One-pot procedure for the synthesis of N-substituted 2-(arylmethyl) pyrrolidines from l-aryl-2-cyclopropylalkynes and primary amines by a hydroamination/cyclopropylimine rearrangement/reduction sequence

Article abstract of DOI:10.1002/ejoc.200900515

A one-pot procedure for the synthesis of N-substituted 2(arylmethyl) pyrrolidines from l-aryl-2-cyclopropylalkynes and primary amines is presented. The procedure proceeded first through an [Ind₂TiMe ₂]-catalyzed regioselective hydroa

Full text of DOI:10.1002/ejoc.200900515

FULL PAPER
DOI: 10.1002/ejoc.200900515
One-Pot Procedure for the Synthesis of N-Substituted
2-(Arylmethyl)pyrrolidines from 1-Aryl-2-cyclopropylalkynes and Primary
Amines by a Hydroamination/Cyclopropylimine Rearrangement/Reduction
Sequence
Kerstin Gräbe,[a] Björn Zwafelink,[a] and Sven Doye*[a]
Keywords: Alkynes / Amines / Reduction / Hydroamination / Titanium / Rearrangement
A one-pot procedure for the synthesis of N-substituted 2-
(arylmethyl)pyrrolidines from 1-aryl-2-cyclopropylalkynes
and primary amines is presented. The procedure proceeded
first through an [Ind2TiMe2]-catalyzed regioselective hydro-
amination of a 1-aryl-2-cyclopropylalkyne with a primary
amine. The resulting cyclopropylimine, which was not iso-
arrangement in the presence of catalytic amounts of NH4Cl
at 145 °C to deliver the corresponding 2-pyrroline. A subse-
quent reduction performed with NaBH3CN and ZnCl2 finally
gave the desired N-substituted 2-(arylmethyl)pyrrolidine.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
lated, was then forced to undergo a cyclopropylimine re- Germany, 2009)
as the substrate in an intramolecular hydroamination reac-
Introduction
tion. However, in most cases the hydroamination approach
is used to obtain 2-methylpyrrolidines (R1 = H) with ad-
ditional substituents in the 4-position (R2, R3 ϶ H). The
Thorpe–Ingold effect is responsible for the fact that with
many hydroamination catalysts only geminally disubsti-
tuted 1-amino-4-pentenes (R2, R3 ϶ H) undergo successful
cyclization reactions. Furthermore, it has been found for
many catalysts that only monosubstituted (R1 = H) or
phenyl-substituted alkene moieties (R1 = Ph) are tolerated.
With these limitations in mind we started a project to de-
velop an alternative hydroamination approach towards the
synthesis of 2-substituted pyrrolidines.
The hydroamination of alkenes[1] is regarded as an envi-
ronmentally friendly and ecologically desirable process.
Consequently, much effort has been spent on the identifica-
tion of catalysts that allow the addition of N–H across car-
bon–carbon double bonds.[1,2] Despite the great progress
achieved during the last few years, it should be noted that
most of the existing catalytic systems are only suitable for
intramolecular reactions of aminoalkenes. The majority of
published examples of hydroamination reactions describe
cyclization reactions of 1-amino-4-pentene derivatives that
give access to the corresponding 2-substituted pyrrolidines
(Scheme 1). However, from a synthetic point of view, this
hydroamination approach towards the synthesis of pyrrolid-
ines is not particularly elegant because the method gen-
erally used for the synthesis of the starting materials, the 1-
amino-4-pentene derivatives,[3] is not very flexible. Usually,
the first step is an alkylation of a suitable nitrile with an
allylic halide. The resulting 4-pentenenitrile is then reduced
in a second step to give the corresponding 1-amino-4-pen-
tene. A final intramolecular hydroamination yields a 2-sub-
stituted and N-unsubstituted pyrrolidine. To obtain the cor-
responding N-substituted products, a further alkylation (or
arylation) is required. Alternatively, the 1-amino-4-pentene
can be converted into a secondary amine, which is then used
[a] Institut für Reine und Angewandte Chemie,
Universität Oldenburg,
Carl-von-Ossietzky-Str. 9–11, 26111 Oldenburg, Germany
Fax: +49-441-798-3329
E-mail: doye@uni-oldenburg.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900515.
Scheme 1. Synthesis of 2-substituted pyrrolidines from 1-amino-4-
pentenes by intramolecular hydroamination.
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In contrast to the intermolecular hydroamination of al- ditions,[8] a catalyst system consisting of 5 mol-% [(PhCN)2-
kenes, the corresponding protocols for the intermolecular PdCl2], 10 mol-% PPh3, and 5 mol-% Cu(OAc)2·H2O was
addition of amines to alkynes are well established.[4] In par- used for this substrate.[8,9]
ticular, Ti complexes have been shown to catalyze the hy-
Table 1. Synthesis of 1-aryl-2-cyclopropylalkynes by Sonogashira
droamination of all classes of alkynes with primary
coupling.
amines.[5] Particularly interesting is the fact that the corre-
sponding reactions of unsymmetrically substituted 1-alkyl-
2-arylalkynes take place with high anti-Markovnikov selec-
tivity. Correspondingly, 1-aryl-2-cyclopropylalkynes un-
dergo hydroamination reactions with primary amines to
give cyclopropylimine derivatives (Scheme 2). However, at
elevated temperatures, cyclopropylimines are known to un-
dergo an acid-catalyzed rearrangement to give 2-pyrro-
lines,[6] which can be further reduced to the desired pyrrol-
idines. Obvious advantages of the envisioned strategy are
the commercial availability of many primary amines and
the easy accessibility of 1-aryl-2-cyclopropylalkynes from
common aryl halides and cyclopropylacetylene by Sonoga-
shira coupling. Additionally, it should be noted that the
cyclopropylimine rearrangement does not require the pres-
ence of any additional substituents in the cyclopropyl ring.
Consequently, the new approach should offer a simple way
to synthesize 2-substituted pyrrolidines that do not possess
any further substituents in the carbon chain of the heterocy-
clic ring.
[a] Reaction conditions: aryl halide (10.0 mmol), cyclopropylacetyl-
ene (10.0 mmol), [PdCl2(PPh3)2] (0.2 mmol, 2.0 mol-%), CuI
(0.4 mmol, 4.0 mol-%), PPh3 (0.4 mmol, 4.0 mol-%), NEt3 (30 mL),
25 °C, 16 h. The yields refer to isolated pure compounds. [b] Dif-
ferent reaction conditions were used for the coupling reaction of 2-
bromo-1,3-thiazole (6): aryl halide (10.0 mmol), alkyne
(10.0 mmol), [(PhCN)2PdCl2] (0.5 mmol, 5.0 mol-%), PPh3
(1.0 mmol, 10.0 mol-%), Cu(OAc)2·H2O (0.5 mmol, 5.0 mol-%), di-
isopropylamine (20 mL), 45 °C, 12 h.
With the 1-aryl-2-cyclopropylalkynes 8–14 in hand we
turned our attention towards the envisioned hydroamin-
ation/cyclopropylimine rearrangement/reduction sequence
(Scheme 2, Table 2). Thus, we performed an initial hydro-
amination reaction between 1-phenyl-2-cyclopropylacetylene
(8) and p-toluidine in the presence of 5 mol-% [Ind2TiMe2]
(Ind = η5-indenyl) in toluene at 105 °C. After 24 h, a sample
of the reaction mixture was transferred into an NMR tube
Scheme 2. Synthesis of 2-(arylmethyl)pyrrolidines from aryl
halides, cyclopropylacetylene, and primary amines.
