6,
HꢀC(2)); 6.13 (t, J ¼ 2.6, HꢀC(3)); 3.98 (d, J ¼ 8.6, HꢀC(4)); 3.32 (t, J ¼ 8.1, CH2(6)); 2.53 – 2.49 (m, 1 H,
HꢀC(8a)); 2.26 – 2.20 (m, CH2(6)); 1.75 – 1.65 (m, 1 H, CH2(7)); 1.65 – 1.53 (m, 3 H, CH2(8), CH2(7));
1.27 (s, Me); 0.97 (s, Me). 13C-NMR (C6D6): 137.9 (Cipso); 134.8 (C(9a)); 134.5 (PhCH¼CH); 130.6
(PhCH¼CH); 128.7 (2 Cm); 127.3 (Cp); 126.8 (2 Co); 118.3 (C(3a)); 116.8 (C(2)); 105.8 (C(3)); 70.5
(C(8a)); 66.5 (C(4)); 53.7 (C(6)); 34.8 (C(9)); 25.0 (Me); 24.0 (C(8)); 23.6 (Me); 22.9 (C(7)).
(5RS,10aRS)-2,3,10,10a-Tetrahydro-10,10-dimethyl-5-[(1E)-2-phenylethenyl]-1H,5H-dipyrrolo[1,2-
c :2’,1’-f]pyrimidine (3b): 1H-NMR (C6D6): 7.25 (d, J ¼ 7.5, 2 Ho); 7.03 – 7.09 (n/d, 3 H, 2 Hm, Hp); 6.61 (dd,
J ¼ 2.8, 1.7, 1 HꢀC(7)); 6.52 (d, J ¼ 16, PhCH¼CH); 6.41 (n/d, HꢀC(8)); 6.23 (dd, J ¼ 16, 8.3,
PhCH¼CH); 6.2 (dd, J ¼ 3.4, 1.7, HꢀC(9)); 4.42 (d, J ¼ 8.3, HꢀC(5)); 2.96 (m, 1 H, CH2(3)); 2.36 (m,
HꢀC(10a)); 1.94 (m, 1 H, CH2(3)); 1.55 (m, CH2(2)); 1.54 – 1.47 (m, CH2(1)); 1.29 (s, Me); 1.00 (s, Me).
Reaction Mixture 3a/3b: ESI-MS: 293.3 (100, [M þ H]þ), 224.3 (60).
Compounds 9a and 9b (racemic). To a soln. containing 6 (25 mg, 0.1 mmol, 1 equiv.) in anh. toluene
(1 ml) was added (E)-cinnamaldehyde (13.2 mg, 0.1 mmol, 1 equiv.), and the mixture was stirred at r.t.
overnight. Then the solvent was evaporated, the product dissolved in CH2Cl2, and the solvent evaporated
(procedure repeated 5 ꢁ ), to yield a yellow solid (37 mg, 98%). The product was 95% pure, as
determined by 1H-NMR. The 1H-NMR spectrum of the 5% by-product could not be completely
determined, but presented a pattern similar to the two regioisomers 9a and 9b. We tentatively propose
that the by-product is the diastereoisomer of 9a. Compound 9b was observed as an intermediate during
the reaction (see Supporting Material3)) and was identified by 1D and 2D 1H-NMR.
(4RS,8aSR)-4,6,7,8,8a,9-Hexahydro-9,9-dimethyl-4-[(1E)-2-phenylethenyl]-2-(trifluoromethyl)-1H-
pyrrolo[3,2-f]indolizine (9a): 1H-NMR (C6D6): 7.78 (br. s, HꢀN(1)); 7.26 (d, J ¼ 7.0, 2 Ho); 7.10 (t, J ¼ 7.0,
2 Hn); 7.05 (t, J ¼ 7.2, Hp); 6.57 (d, J ¼ 15.8, PhCH¼CH); 6.43 (q, J ¼ 1.1, HꢀC(3)); 6.23 (dd, J ¼ 15.8, 8.7,
PhCH¼CH); 3.75 (d, J ¼ 8.7, HꢀC(4)); 3.21 (t, J ¼ 8.3, 1 H, CH2(6)); 2.34 (t, J ¼ 8.1, HꢀC(8a)); 2.12 – 2.10
(m, 1 H, CH2(6)); 1.69 – 1.58 (m, 1 H, CH2(7)); 1.57 – 1.44 (m, 3 H, CH2(8), CH2(7)); 1.11 (s, Me); 0.74 (s,
Me). 13C-NMR (C6D6): 139.1 (C(9a)); 137.4 (Cipso); 132.8 (PhCH¼CH); 131.6 (PhCH¼CH); 128.8 (2 ꢁ
Cm); 127.7 (Cp); 126.9 (2 ꢁ Co); 122.4 (q, J ¼ 266, CF3); 119.7 (C(3a)); 119.0 (q, J ¼ 39.2, C(2)); 108.3 (q,
J ¼ 3, C(3)); 70.1 (C(8a)); 66.7 (C(4)); 53.5 (C(6)); 34.9 (C(9)); 24.1 (Me); 23.8 (C(8)); 23.1 (Me); 22.8
(C(7)).
