3,4-Dihydro-2H-pyrrole-2-carbonitriles: Useful Intermediates in the Synthesis of Fused Pyrroles and 2,2′-Bipyrroles

Article abstract of DOI:10.1021/acs.joc.6b00393

Various heterocyclic structures containing the pyrrole moiety have been synthesized from easily accessible 3,4-dihydro-2H-pyrrole-2-carbonitriles in one-pot procedures. 5,6,7,8-Tetrahydroindolizines, 2,3-dihydro-1H-pyrrolizines as well as 6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepines were obtained from these precursors in high yields in an alkylation/annulation sequence. The same conditions were applied in the synthesis of a 5,8-dihydroindolizine, which could easily be transformed to the corresponding indolizine by dehydrogenation. Furthermore, oxidative couplings of 3,4-dihydro-2H-pyrrole-2-carbonitriles with copper(II)-salts furnished 2,2′-bipyrroles as well as 5,5′-bis(5-cyano-1-pyrrolines), depending on the reaction conditions. Overall, these methods give high yielding access to a variety of pyrrole-containing heterocyles in two steps from commercially available starting materials.

Full text of DOI:10.1021/acs.joc.6b00393

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Article
3,4-Dihydro-2H-pyrrole-2-carbonitriles – Useful Intermediates
in the Synthesis of Fused Pyrroles and 2,2’-Bipyrroles
Marco Mathias Nebe, Murat Kucukdisli, and Till Opatz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00393 • Publication Date (Web): 21 Apr 2016
Downloaded from http://pubs.acs.org on April 22, 2016
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3,4-Dihydro-2H-pyrrole-2-carbonitriles – Useful Intermediates
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in the Synthesis of Fused Pyrroles and 2,2’-Bipyrroles
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Marco M. Nebe, Murat Kucukdisli, and Till Opatz*
Institute of Organic Chemistry, University of Mainz, Duesbergweg 10ꢀ14, Dꢀ55128
Mainz, Germany
E-mail: opatz@uni-mainz.de
Abstract
Various heterocyclic structures containing the pyrrole moiety have been synthesized
from easily accessible 3,4ꢀdihydroꢀ2Hꢀpyrroleꢀ2ꢀcarbonitriles in one pot procedures.
5,6,7,8ꢀTetrahydroindolizines, 2,3ꢀdihydroꢀ1Hꢀpyrrolizines as well as 6,7,8,9ꢀtetrahydroꢀ
5Hꢀpyrrolo[1,2ꢀa]azepines were obtained from these precursors in high yields in an
alkylation/annulation sequence. The same conditions were applied in the synthesis of a
5,8ꢀdihydroindolizine, which could easily be transformed to the corresponding indolizine
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by dehydrogenation. Furthermore, oxidative couplings of 3,4ꢀdihydroꢀ2Hꢀpyrroleꢀ2ꢀ
carbonitriles with copper(II)ꢀsalts furnished 2,2’ꢀbipyrroles as well as 5,5’ꢀbis(5ꢀcyanoꢀ1ꢀ
pyrrolines), depending on the reaction conditions. Overall, these methods give high
yielding access to a variety of pyrroleꢀcontaining heterocyles in two steps from
commercially available starting materials.
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Introduction
The pyrrole ring is a ubiquitous heteroaromatic system found in countless natural
products1ꢀ4 as well as in synthetic drugs,5ꢀ7 which can exert antimicrobial,8ꢀ12 antiviral13ꢀ17
as well as antitumor activity.18ꢀ22 Pyrrole substructures are also contained in more
complex heterocyclic systems found in nature such as the lamellarins,23,24 the
polygonatines,25 (−)ꢀrhazinilam,26 (−)ꢀchlorizidine A (Figure 1).27 Likewise, there are also
interesting synthetic “embedded” pyrroles such as the nonsteroidal antiꢀinflammatory
drug ketorolac28 or analogues of the cytotoxic antibiotic mitomycin.29 Frequently
occurring structural frameworks are the 5,6,7,8ꢀtetrahydroindolizine or the 2,3ꢀdihydroꢀ
1Hꢀpyrrolizine ring system. The development of new synthetic methods for the
preparation of these compounds has seen considerable progress in recent years30ꢀ36
and 5,6,7,8ꢀtetrahydroindolizines are now often being utilized as a key intermediate in
the total synthesis of fully saturated indolizidine alkaloids.37ꢀ40 Commonly applied
strategies for the synthesis of 5,6,7,8ꢀtetrahydroindolizines or 2,3ꢀdihydroꢀ1Hꢀ
pyrrolizines are condensation reactions,34,41,42 Lewis acid36,43,44 or transition metal
catalyzed
cyclizations,30,31,45ꢀ47
hydroacylations
or
hydroaminations,33,48,49
cycloadditions50,51 as well as the reduction of indolizines.32,35 However, most of these
methods are limited to the preparation of only one class of the mentioned compounds.
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Herein, we report modular one pot procedures for the synthesis of
5,6,7,8ꢀtetrahydroindolizines, 2,3ꢀdihydroꢀ1Hꢀpyrrolizines and 6,7,8,9ꢀtetrahydroꢀ5Hꢀ
pyrrolo[1,2ꢀa]azepines as well as of 2,2’ꢀbipyrroles and 5,5’ꢀbis(5ꢀcyanoꢀ1ꢀpyrrolines)
from readily available 3,4ꢀdihydroꢀ2Hꢀpyrroleꢀ2ꢀcarbonitriles as the common precursors.
The starting materials can conveniently be prepared in one step from commercially
available substrates in up to 90% yield.52,53 To the best of our knowledge, no access to
these compound classes of similar brevity and diversity from commercially available
substrates has been reported so far.
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Figure 1. Biologically relevant compounds containing indolizines or pyrrolizines
Results and Discussion
3,4ꢀDihydroꢀ2Hꢀpyrroleꢀ2ꢀcarbonitriles 1 can be obtained in a single step from
commercially available aminoacetonitrile hydrochloride by condensation with enones via
a 6πꢀelectrocyclization.52 This reaction was successfully employed in the synthesis of
pyrroleꢀ2ꢀcarboxylates and lamellarin alkaloids.54,55 Cyanopyrrolines of this type can also
be transformed to the corresponding pyrroles 2 or pyrroleꢀ2ꢀcarbonitriles 3 by
dehydrocyanation or dehydrogenation as well as to the corresponding pyrrolizidines 4 by
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base catalyzed MichaelꢀAddition with subsequent reductive amination.52,56 Their
αꢀalkylation produces 5ꢀalkylated cyanopyrrolines which can be transformed to the
corresponding 1Hꢀpyrroles 5 in situ by further addition of base.53 Here, we report
oxidative dimerizations of compounds 1 as a simple entry to 2,2’ꢀbipyrroles 6, or 5,5’ꢀ
bis(5ꢀcyanoꢀ1ꢀpyrrolines) 7 as well as a consecutive intramolecular annulation reaction
with α,ωꢀdihalide electrophiles to furnish pyrroleꢀfused bicyclic structures 8 with variable
ring size and a bridgehead nitrogen atom (Scheme 1).
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Scheme 1. Transformations of 5ꢀcyanoꢀ1ꢀpyrrolines 1 to various heterocycles
Addition of a slight excess of LDA to a solution of 3,4ꢀdihydroꢀ2Hꢀpyrroleꢀ2ꢀcarbonitriles
1 provides Liꢀsalts 9 which were reacted with several αꢀbromoꢀωꢀchloroalkanes 10 to
provide the respective 5ꢀcyanoꢀ5ꢀ(ωꢀchloroalkyl)ꢀ1ꢀpyrrolines 11. These can be
transformed to the bicyclic structures 8 by reaction with additional LDA in situ
(Scheme 2). αꢀBromoꢀωꢀchloroalkanes 10 were employed, exploiting the different
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reactivities of the respective leaving group, since it was anticipated that side reactions
like dimerization would occur if the respective dichloroꢀ or dibromocompounds were
used (vide infra).
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Scheme 2. Proposed reaction course in the synthesis of compounds 8
Since 5ꢀalkylꢀ5ꢀcyanoꢀ1ꢀpyrrolines react to pyrroles in the presence of LDA (weaker
bases like KHMDS are unsuitable),53 the annulation step might well proceed via the
intermediate 1Hꢀpyrroles 12 which thereupon react in a nucleophilic Exo-Tet cyclization.
This hypothesis is supported by LCꢀMSꢀdata indicating the intermediate occurrence of
compound 12 during the course of the reaction. Using this simple annulation strategy,
various 2,4ꢀdisubstituted pyrroles fused to saturated 5ꢀ, 6ꢀ and 7ꢀmembered rings could
be obtained (Table 1).
Table 1. Synthesis of heterobicycles 8a–qa
Entry
Pyrroline
R1
R2
n
Method
t (h)
Product
Yield (%)
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1
1a
1a
1a
1a
1b
1b
1b
1c
1c
1d
1d
1e
1e
1f
Ph
Ph
2
2
A
B
A
A
A
A
A
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A
A
A
A
A
A
A
A
A
A
A
2
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8a
8a
8b
8c
8d
8e
8f
88
52
97
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88
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53
79
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71
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17
ꢀ
2
Ph
Ph
3
Ph
Ph
1
2
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Ph
Ph
3
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Ph
4ꢀCN–C6H4
4ꢀCN–C6H4
4ꢀCN–C6H4
2,3ꢀCl–C6H3
2,3ꢀCl–C6H3
Ph
2
6
Ph
1
1
7
Ph
3
20
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Ph
2
8g
8h
8i
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Ph
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2
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2ꢀNaph
2ꢀNaph
2ꢀNaph
2ꢀNaph
4ꢀF–C6H4
4ꢀF–C6H4
4ꢀF–C6H4
4ꢀF–C6H4
Me
2
2
Ph
1
2
8j
2ꢀBr–C6H4
2ꢀBr–C6H4
2ꢀCl–C6H4
2ꢀCl–C6H4
4ꢀOMe–C6H4
4ꢀOMe–C6H4
Ph
2
2.5
2.5
1
8k
8l
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2
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8n
8o
8p
8q
-
1f
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1
1g
1g
1h
1i
2
1
1
1
2
2
4ꢀCl–C6H4
3ꢀNO2–C6H4
1,2,3
ꢀ
aReaction conditions: method A: cyanopyrroline 1 (0.5 mmol), THF (10 mL), LDA (0.6 mmol), alkylhalide
10 (0.6 mmol), −78 °C → rt, 1 h, then LDA (1.2 mmol), −78 °C → rt, reaction time stated in the table;
method B: cyanopyrroline 1 (0.5 mmol), THF (10 mL), LDA (1.8 mmol), alkylhalide 10 (0.6 mmol), −78 °C
c
→ rt, 2 h; a complex reaction mixture was obtained; no desired product or intermediate could be
observed.