Results and Discussion
Initial Sonogashira coupling reactions performed with and diluted with CDCl3. NMR analysis of this sample
the commercially available aryl halides 1–6 (Table 1) or 2- showed that the alkyne 8 was completely transformed into
iodofuran (7) and cyclopropylacetylene[7] gave the desired the corresponding (p-tolylmethyl)cyclopropylimine. The re-
1-aryl-2-cyclopropylalkynes 8–14 in moderate to excellent gioselectivity of the addition was determined to be Ͼ98:2.
yields (58–96%). The coupling reactions were usually per- The subsequent cyclopropylimine rearrangement was then
formed under standard Sonogashira conditions in the pres- achieved by the direct addition of 20 mol-% NH4Cl and
ence of 2 mol-% [(PPh3)2PdCl2], 4 mol-% PPh3, and 4 mol- heating of the reaction mixture at 145 °C for 8 h. After that
% CuI. Because coupling reactions employing 2-bromo- time, the formation of the expected 2-pyrroline was con-
1
thiazole (6) do not give satisfactory yields under these con- firmed by H NMR spectroscopy. For the final reduction,
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Synthesis of N-Substituted 2-(Arylmethyl)pyrrolidines
NaBH3CN, ZnCl2, and methanol were added to the reac- Table 2. One-pot synthesis of 2-(arylmethyl)pyrrolidines from 1-
aryl-2-cyclopropylalkynes by a hydroamination/cyclopropylimine
rearrangement/reduction sequence.
tion mixture, which was stirred at room temperature for
20 h. It was possible to isolate the desired pyrrolidine 15 in
90% yield (Table 2, Entry 1). Surprisingly, the obtained
pure product 15 turned out to be relatively unstable, and
complete decomposition of 15 took place within 1 h.
Having identified a suitable experimental protocol for the
envisioned synthetic strategy we performed a number of re-
actions under identical conditions with various alkynes and
amines (Table 2). First, it was recognized that comparably
high yields (86 and 70%) of the stable pyrrolidines 16 and
17 (Table 2, Entries 2 and 3) were obtained when the alk-
ylamines cyclopentylamine or tert-butylamine were used
with alkyne 8. In contrast, the reaction with benzylamine
gave the desired pyrrolidine 18 with a significantly de-
creased yield of only 23%. A simple explanation for this
observation could be the decreased reactivity of high-boil-
ing and sterically less hindered amines in the [Ind2TiMe2]-
catalyzed hydroamination reactions of alkynes.[5m] Because
it has previously been found[5m] that much higher yields
from [Ind2TiMe2]-catalyzed hydroamination reactions are
obtained when amines like benzylamine are added slowly
to the reaction mixture, an additional reaction with a corre-
spondingly changed experimental protocol in which ben-
zylamine was added slowly to the reaction mixture over a
period of 4 h at 105 °C was performed. In this experiment,
the desired pyrrolidine 18 was formed in 63% yield (Table 2,
Entry 4). Correspondingly, all other reaction sequences in-
volving the use of benzylamine were performed under these
conditions. Although the corresponding reactions per-
formed with 1-cyclopropyl-2-(p-tolyl)acetylene (9) and one
of the four amines (p-toluidine, cyclopentylamine, tert-
butylamine, benzylamine) gave results (Table 2, Entries 5–8)
that are almost identical to those obtained with 1-cyclopro-
pyl-2-phenylacetylene (8), the reaction sequence performed
with the ortho-substituted alkyne 10 and tert-butylamine
only led to trace amounts of pyrrolidine 25. Because 70%
of the alkyne 10 could be recovered from the reaction mix-
ture, it can be assumed that this poor result is mainly
caused by steric repulsion between the bulky amine and the
ortho substituent of the alkyne during the hydroamination
step. The improved results obtained with the sterically less
demanding amines p-toluidine, cyclopentylamine, and ben-
zylamine (Table 2, Entries 9, 10, 12) are in good agreement
with this explanation. However, 25 could be isolated with a
slightly better yield of 22% (Table 2, Entry 11, footnote [c])
when the cyclopropylimine rearrangement was performed
in the presence of stoichiometric amounts of NH4Cl
(1 equiv.). This result suggests that the sterically demanding
tert-butyl substituent at the nitrogen atom of the initially
formed imine in combination with a bulky aryl system also
leads to a less efficient rearrangement reaction.
In contrast to the phenyl-substituted alkynes 8–10, the
pyridine-containing alkyne 11 turned out to be a poor sub-
strate (Table 2, Entries 13–17). Employing this alkyne in
combination with p-toluidine, cyclopentylamine, tert-
butylamine, or benzylamine led to the isolation of only one
of the desired pyrrolidines (27, Table 2, Entry 13) in poor
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K. Gräbe, B. Zwafelink, S. Doye
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Table 2. (Continued)
Table 2. (Continued)
[a] Reaction conditions: (a) alkyne (2.40 mmol), amine
(2.64 mmol), [Ind2TiMe2] (0.12 mmol, 5.0 mol-%), 105 °C, 24 h; (b)
NH4Cl (0.48 mmol, 20 mol-%), 145 °C, 5–7 h; (c) NaBH3CN
(4.80 mmol), ZnCl2 (2.40 mmol), MeOH, 25 °C, 20 h. [b] The
amine was added slowly to the reaction mixture over a period of
4 h. [c] A yield of 22% was obtained when the cyclopropylimine
rearrangement step was performed with 2.40 mmol of NH4Cl
(100 mol-%). [d] Estimated by NMR spectroscopy.
yield (15%) along with a large amount of decomposition
products. All the other reactions performed with 11 led to
the complete consumption of the alkyne and the formation
of a number of unidentified compounds. Owing to the fact
that the only successful reaction was achieved with the aryl-
amine p-toluidine we also performed the reaction with 4-
methoxyaniline (Table 2, Entry 17), which gave the desired
pyrrolidine in 18% yield. This result suggests that this one-
pot procedure with alkyne 11 can only be successfully per-
formed with arylamines. Fortunately, not all heteroaromatic
systems cause comparable problems. By using p-toluidine,
cyclopentylamine, or tert-butylamine, it was possible to
convert the thiophene-containing alkyne 12 (Table 2, En-
tries 18–20) into the corresponding pyrrolidines 32, 33, and
34 in 72, 87, and 71% yields, respectively. In addition, the
corresponding N-benzyl-substituted product 35 was iso-
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Synthesis of N-Substituted 2-(Arylmethyl)pyrrolidines
lated in an acceptable yield of 57% from a reaction in which p-toluidine resulted in the formation of a diastereomeric
the amine was added slowly to the reaction mixture mixture of the desired pyrrolidine 47. However, it was found
(Table 2, Entry 21). Further reactions performed with the that the initial hydroamination reaction is slow, which can
thiazolyl-substituted alkyne 13 (Table 2, Entries 22–26) gave probably be explained by the steric hindrance caused by
results similar to those obtained with the pyridine-contain- the bulky 1-phenylcyclopropyl substituent of the alkyne 45.
ing alkyne 11. Although the reaction sequence performed After some optimization, we performed the initial hydro-
with p-toluidine gave the pyrrolidine 36 in a very good yield amination in the presence of 10 mol-% [Ind2TiMe2] at 160 °C
(86%), it was not possible to isolate the desired products for 48 h and the subsequent cyclopropylimine rearrange-
from the reactions performed with cyclopentylamine, tert- ment with 50 mol-% NH4Cl at 145 °C for 8 h. After subse-
butylamine, or benzylamine. In all these cases, a number of quent reduction of the formed enamines 46a and 46b, the
unidentified compounds were formed. However, an ad- desired pyrrolidine 47 was obtained as a 54:46 mixture of
ditional experiment with 4-methoxyaniline gave the corre- two diastereomers in 48% yield. Owing to the slow hydro-
sponding product in 35% yield (Table 2, Entry 26). This re- amination step, 43% of the starting material 45 was also
sult suggests that the thiazole-containing alkyne 13 is an- recovered.