(5RS,10aRS)-2,3,10,10a-Tetrahydro-10,10-dimethyl-5-[(1E)-2-phenylethenyl]-7-(trifluoromethyl)-
1H,5H-dipyrrolo[1,2-c :2’,1’-f]pyrimidine (9b): 1H-NMR (C6D6): 7.22 (d, J ¼ 7.5, 2 Ho); 7.07 – 7.05 (m,
2 Hm, Hp); 6.78 (d, J ¼ 3.9, HꢀC(8)); 6.61 (d, J ¼ 15.6, PhCH¼CH); 6.11 (dd, J ¼ 15.6, 8.1, PhCH¼CH);
5.9 (d, J ¼ 3.9, HꢀC(9)); 4.85 (d, J ¼ 8.1, HꢀC(5)); 2.95 (t, J ¼ 7.3, 1 H, CH2(3)); 2.28 – 2.22 (m,
HꢀC(10a)); 1.96 – 1.89 (m, 1 H, CH2(3)); 1.45 – 1.40 (m, CH2(1), CH2(2)); 1.32 (s, Me); 1.10 (s, Me).

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Helvetica Chimica Acta – Vol. 95 (2012)
Reaction Mixture 9a/9b: ESI-MS: 361.5 (100, [M þ H]þ), 292.4 (20, [M ꢀ CF3 þ H]þ).
Reaction of 2, 6, or 8 in the Presence and in the Absence of CF3COOH, Followed by NMR. To a soln.
of 2, 6, or 8 (0.015 mmol, 1 equiv.) in C6D6 (0.5 ml) was added (E)-cinnamaldehyde (0.2 ml of a 0.0825m
stock soln. in C6D6, 0.0165 mmol, 1.1 equiv.), in an NMR tube, and the reaction was followed by NMR at
r.t. For the reactions in the presence of CF3COOH, 0.2 ml of a CF3COOH stock soln. in C6D6 (0.075m,
0.015 mmol) were added instead of 0.2 ml of C6D6.
Methyl (4RS,8aSR)-4,6,7,8,8a,9-Hexahydro-9,9-dimethyl-4-[(1E)-2-phenylethenyl]-1H-pyrrolo[3,2-
1
f]indolizine-2-carboxylate (10a): H-NMR (C6D6): 8.98 (br. s, HꢀN(1)); 7.26 – 7.25 (m, 2 Ho); 7.13 – 7.10
(m, 2 Hm); 7.03 – 6.98 (m, Hp); 6.94 (br. s, HꢀC(3)); 6.60 (d, J ¼ 15.8, PgCH¼CH); 6.31 (dd, J ¼ 15.8, 8.6,
PhCH¼CH); 3.81 (d, J ¼ 8.6, HꢀC(4)); 3.52 (s, MeO); 3.24 – 3.20 (m, 1 H, CH2(6)); 2.38 – 2.35 (m,
HꢀC(8a)); 2.17 – 2.08 (m, 1 H, CH2(6)); 1.66 – 1.56 (m, 1 H, CH2(7)); 1.52 – 1.47 (m, 1 H, CH2(7)); 1.53 –
1.44 (m, 2 H, CH2(8)); 1.15 (s, Me); 0.81 (s, Me).
Methyl (5RS,10aRS)-2,3,10,10a-Tetrahydro-10,10-dimethyl-5-[(1E)-2-phenylethenyl]-1H,5H-dipyr-
rolo[1,2-c :2’,1’-f]pyrimidine-7-carboxylate (10b): 1H-NMR (C6D6): 7.27 (d, J ¼ 4, HꢀC(8)); 7.21 – 7.20 (m,
2 Ho); 7.03 – 7.00 (m, 2 Hm, Hp); 6.93 (d, J ¼ 15.8, PhCH¼CH); 6.20 (dd, J ¼ 15.8, 7.09, PhCH¼CH); 6.00
(d, J ¼ 4, HꢀC(9)); 5.80 (d, J ¼ 7.09, HꢀC(5)); 3.4 (s, MeO); 3.09 – 3.05 (m, 1 H, CH2(3)); 2.45 – 2.42 (m,
HꢀC(10a)); 2.18 – 2.10 (m, 1 H, CH2(3)); 1.52 – 1.47 (m, 1 H, CH2(2)); 1.43 – 1.37 (m, 1 H, CH2(2));
1.41 – 1.35 (m, 2 H, CH2(1)); 1.36 (s, Me); 1.09 (s, Me).
Methyl (4RS,8aSR)-4,6,7,8,8a,9-Hexahydro-9,9-dimethyl-4-[(1E)-2-phenylethenyl]-1H-pyrrolo[3,2-
f]indolizine-2-carboxylate (10c): 1H-NMR (C6D6): 7.31 (d, J ¼ 4, HꢀC(3)); 7.14 (m, 2 Ho); 7.03 – 6.98 (m,
2 Hm, Hp); 6.86 (d, J ¼ 6.8, HꢀC(4)); 6.49 (d, J ¼ 15.8, PhCH¼CH); 6.30 (dd, J ¼ 15.8, 6.8, PhCH¼CH);
3.41 (s, MeO); 2.97 – 2.93 (m, HꢀC(8a)); 2.83 – 2.79 (m, 1 H, CH2(6)); 2.52 – 2.50 (m, 1 H, CH2(6)); 1.52 –
1.47 (m, 1 H, CH2(7)); 1.35 – 1.30 (m, 1 H, CH2(7)); 1.38 – 1.35 (m, CH2(8)); 1.25 (s, Me); 1.19 (s, Me).
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Received August 13, 2012