The reactions leading to 5ꢀ or 6ꢀmembered fused rings generally proceeded smoothly
with high to excellent yields when αꢀbromoꢀωꢀchloroalkanes were used as electrophiles.
For the annulation reactions providing 7ꢀmembered rings, i.e. 6,7,8,9ꢀtetrahydroꢀ5Hꢀ
pyrrolo[1,2ꢀa]azepines, the obtained yields were slightly lower but still satisfactory
(entries 4 and 7). It is beneficial to execute these reactions in a stepwise manner
(method A) since lower yields were encountered for the synthesis of 8a by only a single
addition of LDA at the beginning of the reaction (method B, 88% vs. 52% yield; entries 1
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and 2). Likewise, lower yields and large amounts of byproducts were found when
1,4ꢀdichlorobutane (21% yield) as well as 1,4ꢀdibromobutane (27% yield, determined by
1H NMR) were applied as electrophile. We assume that the lower leaving group
tendency of chloride and the resulting higher activation energy needed for the Cꢀ
alkylation step promotes side reactions of intermediate anion 9 when 1,4ꢀdichlorobutane
was used. In contrast to bromide 10a, the electrophilic reactivity of 1,4ꢀdichlorobutane
should not differ significantly from intermediate 11a which can also lead to undesired
dimerization reactions. LCꢀMS data obtained during the reaction supports this
assumption. The latter consideration similarly applies to the reactions employing 1,4ꢀ
dibromobutane and significant amounts of byproducts resulting from dimerization (21%)
along with 2ꢀ(butꢀ3ꢀenꢀ1ꢀyl)ꢀ3,5ꢀdiphenylꢀ1Hꢀpyrrole (21%) resulting from HBrꢀelimination
from intermediate 11a could be isolated. When the general reaction conditions were
applied to pyrroline 1h carrying an aliphatic substituent R1, the yield was notably lower
(17%) than for the arylꢀsubstituted cyanopyrrolines (entry 18). It is however unclear if
this is due to the presence of an additional CHꢀacidic moiety in the starting material 1h
or intermediate 11h, respectively, or to a lower stability of product 8q towards oxidation
or polymerization reactions. Interestingly, no successful annulation could be observed
when cyanopyrrolines carrying a nitroaryl substituent were employed in the reaction (1i
entry 19). We hypothesize that in this case the alkylation step fails due to an
intermolecular addition of anion 9 to the nitroaromatic ring of a second
cyanopyrrolineꢀmolecule since we could observe compounds of the corresponding mass
by LCꢀMS.
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Inspired by these results, the annulation was extended to the preparation of indolizines
by employing commercially available (Z)ꢀ1,4ꢀdichlorobutꢀ2ꢀene (13) as an electrophile to
yield 5,8ꢀdihydroindolizine intermediates. To avoid side reactions such as dimerizations
(vide supra), the reaction conditions were modified. The lithium salt 9a, prepared in
solution by previously deprotonating 1a with LDA, was added to a solution of 13, thus
providing a permanent excess of the electrophile. In this fashion, we were able to isolate
the corresponding 1,3ꢀdiphenylꢀ5,8ꢀdihydroindolizine (14) in 20% yield. The following
oxidation with DDQ afforded 1,3ꢀdiphenylindolizine (15) but the sequence suffered from
low efficiency and poor reproducibility (Scheme 3).
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Scheme 3: Synthesis of 1,3ꢀdiphenylindolizine 15 via 1,3ꢀdiphenylꢀ5,8ꢀdihydroindolizine
14
When cyanopyrroline 1a was treated with Cu(OAc)2 in DMF at 100 °C, 2,2’ꢀ1H,1’Hꢀ
bipyrrole 6a was obtained in 49% yield (Table 2, entry 1). This reaction also produced
pyrroleꢀ2ꢀcarbonitrile 3a, the structure of which was elucidated by NMR. Unfortunately,
all attempts to increase the yield of bipyrrole 6 failed. Replacing Cu(OAc)2 with CuSO4,
Cu(OTf)2, or CuCl2 did not yield the desired dimerization product which also could not be
obtained using other oxidants FeCl3, Mn(OAc)3, I2, or PIFA. When the previously found
reaction conditions were applied to cyanopyrroline 1c, bipyrrole 6c was obtained in 10%
yield along with the corresponding pyrroleꢀ2ꢀcarbonitrile 3c (40% yield, entry 3).
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Table 2. Synthesis of 2,2’ꢀBipyrroles
7
8
9
R2
Cu(OAc)2 H2O
DMF, 100 °C
microwaves
R2
CN
H
N
R1
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R1
N
R1
N
H
R2
1
6
Entry R1
R2
Product Yield (%)
1
2
3
Ph
2ꢀNaph
Ph
6a
6b
49
Ph
31a
10b
4ꢀCl–C6H4 3ꢀNO2–C6H4 6c
a Anhydrous copper(II) acetate was used. b Pyrroleꢀ2ꢀcarbonitrile 3c was isolated in 40% yield.
To examine whether bipyrrole formation proceeds through the pyrrole stage (path A) or
through a pyrroline dimer (Path B, Scheme 4), pyrrole 2a (prepared by thermal
dehydrocyanation of cyanopyrroline 1a)56 was subjected to identical conditions and no
bipyrrole 6a was detected. However, intermediates 7a and 16a were detected by LCꢀ
MS, so that path A can be ruled out and the reaction most probably proceeds through
path B.
Scheme 4. Possible reaction pathways for the synthesis of bipyrroles 6
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Bis(cyanopyrroline) 7a could be prepared by a different route. Cyanopyrroline 1a was
deprotonated by LDA in THF at –78 °C and treated with CuCl2 (1.20 equiv) to furnish
dimerized cyanopyrroline 7a as a major diastereomer in 59% yield. The total yield of
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1
homocoupled cyanopyrrolines was 83% From the H NMR spectrum of the crude
reaction mixture, the diastereomeric purity57 of the major diastereoisomer 7a was
calculated as 71% (Table 3, entry 1). The relative configuration of the major
diastereomer 7a was unambiguously determined by Xꢀray crystallography (see
Supporting Information).
Table 3. Diastereoselective Homocoupling of Cyanopyrroline 1
Entry
R1
R2
Product dp(%)a Yield (%)b
1
2
3
4
Ph
Ph
Ph
7a
7b
7c
7d
71
>84
74
59 (83)
54 (62)
33 (47)
62 (81)
2ꢀNaph
Ph
4ꢀCN–C6H4
4ꢀF–C6H4 4ꢀMeO–C6H4
>71
a dp:diastereomeric purity was calculated by integrating the Hꢀ3 signals of the major diastereomer relative
to all diastereomers. Isolated yield of major diastereomer. Total yield of dimerized product calculated
from the formula: (isolated yield of the major diastereomer) / (dp of the major diastereomer) ×100 is given
in parentheses.
b
Furthermore, deprotonation of the dimerized cyanopyrroline 7a with LDA at –78 °C in
THF gave a mixture of bipyrrole 6a, pyrroleꢀ2ꢀcarbonitrile 3a, and cyanopyrroline 1a.
Clearly, two competing reactions exist under these conditions (Scheme 5). In addition to
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the baseꢀinduced double dehydrocyanation, cyanopyrroline 1a and pyrroleꢀ2ꢀcarbonitrile
3a can be formed by a cleavage of the central C2–C2’ bond.
7
8
9
Ph
CN
Ph
CN
Ph
N
H
Ph
N
LDA
THF
Li
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N
NC
Ph
N
NC
Ph
Ph
Ph
7a
Ph
Ph
CN
H
N
Ph
CN
Ph
+
Ph
N
Ph
N
H
Ph
N
H
Ph
6a
1a
3a
at 94 °C:
at 0 °C:
13%
14%
37%
56%
27%
Scheme 5. Reaction of compound 7a with LDA
The latter process possibly accounts for the limited efficiency of bipyrrole formation.
While the reaction of bis(cyanopyrroline) 7a with LDA in THF at –94 °C gave bipyrrole
1
6a as a major product in 56% yield (determined by H NMR using an internal standard),
this figure decreased to 27% at 0 °C under otherwise identical reaction conditions.
Conclusion
A simple, high yielding method for the oneꢀpot synthesis of 1,3ꢀdisubstituted 5,6,7,8ꢀ
tetrahydroindolizines, 5,7ꢀdisubstituted 2,3ꢀdihydroꢀ1Hꢀpyrrolizines as well as
1,3ꢀdisubstituted 6,7,8,9ꢀtetrahydroꢀ5Hꢀpyrrolo[1,2ꢀa]azepines has been developed. The
readily available 3,4ꢀdihydroꢀ2Hꢀpyrroleꢀ2ꢀcarbonitriles serve as intermediates in all
cases. Moreover, the exposure of 3,4ꢀdihydroꢀ2Hꢀpyrroleꢀ2ꢀcarbonitriles to copper(II)
acetate provides a convenient access to bis(cyanopyrrolines) by dimerization or to 2,2’ꢀ
bipyrroles by subsequent double dehydrocyanation.
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Experimental Section
General Methods
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All reactions described were carried out under an inert atmosphere of argon in flameꢀ or
oven dried glassware. The stated reaction temperatures refer to the temperature of the
respective cooling bath. All reagents were reagent grade and used without further
purification unless otherwise noted. LDA was purchased in solution from a commercial
supplier and titrated against Nꢀbenzylbenzamide prior to use.58 Cyanopyrrolines 1a–g
were synthesized as previously reported.52,53,56 Melting points were determined in open
capillary tubes using an electronic apparatus. NMR spectra were recorded on a 400
MHz spectrometer equipped with a 5 mm BBFO probe head with zꢀgradient and ATM
capability. Chemical shifts were referenced to the deuterated solvent (e.g., for CDCl3,
δ = 7.26 ppm and 77.16 ppm, for DMSOꢀd6, δ = 2.50 ppm and 39.52 ppm for 1H and 13C
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NMR, respectively) and reported in parts per million (ppm, δ) relative to tetramethylsilane
(TMS, δ = 0.00 ppm).59 Coupling constants (J) are stated in Hz using the splitting
abbreviations: s, singlet; d, doublet; t, triplet; quin., quintet; m, multiplet; br, broad.