other example of a substrate that can only be used in com-
bination with an aromatic amine. Finally, reactions with the
furan-containing alkyne 14 turned out to be unsuccessful
with all the amines employed. In this context, it should be
Conclusions
We have developed a new one-pot procedure for the syn-
thesis of N-substituted 2-(arylmethyl)pyrrolidines from 1-
aryl-2-cyclopropylalkynes and primary amines. The pro-
cedure proceeds first by a regioselective hydroamination of
a 1-aryl-2-cyclopropylalkyne with a primary amine per-
formed in the presence of 5 mol-% [Ind2TiMe2]. The re-
sulting cyclopropylimine, which is not isolated, is then
forced to undergo a cyclopropylimine rearrangement in the
presence of substoichiometric amounts of NH4Cl at 145 °C
to give the corresponding 2-pyrroline. Subsequent re-
duction using NaBH3CN and ZnCl2 finally gives the de-
sired N-substituted 2-(arylmethyl)pyrrolidine. Obvious ad-
vantages of the new protocol are the commercial availability
of many primary amines and the easy accessibility of 1-
aryl-2-cyclopropylalkynes from common aryl halides and
cyclopropylacetylene by Sonogashira coupling. As a conse-
quence, structural variations of the aromatic substituent as
well as changes of the substituent at the nitrogen atom of
the pyrrolidine product can easily be achieved. Further
studies extending the method to more substituted alkyne
substrates are presently underway in our laboratories.
noted that although the desired products 41–44 could not
be isolated, in situ H NMR studies undoubtedly proved
1
the formation of pyrrolidine derivatives during the reaction
performed with 14 and p-toluidine. Unfortunately, this reac-
tion seems to take place along with a decomposition of the
acid-sensitive furan ring.
To extend the method to the synthesis of more substi-
tuted pyrrolidines, we synthesized alkyne 45 (Scheme 3),
which contains a 1,1-disubstituted cyclopropyl ring. To this
end, the propargylic position of alkyne 9 was first lithiated.
Subsequent transmetalation with ZnCl2 and Negishi cou-
pling with iodobenzene (1) gave the desired alkyne 45 in
91% yield.[11] Fortunately, the hydroamination/cyclopro-
pylimine rearrangement/reduction sequence performed with
Experimental Section
General: All reactions were performed under argon or nitrogen in
oven-dried Duran glassware using standard Schlenk-line and glove-
box techniques. [Ind2TiMe2] was synthesized according to a litera-
ture procedure.[10] Toluene (toluene extra dry with molecular sieves,
99.85%, water Ͻ 50 ppm) and methanol (methanol extra dry,
99.9%, water Ͻ 50 ppm) were purchased from Acros Organics. Cy-
clopropylacetylene was either purchased from Acros Organics or
synthesized according to a literature procedure.[7] p-Toluidine was
purified by Kugelrohr distillation. 2-Iodofuran (7) was synthesized
according to a literature procedure.[12] Cyclopentylamine, benzyla-
mine, triethylamine, and tert-butylamine were purified and dried
by distillation (20 cm Vigreux column) from CaH2 on molecular
sieves at ambient pressure under an inert gas. All other reagents
were purchased from commercial sources and were used without
further purification. All alkynes, amines and [Ind2TiMe2] were
stored in
a nitrogen-filled glove box (M. Braun, Unilab).
Scheme 3. Synthesis of the 1,2,3-trisubstituted pyrrolidine 47. [a]
43% of unconsumed starting material (45) was recovered.
[Ind2TiMe2] was cooled to –30 °C. Unless otherwise noted, yields
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refer to isolated yields of pure compounds as gauged by thin-layer
chromatography (TLC) and 1H and 13C NMR spectroscopy. All
products were characterized by 1H and 13C NMR, and IR spec-
troscopy and mass spectrometry (MS). Additional characterization
data were obtained by high-resolution mass spectrometry (HRMS).
NMR spectra were recorded with the following spectrometers:
Bruker Avance DPX 300, Bruker Avance DRX 500, and Bruker
Alkyne 10: General procedure A was used to synthesize alkyne 10
from 2-iodotoluene (3) and cyclopropylacetylene. After purification
by Kugelrohr distillation (90 °C, 0.56 mbar) and subsequent flash
chromatography (PE), compound 10 (1.10 g, 7.04 mmol, 70%) was
1
isolated as a light-yellow liquid. H NMR (500 MHz, CDCl3): δ =
0.77–0.84 (m, 2 H, 10-H), 0.86–0.92 (m, 2 H, 10-H), 1.46–1.53 (m,
1 H, 9-H), 2.39 (s, 3 H, 11-H), 7.06–7.12 (m, 1 H, Ar-H), 7.13–7.18
1
3
Avance III 500. All H NMR spectra are reported in δ units (ppm)
(m, 2 H, Ar-H), 7.35 (d, JH,H = 7.5 Hz, 2 H, Ar-H) ppm. 13C
relative to the signal for CDCl3 at δ = 7.26 ppm. All 13C NMR NMR (126 MHz, DEPT, CDCl3): δ = 0.3 (CH), 8.8 (CH2), 20.6
spectra are reported in δ units (ppm) relative to the central line of
the triplet for CDCl3 at δ = 77.0 ppm. IR spectra were recorded
with a Bruker Tensor 27 spectrometer using an attenuated total
reflection (ATR) method. Mass spectra were recorded with a Finni-
gan MAT 95 spectrometer (EI with an ionization potential of 70 eV
or CI with isobutane as ionization gas). GC analyses were per-
formed with a Shimadzu GC-2010 gas chromatograph equipped
with a flame-ionization detector. GC–MS analyses were performed
with a Thermo Finnigan Focus gas chromatograph equipped with
a DSQ mass detector. TLC analyses were performed with Poly-
gram® SIL G/UV254 plates from Macherey–Nagel. Compounds
were detected by using UV light or iodine. Silica gel 60 from Fluka
(230–400 mesh, particle size 40–63 µm) was used for flash
chromatography (PE: light petroleum ether, b.p. 40–60 °C).
(CH3), 74.5 (C), 97.5 (C), 123.7 (C), 125.4 (CH), 127.4 (CH), 129.2
(CH), 131.8 (CH), 140.0 (C) ppm. IR (neat): ν = 3095, 3015, 2922,
˜
2231, 1602, 1488, 1457, 1030, 956, 755, 718 cm–1. MS (EI): m/z (%)
= 156 (100) [M]+, 141 (57) [M – CH3]+, 128 (45) [M – C2H4]+, 115
(62) [M – C3H5]+. HRMS (EI): calcd. for C12H12 156.0939; found
156.0936.
Alkyne 11: General procedure A was used to synthesize alkyne 11
from 2-iodopyridine (4) and cyclopropylacetylene. After purifica-
tion by Kugelrohr distillation (125 °C, 0.56 mbar) and subsequent
flash chromatography (PE/EtOAc, 5:1), compound 11 (1.29 g,
9.13 mmol, 91%) was isolated as a colorless solid. 1H NMR
(500 MHz, CDCl3): δ = 0.82–0.87 (m, 4 H, 10-H), 1.39–1.47 (m, 1
3
4
H, 9-H), 7.10 (ddd, JH,H = 7.7, 5.0, JH,H = 0.8 Hz, 1 H, Ar-H),
7.30 (br. d, 3JH,H = 7.9 Hz, 1 H, Ar-H), 7.58 (td, 3JH,H = 7.6, 4JH,H
Sonogashira Coupling. General Procedure A: CuI (77 mg, 0.4 mmol, = 1.7 Hz, 1 H, Ar-H), 8.46 (br. d, 3JH,H = 4.4 Hz, 1 H, Ar-H) ppm.
4.0 mol-%), [(PPh3)2PdCl2] (141 mg, 0.2 mmol, 2.0 mol-%), PPh3 13C NMR (126 MHz, DEPT, CDCl3): δ = 0.0 (CH), 8.7 (CH2),
(105 mg, 0.4 mmol, 4.0 mol-%), and NEt3 (30 mL) were placed in a
round-bottomed flask equipped with a magnetic stirring bar. After
addition of the aryl halide (10.0 mmol), the mixture was stirred at
25 °C for 30 min, and cyclopropylacetylene (661 mg, 10.0 mmol)
was then added. After this had been stirred at 25 °C for 16 h, satu-
rated NH4Cl solution was added. The mixture was extracted with
tert-butyl methyl ether (3ϫ50 mL). The combined organic layers
were dried with MgSO4 and concentrated under vacuum. The resi-
due was purified by Kugelrohr distillation and subsequent flash
chromatography (SiO2).