Standard pulse sequences were used for the 2D experiments. FTꢀInfrared spectra were
recorded using a diamond ATR unit. Highꢀresolution mass spectrometry was executed
on a QToFꢀInstrument with a dual electrospray source and a suitable external calibrant.
Thinꢀlayer chromatography (TLC) was performed on 0.25 mm silica gel plates (60F254)
visualizing with UVꢀlight and developing with an anisaldehyde solution (4.1 mL of
pꢀanisaldehyde, 1.7 mL AcOH and 5.6 mL H2SO4 in 450 mL EtOH) or potassium
permanganate solution (2.0 g KMnO4 and 5.5 g NaCO3 in 250 mL H2O). Flash
chromatography was carried out using the indicated solvent system on 35–70 ꢁm silica
gel.
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General procedure for the microwave synthesis of 2,2’-bipyrroles 6. A 10 mL
microwave vessel was charged with cyanopyrroline 1 (1.00 equiv) and a stir bar. The
starting material was dissolved in DMF (4.00 mL/ 1 mmol 1) and Cu(OAc)2—H2O (3.00
equiv) was added. The reaction mixture was heated to 100 °C (microwave irradiation,
150 W) for 15 min. The solution was diluted with ethyl acetate and filtered through a pad
of celite. The crude product was purified by a column chromatography.
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3,3’,5,5’-Tetraphenyl-1H,1’H-2,2’-bipyrrole (6a). The title compound was prepared
according to the general procedure described above from cyanopyrroline 1a (246 mg,
1.000 mmol) and Cu(OAc)2—H2O (599 mg, 3.000 mmol). The crude product was purified
by column chromatography (SiO2, Cy/EtOAc 10:1) to obtain bipyrrole 6a (107 mg,
0.245 mmol, 49%) as a colorless foam: Rf = 0.73 (SiO2, Cy/EtOAc 5:1); 1H NMR, COSY
(400 MHz, DMSOꢀd6) δ (ppm) = 11.71 (d, J = 2.6 Hz, 2H, Hꢀ1), 7.81–7.79 (m, 4H, Hꢀ
2’’,6’’), 7.38–7.31 (m, 8H, Hꢀ3’’,5’’, Hꢀ2’,6’), 7.20–7.12 (m, 6H, Hꢀ4’’, Hꢀ3’,5’), 7.07 (d, J =
2.6 Hz, 2H, Hꢀ4), 7.02–6.98 (m, 2H, Hꢀ4’); 13C NMR, HSQC, HMBC (100.6 MHz, DMSOꢀ
d6) δ (ppm) = 136.1 (2C, Cꢀ1’), 132.6 (2C, Cꢀ1’’), 131.9 (2C, Cꢀ5), 128.9 (4C, Cꢀ3’’,5’’),
128.4 (4C, Cꢀ3’,5’), 126.0 (2C, Cꢀ4’’), 125.8 (4C, Cꢀ2’,6’), 125.2 (2C, Cꢀ4’), 124.7 (2C,
Cꢀ3), 123.8 (4C, Cꢀ2’’,6’’), 121.7 (2C, Cꢀ2), 105.5 (2C, Cꢀ4) ppm; IR (ATR):
ꢀ (cm−1) = 3412, 3060, 3025, 2957, 2924, 2855, 1723, 1602, 1490, 1462, 1278, 1025,
758, 694; ESIꢀHRMS calcd for [C32H24N2]+ 436.1939, found 436.1932.
5,5’-Di(naphthalen-2-yl)-3,3’-diphenyl-1H,1’H-2,2’-bipyrrole (6b). The title compound
was prepared according to the general procedure described above from cyanopyrroline
1d (148 mg, 0.500 mmol) and Cu(OAc)2 (272 mg, 1.500 mmol). The crude product was
purified by column chromatography (SiO2, Cy/EtOAc 6:1) to obtain bipyrrole 6b (42 mg,
1
0.079 mmol, 31%) as a yellow foam: Rf = 0.39 (SiO2, Cy/EtOAc 6:1); H NMR, COSY
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(300 MHz, DMSOꢀd6) δ (ppm) = 11.91 (d, J = 2.5 Hz, 2H, NH), 8.33 (br s, 2H, Hꢀ1’’), 8.02
(dd, J = 8.7, 1.7 Hz, 2H, Hꢀ3’’), 7.92 (d, J = 8.7 Hz, 2H, Hꢀ4’’), 7.87 (dd, J = 8.0, 1.3 Hz,
2H, Hꢀ5’’), 7.82 (dd, J = 8.3, 1.2 Hz, 2H, Hꢀ8’’), 7.49 (ddd, J = 8.3, 6.9, 1.3 Hz, 2H, Hꢀ7’’),
7.44 (ddd, J = 8.0, 6.9, 1.2 Hz, 2H, Hꢀ6’’), 7.40–7.37 (m, 4H, Hꢀ2’,6’), 7.26 (d, J = 2.5 Hz,
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2H, Hꢀ4), 7.18–7.14 (m, 4H, Hꢀ3’,5’), 7.04–6.99 (m, 2H, Hꢀ4’); C NMR, HSQC, HMBC
(75.5 MHz, DMSOꢀd6) δ (ppm) = 135.8 (2C, Cꢀ1’), 133.5 (2C, Cꢀ8a’’), 131.8 (2C, Cꢀ5),
131.5 (2C, Cꢀ4a’’), 129.8 (2C, Cꢀ2’’), 128.21 (4C, Cꢀ3’,5’), 128.15 (2C, Cꢀ4’’), 127.6 (2C,
Cꢀ5’’), 127.5 (2C, Cꢀ8’’), 126.5 (2C, Cꢀ7’’), 125.6 (4C, Cꢀ2’,6’), 125.2 (2C, Cꢀ6’’), 125.1
(2C, Cꢀ4’), 124.7 (2C, Cꢀ3), 123.1 (2C, Cꢀ3’’), 122.0 (2C, Cꢀ2), 120.8 (2C, Cꢀ1’’), 106.1
(2C, Cꢀ4); IR (ATR): ꢀ (cm−1) = 3393, 3055, 2954, 2922, 1628, 1598, 1502, 1160, 799,
765; ESIꢀHRMS calcd for [C40H28N2 + H]+ 537.2331, found 537.2323.
5,5’-Bis(4-chlorophenyl)-3,3’-bis(3-nitrophenyl)-1H,1’H-2,2’-bipyrrole (6c). The title
compound was prepared according to the general procedure described above from
cyanopyrroline 1i (162 mg, 0.500 mmol) and Cu(OAc)2—H2O (300 mg, 1.500 mmol). The
crude product was purified by column chromatography (SiO2, Cy/EtOAc 10:1) to obtain
bipyrrole 6c (14 mg, 0.024 mmol, 10%) as a yellow foam: Rf = 0.21 (SiO2, Cy/EtOAc
1
10:1); H NMR, COSY (400 MHz, DMSOꢀd6) δ (ppm) = 12.08 (d, J = 2.7 Hz, 2H, NH),
7.96 (t, J = 2.0 Hz, 2H, Hꢀ2’), 7.90–7.85 (AA’ part of AA’–BB’ system, 4H, Hꢀ2’’,6’’), 7.80
(ddd, J = 8.2, 2.0, 1.0 Hz, 2H, Hꢀ4’), 7.60 (ddd, J = 7.8, 2.0, 1.0 Hz, 2H, Hꢀ6’), 7.51–7.44
(BB’ part of AA’–BB’ system, 4H, Hꢀ3’’,5’’), 7.38 (pseudoꢀt, Japp ≈ 8 Hz, 2H, Hꢀ5’), 7.25
(d, J = 2.7 Hz, 2H, Hꢀ4); 13C NMR, HSQC, HMBC (100.6 MHz, DMSOꢀd6) δ (ppm) =
147.7 (2C, Cꢀ3’), 137.4 (2C, Cꢀ1’), 132.2 (2C, Cꢀ6’), 131.8 (2C, Cꢀ5), 130.8 (2C, Cꢀ1’’),
130.6 (2C, Cꢀ4’’), 129.6 (2C, Cꢀ5’), 128.8 (4C, Cꢀ3’’,5’’), 125.5 (4C, Cꢀ2’’,6’’), 122.3 (2C,
Cꢀ3), 122.0 (2C, Cꢀ2), 120.0 (2C, Cꢀ2’), 119.8 (2C, Cꢀ4’), 106.6 (2C, Cꢀ4); IR (ATR):
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ꢀ (cm−1) = 3364, 3191, 2954, 2923, 2853, 1648, 1527, 1463, 1347, 1095, 800, 742; ESIꢀ
HRMS calcd for [C32H20N4O4Cl2 + Na]+ 617.0759, found 617.0775.
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General procedure for the copper(II)-mediated homocoupling of cyanopyrrolines.
To a solution of cyanopyrroline 1 (1.00 equiv) in freshly distilled THF (10 mL/ mmol 1)
were added a solution of LDA (1.20 equiv) in THF/heptane/ethylbenzene at –78 °C
under argon athmosphere. After stirring 3 min, solid CuCl2 (1.10 equiv) was added in
small portions at the same temperature. The reaction mixture was stirred 1–3 h until
almost all starting materials were consumed. Then, it was quenched with H2O (2 mL).
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The solution was diluted with ethyl acetate (40 mL/mmol 1) and washed with 0.25
M
EDTA (20 mL × 5) solution (pH 10), and brine. The organic phase was dried over
MgSO4 and concentrated under reduced pressure. The diastereomeric ratio was
calculated form the 1H NMR spectrum of the crude product by integrating the Hꢀ3 proton.
Bispyrroline 7 was obtained after recrystallization from proper solvent mixtures.