75.5 (C), 94.1 (C), 122.0 (CH), 126.6 (CH), 135.9 (CH), 143.8 (C),
149.7 (CH) ppm. IR (neat): ν = 3047, 3007, 2237, 2221, 1580, 1466,
˜
1429, 1061, 961, 782, 747 cm–1. MS (EI): m/z (%) = 143 (100)
[M]+, 142 (70) [M – H]+, 117 (98) [M – C2H2]+, 115 (35) [M –
C2H4]+. HRMS (EI): calcd. for C10H9N 143.0735; found 143.0734.
Alkyne 12: General procedure A was used to synthesize alkyne 12
from 2-iodothiophene (5) and cyclopropylacetylene. After purifica-
tion by Kugelrohr distillation (70 °C, 0.50 mbar) and subsequent
flash chromatography (PE), compound 12 (1.26 g, 8.50 mmol,
85%) was isolated as light-brown liquid. 1H NMR (500 MHz,
CDCl3): δ = 0.79–0.84 (m, 2 H, 9-H), 0.84–0.91 (m, 2 H, 9-H),
Alkyne 8: General procedure A was used to synthesize alkyne 8
from iodobenzene (1) and cyclopropylacetylene. After purification
by Kugelrohr distillation (130 °C, 0.56 mbar) and subsequent flash
3
1.43–1.50 (m, 1 H, 8-H), 6.91 (dd, JH,H = 5.1, 3.7 Hz, 1 H, Ar-
3
3
H), 7.10 (d, JH,H = 3.5 Hz, 1 H, Ar-H), 7.15 (d, JH,H = 5.0 Hz,
chromatography (PE), compound 8 (1.29 g, 9.13 mmol, 91%) was
1 H, Ar-H) ppm. 13C NMR (126 MHz, DEPT, CDCl3): δ = 0.3
1
isolated as a light-yellow liquid. H NMR (500 MHz, CDCl3): δ = (CH), 8.7 (CH2), 68.8 (C), 97.4 (C), 124.2 (C), 125.9 (CH), 126.7
0.78–0.82 (m, 2 H, 8-H), 0.83–0.89 (m, 2 H, 8-H), 1.41–1.48 (m, 1 (CH), 131.2 (CH) ppm. IR (neat): ν = 3093, 3012, 2222, 1519, 1428,
˜
H, 7-H), 7.23–7.28 (m, 3 H, Ar-H), 7.35–7.39 (m, 2 H, Ar-H) ppm. 1243, 1204, 1173, 1028, 931, 850, 828, 810, 693 cm–1. MS (EI): m/z
13C NMR (126 MHz, DEPT, CDCl3): δ = 0.1 (CH), 8.6 (CH2), (%) = 148 (100) [M]+, 147 (95) [M – H]+, 115 (30) [M – HS]+,
75.8 (C), 93.4 (C), 123.9 (C), 127.4 (CH), 128.2 (CH), 131.6 (CH) 43 (22) [C3H7]+. HRMS (EI): calcd. for C9H8S 148.0348; found
ppm. IR (neat): ν = 3083, 3057, 3015, 2235, 1599, 1494, 1030, 955,
148.0347.
˜
834, 813, 755, 692 cm–1. MS (EI): m/z (%) = 142 (95) [M]+, 141
(100) [M – H]+, 115 (32) [M – C2H2]+, 43 (38) [C3H7]+. HRMS
(EI): calcd. for C11H10 142.0783; found 142.0786.
Alkyne 13: Cu(OAc)2·H2O (200 mg, 1.0 mmol, 10.0 mol-%),
[(PhCN)2PdCl2] (193 mg, 0.5 mmol, 5.0 mol-%), PPh3 (262 mg,
1.0 mmol, 10.0 mol-%), and diisopropylamine (30 mL) were placed
in a round-bottomed flask equipped with a magnetic stirring bar.
After the addition of 2-bromo-1,3-thiazole (6; 1.64 g, 10.0 mmol),
the mixture was stirred at 25 °C for 30 min, and cyclopropylacetyl-
ene (661 mg, 10.0 mmol) was then added. After this mixture had
Alkyne 9: General procedure A was used to synthesize alkyne 9
from 4-iodotoluene (2) and cyclopropylacetylene. After purification
by Kugelrohr distillation (80 °C, 0.30 mbar) and subsequent flash
chromatography (PE), compound 9 (1.50 g, 9.60 mmol, 96%) was
1
isolated as a light-yellow liquid. H NMR (500 MHz, CDCl3): δ = been stirred at 25 °C for 16 h, a saturated NH4Cl solution was
0.79–0.84 (m, 2 H, 8-H), 0.84–0.90 (m, 2 H, 8-H), 1.43–1.49 (m, 1 added. The mixture was extracted with tert-butyl methyl ether
3
H, 7-H), 2.34 (s, 3 H, 9-H), 7.09 (d, JH,H = 8.1 Hz, Ar-H), 7.29
(3ϫ50 mL). The combined organic layers were dried with MgSO4
and concentrated under vacuum. After purification by Kugelrohr
(d, JH,H = 8.1 Hz, 2 H, Ar-H) ppm. 13C NMR (126 MHz, DEPT,
3
CDCl3): δ = 0.1 (CH), 8.5 (CH2), 21.3 (CH3), 75.8 (C), 92.5 (C), distillation (140 °C, 1.3 mbar) and subsequent flash chromatog-
120.8 (C), 128.9 (CH), 131.4 (CH), 137.3 (C) ppm. IR (neat): ν = raphy (PE/EtOAc, 5:1), compound 13 (1.01 g, 6.80 mmol, 68%)
˜
1
3081, 3011, 2921, 2864, 2234, 1510, 1052, 1028, 954, 839, 814 cm–1. was isolated as a yellow liquid. H NMR (500 MHz, CDCl3): δ =
MS (CI): m/z (%) = 157 (100) [M + H]+, 156 (97) [M]+, 141 (22) 0.85–1.03 (m, 4 H, 9-H), 1.41–1.56 (m, 1 H, 8-H), 7.25 (d, JH,H
=
3
[M – CH3]+, 105 (12) [M – C4H3]+. HRMS (CI): calcd. for C12H12 3.3 Hz, 1 H, Ar-H), 7.74 (d, JH,H = 3.2 Hz, 1 H, Ar-H) ppm. 13C
3
+ H 157.1017; found 157.1019.
NMR (126 MHz, DEPT, CDCl3): δ = 0.2 (CH), 8.9 (CH2), 69.2
5570
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5565–5575

Synthesis of N-Substituted 2-(Arylmethyl)pyrrolidines
(C), 99.4 (C), 119.7 (CH), 143.0 (CH), 149.5 (C) ppm. IR (neat): ν (126 MHz, CDCl3): δ = 22.7 (CH2), 23.7 (CH2), 24.0 (CH2), 29.0
˜
= 3114, 3082, 3011, 2221, 1480, 1225, 1138, 1084, 1053, 936, 873,
(CH2), 29.8 (CH2), 32.1 (CH2), 40.8 (CH2), 51.3 (CH2), 64.1 (CH),
814, 721, 619 cm–1. MS (EI): m/z (%) = 149 (56) [M]+, 58 (58) 64.4 (CH), 125.8 (CH), 128.2 (CH), 129.1 (CH), 140.4 (C) ppm.
[C2H2S]+, 43 (100) [C3H7]+. HRMS (EI): calcd. for C8H7NS
149.0299; found 149.0298.
IR (neat): ν = 3027, 2954, 2869, 2789, 1605, 1496, 1454, 1344, 1215,
˜
1134, 742, 700 cm–1. MS (CI, 25 °C): m/z (%) = 230 (100) [M +
H]+, 138 (45) [M – C7H7]+. HRMS (CI): calcd. for C16H23N + H
230.1909; found 230.1911.