3,3’,5,5’-Tetraphenyl-3,3’,4,4’-tetrahydro-2H,2’H-[2,2’-bipyrrole]-2,2’-dicarbonitrile
(7a). The title compound was prepared according to the general procedure described
above from cyanopyrroline 1a (1.231 g, 5.00 mmol), LDA (6.00 mmol), and CuCl2
(739 mg, 5.50 mmol). Recrystallization from hexanes/EtOAc (10:1) provided compound
7a (720 mg, 1.47 mmol, 59%) as a yellowish solid: mp = 220–221 °C (hexanes/EtOAc);
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Rf = 0.19 (SiO2, hexanes/EtOAc 4:1); H NMR, COSY (400 MHz, CDCl3) δ (ppm) =
7.73–7.69 (m, 2H, Hꢀ2’’,6’’), 7.45–7.40 (m, 1H, Hꢀ4’’), 7.39–7.29 (m, 7H, Hꢀ2’,6’, Hꢀ
3’,5’,Hꢀ4’, Hꢀ3’’,5’’), 4.55 (dd, J = 9.2, 2.6 Hz, 1H, Hꢀ3), 3.62 (dd, J = 18.0, 9.2 Hz, 1H, Hꢀ
4a), 3.33 (dd, J = 18.0, 2.6 Hz, 1H, Hꢀ4b); 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3)
δ (ppm) = 181.0 (2C, Cꢀ5), 141.1 (2C, Cꢀ1’), 132.3 (2C, Cꢀ4’’), 132.1 (2C, Cꢀ1’’), 129.2
(4C, Cꢀ3’,5’), 128.8 (4C, Cꢀ3’’,5’’), 128.3 (2C, Cꢀ4’), 128.2 (4C, Cꢀ2’’,6’’), 127.8 (4C,
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Cꢀ2’,6’), 117.0 (2C, CN), 88.6 (2C, Cꢀ2), 49.0 (2C, Cꢀ3), 45.6 (2C, Cꢀ4); IR (ATR):
ꢀ (cm−1) = 3063, 3031, 2961, 2926, 2210, 1608, 1575, 1347, 1057, 760, 740; ESIꢀ
HRMS calcd for [C34H26N4 + H]+ 491.2236, found 491.2234.
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5,5’-Di(naphthalene-2-yl)-3,3’-diphenyl-3,3’,4,4’-tetrahydro-2H,2’H-[2,2’-bipyrrole]-
2,2’-dicarbonitrile (7b). The title compound was prepared according to the general
procedure described above from cyanopyrroline 1d (274 mg, 0.92 mmol), LDA
(1.10 mmol), and CuCl2 (137 mg, 1.02 mmol). Recrystallization from hexanes/CH2Cl2
(4:1) provided compound 7b (145 mg, 0.25 mmol, 54%) as yellowish solid: mp = 226–
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228 °C (hexanes/CH2Cl2); Rf = 0.33 (hexanes/EtOAc 2:1); H NMR, COSY (400 MHz,
CDCl3) δ (ppm) = 7.98–7.94 (m, 4H, Hꢀ1’’, Hꢀ3’’), 7.75–7.70 (m, 4H, Hꢀ4’’, Hꢀ5’’), 7.67–
7.64 (m, 2H, Hꢀ8’’), 7.48 (ddd, J = 8.2, 6.9, 1.3 Hz, 2H, Hꢀ6’’), 7.43–7.32 (m, 12H, Hꢀ7’’,
Hꢀ2’,6’, Hꢀ3’,5’, Hꢀ4’), 4.65 (dd, J = 9.2, 2.6 Hz, 2H, Hꢀ3), 3.78 (dd, J = 17.8, 9.2 Hz, 2H,
Hꢀ4a), 3.47 (dd, J = 17.8, 2.6 Hz, 2H, Hꢀ4b); 13C NMR, HSQC, HMBC (100.6 MHz,
CDCl3) δ (ppm) = 181.0 (2C, Cꢀ5), 141.2 (2C, Cꢀ1’), 135.1 (2C, Cꢀ4a’’), 132.6 (2C,
Cꢀ8a’’), 129.8 (2C, Cꢀ1’’), 129.6 (2C, Cꢀ2’’), 129.3 (4C, Cꢀ3’,5’), 128.9 (2C, Cꢀ8’’), 128.7
(2C, Cꢀ4’’), 128.3 (2C, Cꢀ4’), 128.1 (2C, Cꢀ6’’), 127.9 (4C, Cꢀ2’,6’), 127.8 (2C, Cꢀ5’’),
126.8 (2C, Cꢀ7’’), 123.9 (2C, Cꢀ3’’), 117.1 (2C, CN), 88.7 (2C, Cꢀ2), 49.1 (2C, Cꢀ3), 45.6
(2C, Cꢀ4); IR (ATR): ꢀ (cm−1) = 3060, 3031, 2963, 2926, 2210, 1606, 1594, 1573, 1354,
861, 822, 736; ESIꢀHRMS calcd for [C42H30N4 + Na]+ 613.2368, found 613.2370.
3,3’-Bis(4-cyanophenyl-5,5’-diphenyl-3,3’,4,4’-tetrahydro-2H,2’H-[2,2’-bipyrrole]-
2,2’-dicarbonitrile (7c). The title compound was prepared according to the general
procedure described above from cyanopyrroline 1b (271 mg, 1.00 mmol), LDA
(1.20 mmol), and CuCl2 (148 mg, 1.10 mmol). Recrystallization from hexanes/CH2Cl2
(8:1) provided compound 7c (88 mg, 0.16 mmol, 33%) as yellow solid: mp = 136–138 °C
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(hexanes/CH2Cl2); Rf = 0.12 (hexanes/EtOAc 6:1); H NMR, COSY (400 MHz, CDCl3)
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δ (ppm) = 7.71–7.68 (m, 4H, Hꢀ2’’,6’’), 7.68–7.65 (AA’ part of AA’–BB’ system, 4H, Hꢀ
3’,5’), 7.49–7.43 (m, 2H, Hꢀ4’’), 7.43–7.39 (BB’ part of AA’–BB’ system, 4H, Hꢀ2’,6’),
7.39–7.30 (m, 4H, Hꢀ3’’,5’’), 4.60 (dd, J = 9.2, 2.8 Hz, 2H, Hꢀ3), 3.68 (dd, J = 18.2, 9.2
Hz, 2H, Hꢀ4a), 3.32 (dd, J = 18.2, 2.8 Hz, 2H, Hꢀ4b); 13C NMR, HSQC, HMBC
(100.6 MHz, CDCl3) δ (ppm) = 181.1 (2C, Cꢀ5), 145.8 (2C, Cꢀ1’), 133.1 (4C, Cꢀ3’,5’),
132.9 (2C, Cꢀ4’’), 131.5 (2C, Cꢀ1’’), 129.0 (4C, Cꢀ3’’,5’’), 128.8 (4C, Cꢀ2’,6’), 128.2 (4C,
Cꢀ2’’,6’’), 118.5 (2C, 4’ꢀCN), 116.6 (2C, 1ꢀCN), 112.5 (2C, Cꢀ4’), 87.9 (2C, Cꢀ2), 49.0
(2C, Cꢀ3), 45.4 (2C, Cꢀ4); IR (ATR): ꢀ (cm−1) = 3063, 2960, 2926, 2854, 2230, 1609,
1575, 1449, 1348, 1057, 850, 763; ESIꢀHRMS calcd for [C36H24N6 + H]+ 541.2141, found
541.2142.
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5,5’-Bis(4-fluorophenyl)-3,3’-bis(4-methoxyphenyl-3,3’,4,4’-tetrahydro-2H,2’H-[2,2’-
bipyrrole]-2,2’-dicarbonitrile (7d): The title compound was prepared according to the
general procedure described above from cyanopyrroline 1g (370 mg, 1.26 mmol), LDA
(1.51 mmol), and CuCl2 (186 mg, 1.38 mmol). Recrystallization from hexanes/EtOAc
(5:1) provided compound 7d (228 mg, 0.39 mmol, 62%) as colorless solid: mp = 121–
1
122 °C (hexanes/EtOAc); Rf = 0.19 (hexanes/EtOAc 2:1); H NMR, COSY (400 MHz,
CDCl3) δ (ppm) = 7.75–7.68 (m, 4H, Hꢀ2’’,6’’), 7.22–7.17 (AA’ part of AA’–BB’ system,
4H, Hꢀ2’,6’), 7.05–6.98 (m, 4H, Hꢀ3’’,5’’), 6.90–6.86 (BB’ part of AA’–BB’ system, 4H, Hꢀ
3’,5’), 4.49 (dd, J = 9.2, 2.8 Hz, 2H, Hꢀ3), 3.79 (s, 6H, OCH3), 3.54 (dd, J = 18.0, 9.2 Hz,
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2H, Hꢀ4a), 3.25 (dd, J = 18.0, 2.8 Hz, 2H, Hꢀ4b); C NMR, HSQC, HMBC (100.6 MHz,
CDCl3) δ (ppm) = 179.5 (2C, Cꢀ5), 165.3 (d, 1JCF = 253.9 Hz, 2C, Cꢀ4’’), 159.5 (2C, Cꢀ4’),
132.8 (2C, Cꢀ1’), 130.4 (d, 3JCF = 8.9 Hz, 4C, Cꢀ2’’,6’’), 128.9 (4C, Cꢀ2’,6’), 128.5 (d, 4JCF
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= 3.3 Hz, 2C, Cꢀ1’’), 117.0 (CN), 116.1 (d, JCF = 22.0 Hz, 4C, Cꢀ3’’,5’’) , 114.6 (4C,
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Cꢀ3’,5’), 88.5 (2C, Cꢀ2), 55.4 (2C, OCH3), 48.4 (2C, Cꢀ3), 45.6 (2C, Cꢀ4); IR (ATR):
ꢀ (cm−1) = 3064, 3003, 2960, 2935, 2838, 2211, 1612, 1603, 1585, 1511, 1343, 1250,
1235, 1057, 840, 808, 735; ESIꢀHRMS calcd for [C36H28N4O2F2 + Na]+ 609.2078, found
609.2083.
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General procedure for the synthesis of bicyclic structures 8a–p. The respective
cyanopyrroline (1a–g) (ca. 0.5 mmol, 1.0 equiv) was dissolved in abs THF (10 mL,
0.05 mol/mL) under an argon atmosphere. The resulting solution was cooled to −78 °C
and LDA (1.2 equiv) was added dropwise. The solution was stirred for about 5 min, after
which the respective alkyl halide (10a–c) (1.2 equiv) was added dropwise. The cooling
bath was removed and stirring was continued until LCꢀMS indicated full conversion of
the starting material (usually about 1 h). The solution was again cooled to −78 °C and
another portion of LDA (2.4 equiv) was added. After stirring for 5 min at that
temperature, the cooling bath was removed and stirring was continued for the time
indicated in table 1, at which point LCꢀMS showed full conversion of the intermediate
alkylated cyanopyrroline. The reaction mixture was quenched by addition of water
(10 mL) and EtOAc (10 mL), the organic layer was washed with water (10 mL) then
brine (10 mL) and the combined aqueous layers were extracted with EtOAc (2 × 10 mL).
The combined organic extracts were dried over sodium sulfate, concentrated under
reduced pressure and the crude product was purified by silica gel column
chromatography.
1,3-Diphenyl-5,6,7,8-tetrahydroindolizine (8a). Method A: The title compound was
prepared according to the general procedure from cyanopyrroline 1a (0.123 g,
0.499 mmol, 1.0 equiv) and 1ꢀbromoꢀ4ꢀchlorobutane (0.07 mL, 0.60 mmol, 1.2 equiv)
using LDA (0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol, 2.4 equiv for
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the annulation step). Purification by column chromatography (SiO2, hexanes/Et2O
(250:1→100:1) yielded 8a (120 mg, 0.439 mmol, 88%) as a colorless solid: mp 111–
112 °C (hexanes/Et2O); Rf = 0.28 (SiO2, hexanes/Et2O 150:1); 1H NMR, COSY (400
MHz, DMSOꢀd6) δ (ppm) = 7.48–7.39 (m, 6H, HPhꢀ2,6, HPh’ꢀ2,6, HPh’ꢀ3,5), 7.36–7.32 (m,
2H, HPhꢀ3,5), 7.32–7.27 (m, 1H, HPh’ꢀ4), 7.17–7.12 (m, 1H, HPhꢀ4), 6.41 (s, 1H, Hꢀ2),
3.96 (t, J = 5.9 Hz, 2H, Hꢀ5), 2.95 (t, J = 6.3 Hz, 2H, Hꢀ8), 1.91–1.85 (m, 2H, Hꢀ6), 1.84–
1.77 (m, 2H, Hꢀ7); 13C NMR, HSQC, HMBC (100.6 MHz, DMSOꢀd6) δ (ppm) = 136.6
(CPhꢀ1), 132.9 (CPh’ꢀ1), 132.1 (Cꢀ3), 128.5 (CPh’ꢀ2,6), 128.4 (CPhꢀ3,5), 128.2 (CPh’ꢀ3,5),
126.9 (Cꢀ8a), 126.6 (CPhꢀ2,6), 126.4 (CPh’ꢀ4), 124.6 (CPhꢀ4), 119.1 (Cꢀ1), 107.6 (Cꢀ2),
44.7 (Cꢀ5), 23.8 (Cꢀ8), 23.1 (Cꢀ6), 20.4 (Cꢀ7); IR (ATR): ꢀ (cm−1) = 3053, 2930, 1602,
1560, 1490, 1451, 1327, 1169, 759, 698; ESIꢀHRMS calcd for [C20H19N + H]+ 274.1596,
found 274.1593. – Method B: The title compound was prepared by a single addition of
LDA (1.81 mmol, 3.6 equiv) to a solution of cyanopyrroline 1a (0.124 g, 0.503 mmol,
1.0 equiv) in abs THF (10 mL) at −78 °C, followed by the addition of 1ꢀbromoꢀ4ꢀ
chlorobutane (0.07 mL, 0.60 mmol, 1.2 equiv). The cooling bath was removed and the
mixture stirred for a further 2 h, at which point LCꢀMS indicated full conversion. Workup
was carried out as described above to yield 8a (71 mg, 0.260 mmol, 52%) as a colorless
solid. The analytical data were in agreement with the abovementioned.
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5,7-Diphenyl-2,3-dihydro-1H-pyrrolizine (8b). The title compound was prepared
according to the general procedure from cyanopyrroline 1a (0.123 g, 0.499 mmol,
1.0 equiv) and 1ꢀbromoꢀ3ꢀchloropropane (0.06 mL, 0.60 mmol, 1.2 equiv) using LDA
(0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol, 2.4 equiv for the
annulation step). Purification by column chromatography (SiO2, hexanes/Et2O 100:1)
yielded 8b (126 mg, 0.486 mmol, 97%) as a light yellow solid: mp 148–
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149 °C (hexanes/Et2O); Rf = 0.23 (SiO2, hexanes/Et2O 150:1); 1H NMR, COSY (400
MHz, CDCl3) δ (ppm) = 7.56–7.51 (m, 4H, HPhꢀ2,6, HPh’ꢀ2,6), 7.43–7.39 (m, 2H, HPhꢀ3,5),
7.39–7.34 (m, 2H, HPh’ꢀ3,5), 7.28–7.22 (m, 1H, HPhꢀ4), 7.20–7.14 (m, 1H, HPh’ꢀ4), 6.74
(s, 1H, Hꢀ6), 4.18 (t, J = 7.1 Hz, 2H, Hꢀ3), 3.15 (t, J = 7.3 Hz, 2H, Hꢀ1), 2.61 (pseudoꢀ
quin., J ≈ 7 Hz, 2H, Hꢀ2); 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3) δ (ppm) = 136.5
(CPh’ꢀ1), 136.0 (Cꢀ7a), 133.5 (C Phꢀ1), 129.4(Cꢀ5), 128.8, 128.7 (2C, CPhꢀ3,5, CPh’ꢀ3,5),
126.1 (CPhꢀ4), 125.9 (CPhꢀ2,6), 125.3 (CPh’ꢀ2,6), 124.8 (CPh’ꢀ4), 116.3 (Cꢀ7), 108.8 (Cꢀ6),
46.8 (Cꢀ3), 28.1 (Cꢀ2), 25.5 (Cꢀ1); IR (ATR): ꢀ (cm−1) = 3032, 2954, 1602, 1492, 1455,
1391, 1298, 1144, 754, 694; ESIꢀHRMS calcd for [C19H17N + H]+ 260.1439, found
260.1439. The spectroscopic data are in accordance to the literature.42
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1,3-Diphenyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine (8c). The title compound
was prepared according to the general procedure from cyanopyrroline 1a (0.128 g,
0.520 mmol, 1.0 equiv) and 1ꢀbromoꢀ5ꢀchloropentane (0.08 mL, 0.60 mmol, 1.2 equiv)
using LDA (0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol, 2.4 equiv for
the annulation step). Purification by column chromatography (SiO2, hexanes/Et2O 150:1)
yielded 8c (82 mg, 0.285 mmol, 55%) as
a
colorless solid: mp 131–
132 °C (hexanes/Et2O); Rf = 0.34 (SiO2, hexanes/Et2O 150:1); 1H NMR, COSY (400
MHz, CDCl3) δ (ppm) = 7.46–7.38 (m, 8H, HPhꢀ2,6, HPhꢀ3,5, HPh’ꢀ2,6, HPh’ꢀ3,5), 7.35–7.30
(m, 1H, HPhꢀ4), 7.27–7.22 (m, 1H, HPhꢀ4), 6.27 (s, 1H, Hꢀ2), 4.09–3.98 (m, 2H, Hꢀ5),
3.06–2.93 (m, 2H, Hꢀ9), 1.98–1.69 (m, 6H, Hꢀ6,7,8); 13C NMR, HSQC, HMBC (100.6
MHz, CDCl3) δ (ppm) = 137.6 (CqPh), 133.8 (CqPh), 133.6 (Cꢀ3), 133.4(Cꢀ9a), 129.3
(CHPh), 128.7 (CHPh), 128.5 (CHPh), 128.4 (CHPh), 126.7 (CqPh), 125.4 (CqPh), 121.6
(Cꢀ1), 108.1 (Cꢀ2), 46.6 (Cꢀ5), 31.2 (Cꢀ7), 29.7 (Cꢀ6), 28.0 (Cꢀ8), 26.0 (Cꢀ9); IR (ATR):
ꢀ (cm−1) = 3029, 2924, 1602, 1490, 1445, 1394, 1344, 909, 757, 699; ESIꢀHRMS calcd
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for [C21H21N + H]+ 288.1752, found 288.1744. The spectroscopic data are in accordance
to the literature.60
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4-(3-Phenyl-5,6,7,8-tetrahydroindolizin-1-yl)benzonitrile (8d). The title compound
was prepared according to the general procedure from cyanopyrroline 1b (0.136 g,
0.501 mmol, 1.0 equiv) and 1ꢀbromoꢀ4ꢀchlorobutane (0.07 mL, 0.60 mmol, 1.2 equiv)
using LDA (0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol, 2.4 equiv for
the annulation step). Purification by column chromatography (SiO2, Cy/EtOAc 15:1)
yielded 8d (131 mg, 0.439 mmol, 88%) as a colorless solid: mp 128.5–
129.5 °C (Cy/EtOAc); Rf = 0.26 (SiO2, Cy/EtOAc 15:1); 1H NMR, COSY (400 MHz,
CDCl3) δ (ppm) = 7.64–7.60 (AA’ part of AA’–BB’ system, 2H, Hꢀ3’,5’), 7.56–7.51 (BB’
part of AA’–BB’ system, 2H, Hꢀ2’,6’), 7.44–7.39 (m, 4H, Hꢀ2’’,6’’, Hꢀ3’’,5’’), 7.36–7.31 (m,
1H, Hꢀ4’’), 6.45 (s, 1H, Hꢀ2), 3.98 (t, J = 5.8 Hz, 2H, Hꢀ5), 3.05 (t, J = 6.3 Hz, 2H, Hꢀ8),
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2.01–1.93 (m, 2H, Hꢀ6), 1.93–1.88 (m, 2H, Hꢀ7); C NMR, HSQC, HMBC (100.6 MHz,
DMSOꢀd6) δ (ppm) = 141.8 (Cꢀ1’), 134.0 (Cꢀ3), 132.9 (Cꢀ1’’), 132.4 (Cꢀ3’,5’), 129.0
(Cꢀ2’’,6’’), 128.7 (Cꢀ8a), 128.6 (C-3’’,5’’), 127.3 (Cꢀ4’’), 127.1 (Cꢀ2’,6’), 119.8 (CN), 118.6
(Cꢀ1), 107.8 (Cꢀ2), 107.7 (Cꢀ4’), 45.3 (Cꢀ5), 24.6 (Cꢀ8), 23.5 (Cꢀ6), 20.9 (Cꢀ7); IR (ATR):
ꢀ (cm−1) = 2945, 2864, 2221, 1602, 1526, 1327, 1174, 842, 763, 700; ESIꢀHRMS calcd
for [C21H18N2 + H]+ 299.1548, found 299.1535.