Alkyne 14: General procedure A was used to synthesize alkyne 14
from 2-iodofuran (7) and cyclopropylacetylene. After purification
by flash chromatography (PE/EtOAc, 40:1), compound 14 (772 mg,
5.84 mmol, 58%) was isolated as a light-yellow liquid. 1H NMR
(500 MHz, CDCl3): δ = 0.82–0.85 (m, 2 H, 9-H), 0.86–0.92 (m, 2
2-Benzyl-1-tert-butylpyrrolidine (17): General procedure B was used
to synthesize pyrrolidine 17 from alkyne 8 and tert-butylamine. Af-
ter purification by flash chromatography (PE/EtOAc, 40:1 Ǟ
EtOAc + 3% 7  NH3 in MeOH), compound 17 (366 mg,
1.68 mmol, 70%) was isolated as an orange liquid. 1H NMR
(500 MHz, CDCl3): δ = 1.17 (s, 9 H, tBu), 1.37–1.46 (m, 1 H), 1.63
(dd, JH,H = 12.3, 6.0 Hz, 1 H), 1.68–1.77 (m, 1 H), 1.78–1.91 (m,
1 H), 2.52 (dd, 2JH,H = 13.3, 3JH,H = 11.0 Hz, 1 H, 6-H), 2.65 (ddd,
3
H, 9-H), 1.43–1.51 (m, 1 H, 8-H), 6.33 (dd, JH,H = 3.2, 2.0 Hz, 1
3
3
H, Ar-H), 6.46 (d, JH,H = 3.4 Hz, 1 H, Ar-H), 7.31 (d, JH,H
=
1.6 Hz, Ar-H) ppm. 13C NMR (126 MHz, DEPT, CDCl3): δ = 0.0
(CH), 8.7 (CH2), 65.9 (C), 97.8 (C), 110.6 (CH), 114.0 (CH), 137.6
(C), 142.7 (CH) ppm. IR (neat): ν = 3120, 3097, 3015, 2235, 1576,
˜
1491, 1213, 1183, 1156, 1016, 965, 908, 812, 738 cm–1. MS (EI):
m/z (%) = 132 (100) [M]+, 131 (23) [M – H]+, 103 (66) [M –
C2H4]+, 78 (41) [M – C4H6]+, 77 (38) [M – C3H3O]+, 76 (22) [M –
C3H4O]+, 50 (21) [C4H2]+. HRMS (EI): calcd. for C9H8O 132.0575;
found 132.0577.
2
3
JH,H = 11.2, 9.0, 5.8 Hz, 1 H, CHN), 2.86 (dd, JH,H = 13.4, JH,H
= 2.8 Hz, 1 H, 6-H), 3.03 (t, J = 7.8 Hz, 1 H, CHN), 3.20 (td, J =
9.7, 2.8 Hz, 1 H, CHN), 7.15–7.21 (m, 3 H, Ar-H), 7.24–7.30 (m,
2 H, Ar-H) ppm. 13C NMR (126 MHz, CDCl3): δ = 24.3 (CH2),
26.8 (CH3), 29.8 (CH2), 45.7 (CH2), 48.6 (CH2), 54.4 (C), 59.6
(CH), 125.9 (CH), 128.3 (CH), 129.2 (CH), 140.8 (C) ppm. IR
Hydroamination/Cyclopropylimine Rearrangement/Reduction Se-
quence. General Procedure B: A Schlenk tube equipped with a Tef-
lon stopcock and a magnetic stirring bar was charged with the
alkyne (2.40 mmol), the amine (2.64 mmol), [Ind2TiMe2] (37 mg,
0.12 mmol, 5.0 mol-%), and toluene (1.0 mL). The resulting mix-
ture was heated at 105 °C for 24 h. After cooling to room tempera-
ture, NH4Cl (26 mg, 0.49 mmol, 20 mol-%) was added, and the
mixture was heated at 145 °C for 8 h. Then the mixture was cooled
to room temperature, and a mixture of NaBH3CN (302 mg,
4.80 mmol) and ZnCl2 (326 mg, 2.40 mmol) in MeOH (10 mL) was
added. After this mixture had been stirred at 25 °C for 20 h,
CH2Cl2 (50 mL) and a saturated Na2CO3 solution (20 mL) were
added. The resulting mixture was filtered, and the solid residue was
washed with CH2Cl2 (50 mL). The organic layer was separated,
and the aqueous layer was extracted with CH2Cl2 (6ϫ50 mL). The
combined organic layers were dried with Mg2SO4. After concentra-
tion under vacuum the residue was purified by flash chromatog-
raphy (SiO2).
(neat): ν = 3025, 2995, 2906, 2868, 2820, 1603, 1452, 1494, 1364,
˜
1228, 1124, 1016, 739, 698 cm–1. MS (CI, 25 °C): m/z (%) = 218
(100) [M + H]+, 126 (35) [M – C7H8]+. HRMS (CI): calcd. for
C15H23N + H 218.1909; found 218.1908.
1,2-Dibenzylpyrrolidine (18): General procedure B was used to syn-
thesize pyrrolidine 18 from alkyne 8 and benzylamine. However, in
contrast to general procedure B, the amine was added slowly to the
reaction mixture over a period of 4 h. After purification by flash
chromatography (PE/EtOAc, 40:1
Ǟ EtOAc), compound 18
(379 mg, 1.51 mmol, 63%) was isolated as an orange liquid. 1H
NMR (300 MHz, CDCl3): δ = 1.54–1.65 (m, 2 H), 1.65–1.79 (m, 2
H), 2.18 (td, JH,H = 9.1, 7.9 Hz, 1 H), 2.54 (dd, 2JH,H = 13.1, 3JH,H
= 9.4 Hz, 1 H, 6-H), 2.63–2.71 (m, 1 H), 2.95 (td, JH,H = 5.9,
2
3
2.7 Hz, 1 H), 3.07 (dd, JH,H = 13.1, JH,H = 4.0 Hz, 1 H, 6-H),
3.30 (d, 2JH,H = 12.9 Hz, 1 H, NCH2Ph), 4.11 (d, JH,H = 12.9 Hz,
2
1 H, NCH2Ph), 7.15–7.39 (m, 10 H, Ar-H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 21.9 (CH2), 30.4 (CH2), 40.9 (CH2), 54.2
(CH2), 58.8 (CH2), 65.8 (CH), 125.9 (CH), 126.8 (CH), 128.2 (CH),
128.2 (CH), 129.0 (CH), 129.2 (CH), 139.4 (C), 140.0 (C) ppm. IR
2-Benzyl-1-(p-tolyl)pyrrolidine (15): General procedure B was used
to synthesize pyrrolidine 15 from alkyne 8 and p-toluidine. After
purification by flash chromatography (PE/EtOAc, 40:1), compound
15 (543 mg, 2.16 mmol, 90%) was isolated as a yellow liquid. 1H
NMR (500 MHz, CDCl3): δ = 1.80 (br. s, 4 H, 3-H, 4-H), 2.29 (s,
(neat): ν = 3028, 2923, 2790, 1604, 1496, 1455, 1359, 1123, 1075,
˜
1030, 917, 736, 698 cm–1. MS (CI, 25 °C): m/z (%) = 252 (100) [M
+ H]+, 160 (10) [M – C7H7]+. HRMS (CI): calcd. for C18H21N +
H 252.1752; found 252.1755.