4-(5-Phenyl-2,3-dihydro-1H-pyrrolizin-7-yl)benzonitrile (8e). The title compound was
prepared according to the general procedure from cyanopyrroline 1b (0.136 g,
0.501 mmol, 1.0 equiv) and 1ꢀbromoꢀ3ꢀchloropropane (0.06 mL, 0.60 mmol, 1.2 equiv)
using LDA (0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol, 2.4 equiv for
the annulation step). Purification by column chromatography (SiO2, Cy/EtOAc 10:1)
yielded 8e (126 mg, 0.443 mmol, 88%) as a colorless solid: mp 217–219 °C (Cy/EtOAc);
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Rf = 0.20 (SiO2, Cy/EtOAc 10:1); 1H NMR, COSY (400 MHz, CDCl3) δ (ppm) = 7.63–
7.59 (AA’ part of AA’–BB’ system, 2H, Hꢀ3’’,5’’), 7.57–7.54 (BB’ part of AA’–BB’ system,
2H, Hꢀ2’’,6’’), 7.52–7.48 (m, 2H, Hꢀ2’,6’), 7.43–7.37 (m, 2H, Hꢀ3’,5’), 7.29–7.24 (m, 1H,
Hꢀ4’), 6.71 (s, 1H, Hꢀ6), 4.19 (t, J = 7.1 Hz, 2H, Hꢀ3), 3.15 (t, J = 7.4 Hz, 2H, Hꢀ1), 2.65
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(pseudoꢀquin., J ≈ 7 Hz , 2H, Hꢀ2); C NMR, HSQC, HMBC (100.6 MHz, DMSOꢀd6) δ
(ppm) = 141.0 (Cꢀ1’’), 137.6 (Cꢀ7a), 132.7 (Cꢀ1’), 132.5 (Cꢀ3’’,5’’), 130.2 (Cꢀ5), 128.8
(Cꢀ3’,5’), 126.5 (Cꢀ4’), 125.9 (Cꢀ2’,6’), 125.0 (Cꢀ2’’,6’’), 119.7 (CN), 114.6 (Cꢀ7), 108.5
(Cꢀ6), 107.2 (Cꢀ4’’), 46.7 (Cꢀ3), 27.8 (Cꢀ2), 25.7 (Cꢀ1); IR (ATR): ꢀ (cm−1) = 2941, 2854,
2221, 1599, 1524, 1300, 1179, 846, 767, 698; ESIꢀHRMS calcd for [C20H16N2 + H]+
285.1392, found 285.1393.
4-(3-Phenyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepin-1-yl)benzonitrile (8f). The
title compound was prepared according to the general procedure from cyanopyrroline 1b
(0.139 g, 0.512 mmol, 1.0 equiv) and 1ꢀbromoꢀ5ꢀchloropentane (0.08 mL, 0.60 mmol,
1.2 equiv) using LDA (0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol,
2.4 equiv for the annulation step). Purification by column chromatography (SiO2,
Cy/EtOAc 30:1) yielded 8f (85 mg, 0.272 mmol, 53%) as a light yellow solid: mp 155–
156 °C (Cy/EtOAc); Rf = 0.30 (SiO2, Cy/EtOAc 20:1); 1H NMR, COSY (400 MHz, CDCl3)
δ (ppm) = 7.66–7.61 (AA’ part of AA’–BB’ system, 2H, Hꢀ3’,5’), 7.48–7.43 (BB’ part of
AA’–BB’ system, 2H, Hꢀ2',6’), 7.43–7.40 (m, 2H, Hꢀ3’’,5’’), 7.37–7.31 (m, 3H, Hꢀ2’’,6’’, Hꢀ
4’’), 6.22 (s, 1H, Hꢀ2), 4.04–4.00 (m, 2H, Hꢀ5), 2.95–2.91 (m, 2H, Hꢀ9), 1.92–1.85 (m,
13
2H, Hꢀ7), 1.85–1.74 (m, 4H, Hꢀ6, Hꢀ8); C NMR, HSQC, HMBC (100.6 MHz, CDCl3) δ
(ppm) = 142.6 (Cꢀ1’), 134.4 (2C, Cꢀ3, Cꢀ9a), 133.2 (Cꢀ1’’), 132.3 (Cꢀ3’,5’), 129.3
(Cꢀ2’’,6’’), 128.8, 128.6 (4C, Cꢀ2’,6’, Cꢀ3’’,5’’), 127.2 (Cꢀ4’’), 120.1 (Cꢀ1),119,7 (CN)
108,4 (Cꢀ4’), 107.8 (Cꢀ2), 46.6 (Cꢀ5), 31.1 (Cꢀ7), 29.5 (Cꢀ6), 27.6 (Cꢀ8), 26.0 (Cꢀ9); IR
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(ATR): ꢀ (cm−1) = 2925, 2851, 2223, 1603, 1346, 910, 844, 761, 731, 702; ESIꢀ
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HRMS calcd for [C22H20N2 + Na]+ 335.1524, found 335.1518.
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1-(2,3-Dichlorophenyl)-3-phenyl-5,6,7,8-tetrahydroindolizine
(8g).
The
title
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compound was prepared according to the general procedure from cyanopyrroline 1c
(0.158 g, 0.501 mmol, 1.0 equiv) and 1ꢀbromoꢀ4ꢀchlorobutane (0.07 mL, 0.60 mmol,
1.2 equiv) using LDA (0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol,
2.4 equiv for the annulation step). Purification by column chromatography (SiO2,
hexanes/Et2O 150:1→100:1) yielded 8g (135 mg, 0.394 mmol, 79%) as a colorless
solid: mp 151–152 °C (hexanes/Et2O); Rf = 0.28 (SiO2, hexanes/Et2O 100:1); 1H NMR,
COSY (400 MHz, CDCl3) δ (ppm) = 7.48–7.44 (m, 2H, Hꢀ2’’,6’’), 7.42–7.37 (m, 2H,
Hꢀ3’’,5’’), 7.36 (ddapp, Japp = 7.8, 1.7 Hz, 1H, Hꢀ4’), 7.31–7.25 (m, 2H, Hꢀ4’’, Hꢀ6’), 7.17
(tapp, Japp = 7.8, 1H, Hꢀ5’), 6.37 (s, 1H, Hꢀ2), 4.02 (t, J = 6.0 Hz, 2H, Hꢀ5), 2.79 (t, J = 6.4
Hz, 2H, Hꢀ8), 2.00–1.94 (m, 2H, Hꢀ6), 1.88–1.81 (m, 2H, Hꢀ7); 13C NMR, HSQC, HMBC
(100.6 MHz, DMSOꢀd6) δ (ppm) = 138.2 (Cꢀ1’), 133.5 (Cꢀ3’), 133.3 (Cꢀ1’’) 132.4 (Cꢀ3),
131.9 ((Cꢀ2’), 130.2 (Cꢀ6’), 128.9 (Cꢀ2’’,6’’), 128.6 (Cꢀ8a), 128.5 (Cꢀ3’’,5’’), 128.2 (Cꢀ4’),
126,7 (2C, Cꢀ5’, Cꢀ4’’), 117.9 (Cꢀ1), 110.0 (Cꢀ2), 45.1 (Cꢀ5), 24.0 (Cꢀ6), 23.6 (Cꢀ8), 20.9
(Cꢀ7); IR (ATR): ꢀ (cm−1) = 2948, 2861, 1601, 1582, 1446, 1403, 1326, 1030, 760, 698;
ESIꢀHRMS calcd for [C20H17NCl2 + H]+ 342.0816, found 342.0813.
7-(2,3-Dichlorophenyl)-5-phenyl-2,3-dihydro-1H-pyrrolizine (8h). The title compound
was prepared according to the general procedure from cyanopyrroline 1c (0.158 g,
0.501 mmol, 1.0 equiv) and 1ꢀbromoꢀ3ꢀchloropropane (0.06 mL, 0.60 mmol, 1.2 equiv)
using LDA (0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol, 2.4 equiv for
the annulation step). Purification by column chromatography (SiO2, hexanes/Et2O 150:1)
yielded 8h (135 mg, 0.411 mmol, 82%) as a colorless oil, which solidified after storing
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for several days at −25 °C: mp 104–106 °C (hexanes/Et2O); Rf = 0.35 (SiO2,
hexanes/Et2O 100:1); 1H NMR, COSY (400 MHz, CDCl3) δ (ppm) = 7.53–7.50 (m, 2H,
Hꢀ2’,6’), 7.41–7.36 (m, 2H, Hꢀ3’,5’), 7.35–7.30 (m, 2H, Hꢀ4’’, Hꢀ6’’), 7.25–7.21 (m, 1H,
Hꢀ4’). 7.18 (tapp, Japp = 7.8, 1H, Hꢀ5’’), 6.65 (s, 1H, Hꢀ6), 4.21 (t, J = 7.0 Hz, 2H, Hꢀ3),
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2.97 (t, J = 7.4 Hz, 2H, Hꢀ1), 2.57 (pseudoꢀquin., J ≈ 7 Hz, 2H, Hꢀ2); C NMR, HSQC,
HMBC (100.6 MHz, DMSOꢀd6) δ (ppm) = 138.0 (Cꢀ3’’), 137.8 (Cꢀ7a), 133.7 (Cꢀ2’’), 133.3
(Cꢀ1’), 130.6 (Cꢀ1’’), 129.2 (Cꢀ6’’), 128.8 (3C, Cꢀ5, Cꢀ3’,5’), 127.8 (Cꢀ4’’), 127.0 (Cꢀ5’’),
126,2 (Cꢀ4’), 125.9 (Cꢀ2’,6’), 114.3 (Cꢀ7), 112.0 (Cꢀ6), 47.2 (Cꢀ3), 28.2 (Cꢀ2), 25.6 (Cꢀ1);
IR (ATR): ꢀ (cm−1) = 2976, 2879, 1603, 1584, 1451, 1402, 1298, 1137, 758, 695; ESIꢀ
HRMS calcd for [C19H15NCl2 + H]+ 328.0660, found 328.0670.
3-(Naphthalen-2-yl)-1-phenyl-5,6,7,8-tetrahydroindolizine (8i). The title compound
was prepared according to the general procedure from cyanopyrroline 1d (0.148 g,
0.499 mmol, 1.0 equiv) and 1ꢀbromoꢀ4ꢀchlorobutane (0.07 mL, 0.60 mmol, 1.2 equiv)
using LDA (0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol, 2.4 equiv for
the annulation step). Purification by column chromatography (SiO2, hexanes/Et2O
150:1→100:1) yielded 8i (115 mg, 0.356 mmol, 71%) as a colorless solid: mp 167–
169 °C (hexanes/Et2O); Rf = 0.20 (SiO2, hexanes/Et2O 100:1); 1H NMR, COSY (400
MHz, CDCl3) δ (ppm) = 7.90–7.82 (m, 4H, HNaph), 7.61 (ddapp, Japp = 8.5, 1.8 Hz, 1H,
HNaph), 7.53–7.44 (m, 4H, 2’,6’ꢀH, 2 × HNaph), 7.41–7.35 (m, 2H, Hꢀ3’,5’), 7.23–7.17 (m,
1H, Hꢀ4’), 6.56 (s, 1H, Hꢀ2), 4.09 (t, J = 5.9 Hz, 2H, Hꢀ5), 3.09 (t, J = 6.4 Hz, 2H, Hꢀ8),
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2.02–1.96 (m, 2H, Hꢀ6), 1.95–1.87 (m, 2H, Hꢀ7); C NMR, HSQC, HMBC (100.6 MHz,
DMSOꢀd6) δ (ppm) = 136.8 (Cꢀ1’), 133.4 (CqNaph), 133.0 (Cꢀ3), 132.1 (CqNaph), 130.8
(CqNaph), 128.4 (Cꢀ3’,5’), 127.9 (2C, CHNaph), 127.7 (CHNaph), 127.5 (Cꢀ8a), 127.3 (3C,
Cꢀ2’,6’, CHNaph), f127.0 (CHNaph), 126.3 (CHNaph), 125.8 (CHNaph), 125,0 (Cꢀ4’), 120.3
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(Cꢀ1), 108.6 (Cꢀ2), 45.3 (Cꢀ5), 24.1 (Cꢀ8), 23.7 (Cꢀ6), 21.0 (Cꢀ7); IR (ATR):
ꢀ (cm−1) = 3053, 2943, 1628, 1601, 1449, 1327, 1170, 908, 762, 698; ESIꢀHRMS calcd
for [C24H21N + H]+ 324.1752, found 324.1763.
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5-(Naphthalen-2-yl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (8j). The title compound was
prepared according to the general procedure from cyanopyrroline 1d (0.148 g,
0.499 mmol, 1.0 equiv) and 1ꢀbromoꢀ3ꢀchloropropane (0.06 mL, 0.60 mmol, 1.2 equiv)
using LDA (0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol, 2.4 equiv for
the annulation step). Purification by column chromatography (SiO2, hexanes/Et2O 150:1)
yielded 8j (130 mg, 0.420 mmol, 84%) as a colorless solid: mp 153.5–154.5 °C
(hexanes/Et2O); Rf = 0.26 (SiO2, hexanes/Et2O 100:1); 1H NMR, COSY (400 MHz,
CDCl3) δ (ppm) = 7.92–7.90 (m, 1H, Hꢀ1’), 7.85 (dapp, Japp = 8.5 Hz, 1H, Hꢀ4’), 7.84–7.80
(m, 2H, Hꢀ5’, Hꢀ8’), 7.71 (ddapp, Japp = 8.5, 1.8 Hz, 1H, Hꢀ3’), 7.58–7.53 (m, 2H, Hꢀ2’’,6’’),
7.48 (dddapp, Japp = 8.1, 6.8, 1.5 Hz, 1H, Hꢀ7’), 7.46 (dddapp, Japp = 8.1, 6.9, 1.4 Hz, 1H,
Hꢀ6’), 7.40–7.35 (m, 2H, Hꢀ3’’,5’’), 7.19–7.15 (m, 1H, Hꢀ4’’), 6.86 (s, 1H, Hꢀ6), 4.29 (t,
J = 7.1 Hz, 2H, Hꢀ3), 3.18 (t, J = 7.4 Hz, 2H, Hꢀ1), 2.65 (pseudoꢀquin., J ≈ 7 Hz, 2H,
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Hꢀ2); C NMR, HSQC, HMBC (100.6 MHz, DMSOꢀd6) δ (ppm) = 136.5 (Cꢀ7a), 136.4
(Cꢀ1’’), 133.8 (Cꢀ8a’), 132.0 (Cꢀ4a’), 130.9 (Cꢀ2’), 129.4 (Cꢀ5), 128.7 (Cꢀ3’’,5’’), 128.4
(Cꢀ4’), 127.9, 127.8 (2C, Cꢀ5’, Cꢀ8’), 126.5 (Cꢀ7’), 125.5 (Cꢀ6’), 125.3 (Cꢀ2’’,6’’), 125.1
(Cꢀ3’), 124,9 (Cꢀ4’’), 123.2 (Cꢀ1’), 116.5 (Cꢀ7), 109.4 (Cꢀ6), 47.0 (Cꢀ3), 28.1 (Cꢀ2), 25.5
(Cꢀ1); IR (ATR): ꢀ (cm−1) = 3052, 2851, 1627, 1602, 1491, 1398, 1141, 818, 758, 694;
ESIꢀHRMS calcd for [C23H19N + H]+ 310.1596, found 310.1606.
1-(2-Bromophenyl)-3-(naphthalen-2-yl)-5,6,7,8-tetrahydroindolizine (8k). The title
compound was prepared according to the general procedure from cyanopyrroline 1e
(0.190 g, 0.506 mmol, 1.0 equiv) and 1ꢀbromoꢀ4ꢀchlorobutane (0.07 mL, 0.60 mmol,
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1.2 equiv) using LDA (0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol,
2.4 equiv for the annulation step). Purification by column chromatography (SiO2,
hexanes/Et2O 150:1→100:1) yielded 8k (161 mg, 0.400 mmol, 79%) as a colorless
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solid: mp
114.5–115.5 °C (hexanes/Et2O);
Rf = 0.24
(SiO2,
hexanes/Et2O
100:1); 1H NMR, COSY (400 MHz, CDCl3) δ (ppm) = 7.91–7.81 (m, 4H, HNaph), 7.66
(ddapp, Japp = 8.0, 1.3 Hz, 1H, Hꢀ3’), 7.63 (ddapp, Japp = 8.6, 1.8 Hz, 1H, HNaph), 7.52–7.43
(m, 2H, HNaph), 7.39 (ddapp, Japp = 7.7, 1.8 Hz, 1H, Hꢀ6’), 7.31 (pseudoꢀtdapp,
3Japp ≈ 7.5 Hz, Japp = 1.3 Hz, 1H, Hꢀ5’), 7.12 (dddapp, Japp = 8.0, 7.3, 1.8 Hz, 1H, Hꢀ4’),
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6.50 (s, 1H, Hꢀ2), 4.12 (t, J = 6.0 Hz, 2H, Hꢀ5), 2.84 (t, J = 6.4 Hz, 2H, Hꢀ8), 2.03–1.97
(m, 2H, Hꢀ6), 1.90–1.84 (m, 2H, Hꢀ7); 13C NMR, HSQC, HMBC (100.6 MHz, DMSOꢀd6) δ
(ppm) = 137.9 (Cꢀ1’), 133.6 (CqNaph), 133.1 (Cꢀ3’), 132.2 (Cꢀ6’), 132.2 (Cꢀ3), 132.1
(CqNaph), 130.9 (CqNaph), 128.6 (Cꢀ8a), 128,0 (CHNaph), 127,9 (CHNaph), 127,8 (CHNaph),
127,7 (Cꢀ4’), 127.4 (CHNaph), 127.1 (Cꢀ5’), 126.8 (CHNaph), 126.4 (CHNaph), 125.8
(CHNaph), 124.3 (Cꢀ2’), 120.0 (Cꢀ1), 110.7 (Cꢀ2), 45.3 (Cꢀ5), 24.1 (Cꢀ6), 23.6 (Cꢀ8), 20.9
(Cꢀ7); IR (ATR): ꢀ (cm−1) = 3053, 2944, 1628, 1600, 1326, 1025, 908, 756, 730, 639;
ESIꢀHRMS calcd for [C24H20NBr + H]+ 402.0857, found 402.0848.
7-(2-Bromophenyl)-5-(naphthalen-2-yl)-2,3-dihydro-1H-pyrrolizine (8l). The title
compound was prepared according to the general procedure from cyanopyrroline 1e
(0.188 g, 0.501 mmol, 1.0 equiv) and 1ꢀbromoꢀ3ꢀchloropropane (0.06 mL, 0.60 mmol,
1.2 equiv) using LDA (0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol,
2.4 equiv for the annulation step). Purification by column chromatography (SiO2,
hexanes/Et2O 100:1) yielded 8l (161 mg, 0.415 mmol, 83%) as a colorless
solid: mp 159.5–160.5 °C (hexanes/Et2O); Rf = 0.18 (SiO2, hexanes/Et2O 100:1);
1H NMR, COSY (400 MHz, CDCl3) δ (ppm) = 7.92–7.90 (m, 1H, HNaph), 7.86–7.79 (m,
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3H, HNaph), 7.70 (ddapp, Japp = 8.6, 1.8 Hz, 1H, HNaph), 7.66 (ddapp, Japp = 8.0, 1.3 Hz, 1H,
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Hꢀ3’’),
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(m,
3H,
2 × HNaph
,
Hꢀ6’’),
7.31
(pseudoꢀtdapp,
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3Japp ≈ 7.5 Hz, 4Japp = 1.3 Hz, 1H, Hꢀ5’’), 7.10 (dddapp, Japp = 8.0, 7.3, 1.8 Hz, 1H, Hꢀ4’’),
6.81 (s, 1H, Hꢀ6), 4.33 (t, J = 7.0 Hz, 2H, Hꢀ3), 3.02 (t, J = 7.4 Hz, 2H, Hꢀ1), 2.61
(pseudoꢀquin., J ≈ 7 Hz, 2H, Hꢀ2); 13C NMR, HSQC, HMBC (100.6 MHz, DMSOꢀd6) δ
(ppm) = 137.8 (Cꢀ7a), 137.5 (Cꢀ1’’), 133.7 (CqNaph), 133.3 (Cꢀ3’’), 131.8 (CqNaph), 131.2
(Cꢀ6’’), 130.7 (CqNaph), 128.3 (2C, Cꢀ5, CHNaph), 127,8 (CHNaph), 127,7 (CHNaph), 127,2
(2C, Cꢀ4’’,5’’), 126.3 (CHNaph), 125.3 (CHNaph), 124.9 (CHNaph), 122.9 (CHNaph), 122.6
(Cꢀ2’’), 116.2 (Cꢀ7), 112.6 (Cꢀ6), 47.4 (Cꢀ3), 28.1 (Cꢀ2), 25.3 (Cꢀ1); IR (ATR):
ꢀ (cm−1) = 3054, 2954, 1628, 1600, 1467, 1129, 1024, 906, 727, 647; ESIꢀHRMS calcd
for [C23H18NBr + H]+ 388.0701, found 388.0704.