3
3 H, 15-H), 2.54 (dd, 2JH,H = 13.0, JH,H = 9.6 Hz, 1 H, 6-H), 3.04
2
(d, JH,H = 13.6 Hz, 1 H, 6-H), 3.10 (dt, JH,H = 7.8, 7.5 Hz, 1 H,
2-(4-Methylbenzyl)-1-(p-tolyl)pyrrolidine (19): General procedure B
was used to synthesize pyrrolidine 19 from alkyne 9 and p-tolu-
idine. After purification by flash chromatography (PE/EtOAc,
100:1), compound 19 (605 mg, 2.28 mmol, 95%) was isolated as an
CHN), 3.35 (br. s, 1 H, CHN), 3.92 (br. s, 1 H, CHN), 6.63 (d,
3
3JH,H = 7.5 Hz, 2 H, pTol-H), 7.10 (d, JH,H = 7.6 Hz, 2 H, pTol-
H), 7.15–7.22 (m, 3 H, Ar-H), 7.27 (m, 2 H, Ar-H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 20.2 (CH3), 22.9 (CH2), 29.4 (CH2), 38.5
(CH2), 48.4 (CH2), 59.7 (CH), 111.8 (CH), 124.2 (C), 125.9 (CH),
128.2 (CH), 129.2 (CH), 129.7 (CH), 139.4 (C), 144.8 (C) ppm. IR
1
orange oil. H NMR (500 MHz, CDCl3): δ = 1.79–1.96 (m, 4 H),
2.29 (s, 3 H, CH3), 2.35 (s, 3 H, CH3), 2.52 (dd, 2JH,H = 13.7, 3JH,H
2
3
= 9.6 Hz, 1 H, 6-H), 3.03 (dd, JH,H = 13.7, JH,H = 3.0 Hz, 1 H,
6-H), 3.12–3.20 (m, 1 H, CHN), 3.36–3.46 (m, 1 H, CHN), 3.88–
(neat): ν = 3062, 3025, 2965, 2922, 2859, 1619, 1518, 1452, 1361,
˜
1165, 978, 798, 738, 698 cm–1.
3
3.96 (m, 1 H, CHN), 6.64 (d, JH,H = 8.5 Hz, 2 H, Ar-H), 7.10 (d,
2-Benzyl-1-cyclopentylpyrrolidine (16): General procedure B was
used to synthesize pyrrolidine 16 from alkyne 8 and cyclopent-
ylamine. After purification by flash chromatography (PE/EtOAc,
40:1 Ǟ EtOAc), compound 16 (473 mg, 2.06 mmol, 86%) was iso-
3JH,H = 8.3 Hz, 2 H, Ar-H), 7.12–7.35 (m, 4 H, Ar-H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 20.2 (CH3), 21.0 (CH3), 23.1 (CH2),
29.5 (CH2), 38.3 (CH2), 48.6 (CH2), 60.0 (CH), 111.9 (CH), 124.5
(C), 129.1 (CH), 129.2 (CH), 129.8 (CH), 135.6 (C), 136.6 (C),
lated as a brown liquid. 1H NMR (500 MHz, CDCl3): δ = 1.48– 145.0 (C) ppm. IR (neat): ν = 3013, 2966, 2920, 2860, 1619, 1518,
˜
2
3
1.86 (m, 11 H), 1.91–2.00 (m, 1 H), 2.44 (dd, JH,H = 13.0, JH,H
= 10.6 Hz, 1 H, 6-H), 2.55 (dt, JH,H = 7.1, 8.9 Hz, 1 H, CHN),
2.93–3.01 (m, 1 H, CHN), 3.02–3.12 (m, 3 H, CHN, 6-H), 7.15–
1362, 1344, 1329, 1165, 797, 731 cm–1. MS (CI, 25 °C): m/z (%) =
266 (68) [M + H]+, 265 (55) [M]+, 161 (11) [M – C8H8]+, 160 (100)
[M – C8H9]+. HRMS (CI): calcd. for C19H23N + H 266.1909; found
7.21 (m, 3 H, Ar-H), 7.24–7.30 (m, 2 H, Ar-H) ppm. 13C NMR 266.1912.
Eur. J. Org. Chem. 2009, 5565–5575
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5571

K. Gräbe, B. Zwafelink, S. Doye
FULL PAPER
1-Cyclopentyl-2-(4-methylbenzyl)pyrrolidine (20): General pro-
cedure B was used to synthesize pyrrolidine 20 from alkyne 9 and
cyclopentylamine. After purification by flash chromatography (PE/
EtOAc, 40:1 Ǟ EtOAc + 3% 7  NH3 in MeOH), compound 20
3
14.3, JH,H = 3.7 Hz, 1 H, 6-H), 3.17 (td, JH,H = 8.8, 7.7 Hz, 1 H,
CHN), 3.45 (td, JH,H = 8.3, 2.8 Hz, 1 H, CHN), 4.02–4.09 (m, 1
3
3
H, CHN), 6.61 (d, JH,H = 8.5 Hz, 2 H, pTol-H), 7.06 (d, JH,H
=
8.4 Hz, 2 H, pTol-H), 7.10–7.23 (m, 4 H, Ar-H) ppm. 13C NMR
(492 mg, 2.02 mmol, 84%) was isolated as a yellow oil. 1H NMR (126 MHz, CDCl3): δ = 20.1 (CH3), 20.2 (CH3), 23.3 (CH2), 29.5
(500 MHz, CDCl3): δ = 1.48–1.86 (m, 11 H), 1.89–1.99 (m, 1 H), (CH2), 35.3 (CH2), 48.5 (CH2), 58.8 (CH), 111.8 (CH), 124.5 (C),
2
3
2.32 (s, 3 H, CH3), 2.37 (dd, JH,H = 13.1, JH,H = 10.6 Hz, 1 H,
125.9 (CH), 126.1 (CH), 129.8 (CH), 130.3 (CH), 136.5 (C), 138.0
6-H), 2.50–2.58 (m, 1 H, CHN), 2.87–2.95 (m, 1 H, CHN), 2.97– (C), 145.1 (C) ppm. IR (neat): ν = 3013, 2965, 1619, 1518, 1459,
˜
3.10 (m, 3 H, CHN, 6-H), 7.05–7.10 (m, 4 H, Ar-H) ppm. 13C 1360, 1344, 1152, 975, 909, 798, 739 cm–1. MS (EI, 25 °C): m/z (%)
NMR (126 MHz, CDCl3): δ = 21.0 (CH3), 22.8 (CH2), 23.8 (CH2), = 265 (5) [M]+, 161 (18) [M – C8H8]+, 160 (100) [M – C8H9]+,
24.1 (CH2), 29.1 (CH2), 29.9 (CH2), 32.3 (CH2), 40.6 (CH2), 51.4 91 (10) [C7H7]+. HRMS (EI): calcd. for C19H23N 265.1830; found
(CH2), 64.1 (CH), 64.5 (CH), 128.9 (CH), 129.0 (CH), 135.3 (C),
265.1829.
137.5 (C) ppm. IR (neat): ν = 2951, 2866, 2787, 2731, 1892, 1514,
˜
1-Cyclopentyl-2-(2-methylbenzyl)pyrrolidine (24): General pro-
cedure B was used to synthesize pyrrolidine 24 from alkyne 10 and
cyclopentylamine. After purification by flash chromatography (PE/
EtOAc, 40:1 Ǟ EtOAc + 3% 7  NH3 in MeOH), compound 24
(472 mg, 1.94 mmol, 81%) was isolated as a dark-orange oil. 1H
NMR (500 MHz, CDCl3): δ = 1.50–1.62 (m, 5 H), 1.63–1.75 (m, 4
1447, 1342, 1212, 1131, 910, 793 cm–1. MS (CI, 25 °C): m/z (%) =
244 (38) [M + H]+, 138 (100) [M – C8H10]+. HRMS (CI): calcd.
for C17H25N + H 244.2065; found 244.2068.