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1-(2-Chlorophenyl)-3-(4-fluorophenyl)-5,6,7,8-tetrahydroindolizine (8m). The title
compound was prepared according to the general procedure from cyanopyrroline 1f
(0.148 g, 0.495 mmol, 1.0 equiv) and 1ꢀbromoꢀ4ꢀchlorobutane (0.07 mL, 0.60 mmol,
1.2 equiv) using LDA (0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol,
2.4 equiv for the annulation step). Purification by column chromatography (SiO2,
hexanes/Et2O 150:1) yielded 8m (122 mg, 0.374 mmol, 76%) as a colorless solid: mp
1
112–113.5 °C (hexanes/Et2O); Rf = 0.32 (SiO2, hexanes/Et2O 100:1); H NMR, COSY
(400 MHz, CDCl3) δ (ppm) = 7.45 (ddapp, Japp = 7.9, 1.5 Hz, 1H, Hꢀ3’), 7.44–7.39 (m, 2H,
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Hꢀ2’’,6’’), 7.36 (ddapp, Japp = 7.6, 1.8 Hz, 1H, Hꢀ6’), 7.25 (pseudoꢀtdapp, Japp ≈ 7.5 Hz,
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4Japp = 1.5 Hz,1H, Hꢀ5’), 7.19 (pseudoꢀtdapp, Japp ≈ 7.5 Hz, 4Japp = 1.8 Hz, 1H, Hꢀ4’),
7.12–7.06 (m, 2H, Hꢀ3’’,5’’), 6.37 (s, 1H, Hꢀ2), 3.97 (t, J = 6.0 Hz, 2H, Hꢀ5), 2.83 (t,
J = 6.4 Hz, 2H, Hꢀ8), 2.01–1.94 (m, 2H, Hꢀ6), 1.88–1.81 (m, 2H, Hꢀ7); 13C NMR, HSQC,
1
HMBC (100.6 MHz, DMSOꢀd6) δ (ppm) = 161.9 (d, JCF = 245.8 Hz, Cꢀ4’’), 135.7 (Cꢀ1’),
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133.5 (Cꢀ2’), 132.1 (Cꢀ6’), 131.2 (Cꢀ3), 130.5 (d, JCF = 8.0 Hz, Cꢀ2’’,6’’), 129.9 (Cꢀ3’),
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129.6 (d, JCF = 3.1 Hz, Cꢀ1’’), 128.4 (Cꢀ8a), 127,3 (Cꢀ4’), 126.5 (Cꢀ5’), 117.8 (Cꢀ1),
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115.4 (d, JCF = 21.3 Hz, Cꢀ3’’,5’’), 110.1 (Cꢀ2), 45.0 (Cꢀ5), 24.0 (Cꢀ6), 23.6 (Cꢀ8), 20.9
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(Cꢀ7); IR (ATR): ꢀ (cm−1) = 3058, 2944, 1594, 1524, 1488, 1222, 909, 839, 757, 732;
ESIꢀHRMS calcd for [C20H17NFCl + H]+ 326.1112, found 326.1119.
7-(2-Chlorophenyl)-5-(4-fluorophenyl)-2,3-dihydro-1H-pyrrolizine (8n). The title
compound was prepared according to the general procedure from cyanopyrroline 1f
(0.148 g, 0.495 mmol, 1.0 equiv) and 1ꢀbromoꢀ3ꢀchloropropane (0.06 mL, 0.60 mmol,
1.2 equiv) using LDA (0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol,
2.4 equiv for the annulation step). Purification by column chromatography (SiO2,
hexanes/Et2O 150:1) yielded 8n (114 mg, 0.366 mmol, 74%) as a light yellow
amorphous solid: mp 92–95 °C (hexanes/Et2O); Rf = 0.23 (SiO2, hexanes/Et2O 100:1);
1H NMR, COSY (400 MHz, CDCl3) δ (ppm) 7.50–7.40 (m, 4H, Hꢀ2’,6’, Hꢀ3’’, Hꢀ6’’), 7.25
(m, 1H, Hꢀ5’’), 7.16 (dddapp, Japp = 7.9, 7.3 1.7 Hz, 1H, Hꢀ4’’), 7.11–7.05 (m, 2H, Hꢀ3’,5’),
6.64 (s, 1H, Hꢀ6), 4.16 (t, J = 7.0 Hz, 2H, Hꢀ3), 3.00 (t, J = 7.3 Hz, 2H, Hꢀ1), 2.57
(pseudoꢀquin., J ≈ 7 Hz, 2H, Hꢀ2); 13C NMR, HSQC, HMBC (100.6 MHz, DMSOꢀd6) δ
(ppm) = 161.5 (d, 1JCF = 245.1 Hz, Cꢀ4’), 137.5 (Cꢀ7a), 135.4 (Cꢀ1’’), 132.3 (Cꢀ2’’), 130.9
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(Cꢀ6’’), 130.2 (Cꢀ3’’), 129.7 (d, JCF = 3.2 Hz, Cꢀ1’), 127.8 (Cꢀ5), 127.5 (d, JCF = 7.8 Hz,
Cꢀ2’,6’), 126,9 (Cꢀ4’’), 126.7 (Cꢀ5’’), 115.7 (d, 2JCF = 21.5 Hz, Cꢀ3’,5’), 114.3 (Cꢀ7), 111.8
(Cꢀ6), 47.0 (Cꢀ3), 28.2 (Cꢀ2), 25.6 (Cꢀ1); IR (ATR): ꢀ (cm−1) = 3061, 2976, 1593, 1525,
1480, 1221, 1157, 835, 756, 732; ESIꢀHRMS calcd for [C19H15NFCl + H]+ 312.0955,
found 312.0966.
3-(4-Fluorophenyl)-1-(4-methoxyphenyl)-5,6,7,8-tetrahydroindolizine (8o). The title
compound was prepared according to the general procedure from cyanopyrroline 1g
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(0.147 g, 0.499 mmol, 1.0 equiv) and 1ꢀbromoꢀ4ꢀchlorobutane (0.07 mL, 0.60 mmol,
1.2 equiv) using LDA (0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol,
2.4 equiv for the annulation step). Purification by column chromatography (SiO2,
Cy/EtOAc 20:1) yielded 8o (131 mg, 0.408 mmol, 82%) as a colorless solid: mp 131.5–
133 °C (Cy/EtOAc); Rf = 0.36 (SiO2, Cy/EtOAc 20:1); 1H NMR, COSY (400 MHz, CDCl3)
δ (ppm) = 7.42–7.36 (m, 4H, Hꢀ2’,6’, Hꢀ2’’,6’’), 7.12–7.06 (m, 2H, Hꢀ3’’,5’’), 6.95–6.91
(AA’ part of AA’–BB’ system, 2H, Hꢀ3’,5’), 6.34 (s, 1H, Hꢀ2), 3.94 (t, J = 5.9 Hz, 2H, Hꢀ5),
3.83 (s, 3H, OCH3), 3.01 (t, J = 6.4 Hz, 2H, Hꢀ8), 1.99–1.92 (m, 2H, Hꢀ6), 1.91–1.83 (m,
2H, Hꢀ7); 13C NMR, HSQC, HMBC (100.6 MHz, DMSOꢀd6) δ (ppm) = 162.0 (d,
1JCF = 246.4 Hz, Cꢀ4’’), 157,4 (Cꢀ4’), 131.9 (Cꢀ3), 130.6 (d, 3JCF = 8.0 Hz, Cꢀ2’’,6’’), 129.7
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(d, JCF = 3.1 Hz, Cꢀ1’’), 129.5 (Cꢀ1’), 128.5 (Cꢀ2’.6’), 126.5 (Cꢀ8a), 119.9 (Cꢀ1), 115.4
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(d, JCF = 21.3 Hz, Cꢀ3’’,5’’), 114.0 (Cꢀ3’,5‘), 108.0 (Cꢀ2), 55.4 (OCH3), 45.1 (Cꢀ5), 24.1
(Cꢀ8), 23.8 (Cꢀ6), 21.2 (Cꢀ7); IR (ATR): ꢀ (cm−1) = 3071, 2937, 1573, 1503, 1244, 1178,
1158, 1033, 835, 728; ESIꢀHRMS calcd for [C21H20NOF + H]+ 322.1607, found
322.1602.
5-(4-Fluorophenyl)-7-(4-methoxyphenyl)-2,3-dihydro-1H-pyrrolizine (8p). The title
compound was prepared according to the general procedure from cyanopyrroline 1g
(0.147 g, 0.499 mmol, 1.0 equiv) and 1ꢀbromoꢀ3ꢀchloropropane (0.06 mL, 0.60 mmol,
1.2 equiv) using LDA (0.60 mmol, 1.2 equiv for the alkylation step, then 1.20 mmol,
2.4 equiv for the annulation step). Purification by column chromatography (SiO2,
Cy/EtOAc 10:1) yielded 8p (113 mg, 0.368 mmol, 74%) as a colorless solid: mp 145.5–
1
146.5 °C (Cy/EtOAc); Rf = 0.28 (SiO2, Cy/EtOAc 10:1); H NMR, COSY (400 MHz,
CDCl3) δ (ppm) = 7.48–7.41 (m, 4H, Hꢀ2’,6’, Hꢀ2’’,6’’), 7.10–7.04 (m, 2H, Hꢀ3’,5’), 6.94–
6.90 (AA’ part of AA’–BB’ system, 2H, Hꢀ3’’,5’’), 6.58 (s, 1H, Hꢀ2), 4.12 (t, J = 7.1 Hz,
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