1-tert-Butyl-2-(4-methylbenzyl)pyrrolidine (21): General procedure
B was used to synthesize pyrrolidine 21 from alkyne 9 and tert-
butylamine. After purification by flash chromatography (PE/
H), 1.76–1.86 (m, 2 H), 1.91–1.99 (m, 1 H), 2.33 (s, 3 H, CH3),
EtOAc, 40:1 Ǟ EtOAc + 3% 7  NH3 in MeOH), compound 21 2.48 (dd, 2JH,H = 13.3, JH,H = 10.8 Hz, 1 H, 6-H), 2.58 (q, JH,H
=
3
(428 mg, 1.85 mmol, 77%) was isolated as a yellow oil. 1H NMR 8.4 Hz, 1 H, CHN), 2.95–3.08 (m, 3 H, CHN, 6-H), 3.13 (quint,
(500 MHz, CDCl3): δ = 1.15 (s, 9 H, tBu), 1.34–1.46 (m, 1 H), 1.61 3JH,H = 8.0 Hz, 1 H, CHN), 7.02–7.21 (m, 4 H, Ar-H) ppm. 13C
(dd, JH,H = 12.3, 6.0 Hz, 1 H), 1.66–1.76 (m, 1 H), 1.76–1.90 (m, NMR (126 MHz, CDCl3): δ = 19.8 (CH3), 22.8 (CH2), 24.0 (CH2),
2
3
1 H), 2.32 (s, 3 H, CH3), 2.46 (dd, JH,H = 13.4, JH,H = 10.9 Hz,
1 H, 6-H), 2.65 (ddd, JH,H = 11.2, 9.0, 5.9 Hz, 1 H, CHN), 2.79
(dd, 2JH,H = 13.4, 3JH,H = 3.0 Hz, 1 H, 6-H), 2.99 (t, JH,H = 7.8 Hz,
24.2 (CH2), 28.6 (CH2), 29.9 (CH2), 32.1 (CH2), 37.8 (CH2), 50.8
(CH2), 62.6 (CH), 63.6 (CH), 125.7 (CH), 125.9 (CH), 129.8 (CH),
130.1 (CH), 136.2 (C), 138.6 (C) ppm. IR (neat): ν = 3018, 2953,
˜
1 H, CHN), 3.15 (td, JH,H = 9.6, 2.5 Hz, 1 H, CHN), 7.05–7.11 2869, 2795, 1689, 1605, 1493, 1453, 1344, 1214, 1119, 911,
(m, 4 H, Ar-H) ppm. 13C NMR (126 MHz): δ = 21.0 (CH3), 24.3 742 cm–1. GC–MS (CI, 25 °C): m/z (%) = 244 (37) [M + H]+, 242
(CH2), 26.9 (CH3), 29.8 (CH2), 45.5 (CH2), 48.6 (CH2), 54.1 (C), (9) [M – H]+, 139 (8) [M – C8H10]+, 138 (100) [M – C8H9]+, 70 (7)
59.5 (CH), 128.9 (CH), 129.1 (CH), 135.3 (C), 137.9 (C) ppm. IR
[C5H10]+. HRMS (EI): calcd. for C17H25N 243.1987; found
(neat): ν = 2965, 2906, 2868, 2820, 1515, 1364, 1255, 1229, 1123, 243.1985.
˜
1017, 794 cm–1. MS (CI, 25 °C): m/z (%) = 232 (45) [M + H]+, 126
1-tert-Butyl-2-(2-methylbenzyl)pyrrolidine (25): General procedure
(100) [M – C8H9]+, 89 (18) [C7H5]+, 70 (19) [C5H10]+. HRMS (CI):
B was used to synthesize pyrrolidine 25 from alkyne 10 and tert-
butylamine. However, in contrast to general procedure B, 100 mol-
% of NH4Cl (128 mg, 2.40 mmol) was used. After purification by
flash chromatography (PE/EtOAc, 40:1 Ǟ EtOAc + 3% 7  NH3
in MeOH), compound 25 (122 mg, 0.53 mmol, 22%) was isolated
as a yellow oil. 1H NMR (500 MHz, CDCl3): δ = 1.15 (s, 9 H,
tBu), 1.36–1.46 (m, 1 H), 1.57 (dd, JH,H = 12.4, 6.3 Hz, 1 H), 1.70–
1.80 (m, 1 H), 1.82–1.94 (m, 1 H), 2.33 (s, 3 H, CH3), 2.64 (dd,
calcd. for C16H25N + H 232.2065; found 232.2061.
1-Benzyl-2-(4-methylbenzyl)pyrrolidine (22): General procedure B
was used to synthesize pyrrolidine 22 from alkyne 9 and benzyl-
amine. However, in contrast to general procedure B, the amine was
added slowly to the reaction mixture over a period of 4 h. After
purification by flash chromatography (PE/EtOAc, 40:1 Ǟ EtOAc),
compound 22 (478 mg, 1.80 mmol, 75%) was isolated as a dark-
1
orange oil. H NMR (500 MHz, CDCl3): δ = 1.51–1.79 (m, 4 H), 3JH,H = 13.9, 10.7 Hz, 1 H, 6-H), 2.69 (ddd, JH,H = 11.2, 9.1,
2
3
2.18 (q, JH,H = 8.8 Hz, 1 H, CHN), 2.31 (s, 3 H, CH3), 2.52 (dd,
6.0 Hz, 1 H, CHN), 2.76 (dd, JH,H = 14.1, JH,H = 3.9 Hz, 1 H,
2JH,H = 13.1, 3JH,H = 9.3 Hz, 1 H, 6-H), 2.59–2.68 (m, 1 H, CHN), 6-H), 3.04 (t, J = 7.9 Hz, 1 H, CHN), 3.31 (m, 1 H, CHN), 7.06–
2.95 (br. t, JH,H = 7.3 Hz, 1 H, CHN), 3.04 (dd, 2JH,H = 13.1, 3JH,H 7.27 (m, 4 H, Ar-H) ppm. 13C NMR (126 MHz): δ = 20.2 (CH3),
= 3.9 Hz, 1 H, 6-H), 3.29 (d, 2J = 12.8 Hz, 1 H, NCH2Ph), 4.12
24.5 (CH2), 26.9 (CH3), 29.7 (CH2), 42.0 (CH2), 48.6 (CH2), 54.1
2
(d, J = 12.9 Hz, 1 H, NCH2Ph), 7.06–7.12 (m, 4 H, Ar-H), 7.22– (C), 58.0 (CH), 125.7 (CH), 125.8 (CH), 129.7 (CH), 130.2 (CH),
7.27 (m, 1 H, Ar-H), 7.29–7.38 (m, 4 H, Ar-H) ppm. 13C NMR 136.4 (C), 139.2 (C) ppm. IR (neat): ν = 3014, 2965, 2907, 2868,
˜
(126 MHz, CDCl3): δ = 21.0 (CH3), 21.9 (CH2), 30.4 (CH2), 40.4 2822, 1491, 1458, 1363, 1228, 1120, 1015, 739 cm–1. MS (CI,
(CH2), 54.3 (CH2), 58.9 (CH2), 65.8 (CH), 126.9 (CH), 128.2 (CH), 25 °C): m/z (%) = 232 (40) [M + H]+, 126 (100) [M – C8H9]+, 70
128.9 (CH), 129.0 (CH), 129.1 (CH), 135.3 (C), 136.9 (C) ppm. IR
(14) [C5H10]+. HRMS (CI): calcd. for C16H25N + H 232.2065;
(neat): ν = 3025, 2920, 2871, 2787, 1514, 1494, 1453, 1357, 1121, found 232.2067.
˜
1028, 799, 734, 697 cm–1. GC–MS (CI, 25 °C): m/z (%) = 265 (2)
1-Benzyl-2-(2-methylbenzyl)pyrrolidine (26): General procedure B
[M]+, 175 (12) [M – C7H6]+, 133 (61) [M – C10H12]+, 132 (100)
[C10H12]+, 105 (19) [C8H9]+. HRMS (EI): calcd. for C19H23N
265.1831; found 265.1835.
was used to synthesize pyrrolidine 26 from alkyne 10 and benzyla-
mine. However, in contrast to general procedure B, the amine was
added slowly to the reaction mixture over a period of 4 h. After
2-(2-Methylbenzyl)-1-(p-tolyl)pyrrolidine (23): General procedure B purification by flash chromatography (PE/EtOAc, 40:1 Ǟ EtOAc),
was used to synthesize pyrrolidine 23 from alkyne 10 and p-tolu-
idine. After purification by flash chromatography (PE/EtOAc,
compound 26 (306 mg, 1.15 mmol, 48%) was isolated as a dark-
yellow oil. H NMR (500 MHz, CDCl3): δ = 1.58–1.70 (m, 2 H),
1
100:1), compound 23 (591 mg, 2.23 mmol, 93%) was isolated as an
1.72–1.84 (m, 2 H), 2.20–2.29 (m, 1 H), 2.32 (s, 3 H, CH3), 2.55–
1
orange oil. H NMR (500 MHz, CDCl3): δ = 1.76–1.87 (m, 2 H), 2.67 (m, 1 H), 2.69–2.81 (m, 1 H), 2.98–3.08 (m, 1 H), 3.14 (dd,
1.91–2.03 (m, 2 H), 2.26 (s, 3 H, CH3), 2.37 (s, 3 H, CH3), 2.56 2JH,H = 13.4, JH,H = 4.0 Hz, 1 H, 6-H), 3.35 (d, JH,H = 12.4 Hz,
3
2
2
3
2
2
(dd, JH,H = 14.2, JH,H = 9.9 Hz, 1 H, 6-H), 3.08 (dd, JH,H
=
1 H, NCH2Ph), 4.14 (d, JH,H = 12.8 Hz, 1 H, NCH2Ph), 7.09–
5572
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5565–5575

Synthesis of N-Substituted 2-(Arylmethyl)pyrrolidines
7.15 (m, 3 H, Ar-H), 7.15–7.19 (m, 1 H, Ar-H), 7.27 (d, JH,H
3
1
=
lated as a brown oil. H NMR (500 MHz, CDCl3): δ = 1.88–1.99
3
7.2 Hz, 1 H, Ar-H), 7.32 (t, JH,H = 7.4 Hz, 2 H, Ar-H), 7.38 (d,
(m, 4 H), 2.26 (s, 3 H, CH3), 2.82 (dd, 2JH,H = 14.8, 3JH,H = 9.3 Hz,
2JH,H = 7.4 Hz, 2 H, Ar-H) ppm. 13C NMR (126 MHz, CDCl3): δ 1 H, 6-H), 3.12–3.18 (m, 1 H, CHN), 3.20 (dd, 2JH,H = 14.8, JH,H
3
= 19.7 (CH3), 21.9 (CH2), 30.5 (CH2), 37.9 (CH2), 54.2 (CH2), 58.9 = 2.6 Hz, 6-H), 3.42–3.50 (m, 1 H, CHN), 3.91–3.98 (m, 1 H,
3
(CH2), 64.6 (CH), 125.8 (CH), 126.1 (CH), 127.0 (CH), 128.3 (CH), CHN), 6.60 (d, JH,H = 8.5 Hz, 2 H, pTol-H), 6.81–6.87 (m, 1 H,
3
3
129.1 (CH), 129.9 (CH), 130.2 (CH), 136.1 (C), 138.1 (C) ppm. IR
Ar-H), 6.98 (dd, JH,H = 5.1, 3.4 Hz, 1 H, Ar-H), 7.08 (d, JH,H =
3
(neat): ν = 3061, 3025, 2925, 2870, 2788, 1660, 1493, 1453, 1357, 8.4 Hz, 2 H, pTol-H), 7.18 (dd, JH,H = 4.9, 1.0 Hz, 1 H, Ar-H)
˜
1124, 1029, 740, 698 cm–1. MS (CI, 25 °C): m/z (%) = 266 (28) [M
+ H]+, 161 (11) [M – C8H8]+, 160 (100) [M – C8H9]+, 91 (32)
ppm. 13C NMR (126 MHz, CDCl3): δ = 20.2 (CH3), 23.1 (CH2),
30.1 (CH2), 33.3 (CH2), 48.8 (CH2), 60.0 (CH), 111.9 (CH), 123.8
[C7H7]+, 89 (23) [C7H5]+. HRMS (CI): calcd. for C19H23N + H (CH), 124.8 (C), 125.4 (CH), 126.8 (CH), 129.9 (CH), 141.6 (C),
266.1909; found 266.1907.
144.9 (C) ppm. IR (neat): ν = 3009, 2965, 2917, 2871, 1619, 1518,
˜
1361, 1342, 1326, 1173, 1159, 798, 691 cm–1. MS (EI, 25 °C): m/z
(%) = 257 (5) [M]+, 160 (100) [C12H16]+. HRMS: calcd. for
C16H19NS 257.1238; found 257.1237.
2-[1-(p-Tolyl)pyrrolidin-2-ylmethyl]pyridine (27): General procedure
B was used to synthesize pyrrolidine 27 from alkyne 11 and p-
toluidine. To separate unconsumed p-toluidine from 27, the crude
product was cooled to 0 °C, and pyridine (15 mL) and p-toluenesul-
fonyl chloride (915 mg, 4.80 mmol) were added. The resulting mix-
ture was stirred while warming to room temperature for 12 h. Then
the solution was acidified with 2  aqueous HCl and washed with
EtOAc (3ϫ50 mL) to remove N-(p-tolyl)-p-toluenesulfonamide.
The aqueous layer was neutralized with 2  NaOH and then ex-
tracted with EtOAc (3ϫ50 mL). The combined organic layers were
subsequently dried with MgSO4. After concentration under vac-
uum, the product was isolated by flash chromatography (PE/
2-(Thiophen-2-ylmethyl)-1-cyclopentylpyrrolidine (33): General Pro-
cedure B was used to synthesize pyrrolidine 33 from alkyne 12 and
cyclopentylamine. After purification by flash chromatography
(EtOAc), compound 33 (493 mg, 2.09 mmol, 87%) was isolated as
a brown liquid. 1H NMR (500 MHz, CDCl3): δ = 1.42–1.84 (m, 11
H), 1.86–1.98 (m, 1 H), 2.51 (td, JH,H = 9.0, 7.0 Hz, 1 H, CHN),
2
3
2.72 (dd, JH,H = 14.4, JH,H = 10.0 Hz, 1 H, 6-H), 2.90–3.07 (m,
3 H, CHN), 3.13 (dd, 2JH,H = 14.4, 3JH,H = 2.9 Hz, 1 H, 6-H), 6.80
(br. d, JH,H = 3.5 Hz, 1 H, Ar-H), 6.91 (dd, JH,H = 5.1, 3.4 Hz,
3
3
EtOAc, 5:1). Compound 27 (91 mg, 0.36 mmol, 15%) was isolated 1 H, Ar-H), 7.12 (dd, 3JH,H = 5.4, 4JH,H = 0.9 Hz, 1 H, Ar-H) ppm.
1
as a red oil. H NMR (500 MHz, CDCl3): δ = 1.82–2.00 (m, 4 H),
13C NMR (126 MHz, CDCl3): δ = 23.1 (CH2), 23.5 (CH2), 24.0
(CH2), 29.4 (CH2), 30.3 (CH2), 32.3 (CH2), 35.8 (CH2), 51.9 (CH2),
64.3 (CH), 64.6 (CH), 123.4 (CH), 124.9 (CH), 126.5 (CH), 142.8
2
3
2.27 (s, 3 H, CH3), 2.74 (dd, JH,H = 13.4, JH,H = 9.5 Hz, 1 H, 6-
2
H), 3.17 (td, JH,H = 8.1, 7.8 Hz, 1 H, CHN), 3.25 (dd, JH,H
=
3
13.4, JH,H = 3.3 Hz, 1 H, 6-H), 3.40–3.47 (m, 1 H, CHN), 4.15 (C) ppm. IR (neat): ν = 2952, 2867, 2789, 1438, 1342, 1212, 1132,
˜
(m, 1 H, CHN), 6.60 (d, JH,H = 8.4 Hz, 2 H, pTol-H), 7.08 (d, 1132, 850, 817, 688 cm–1. MS (CI, 25 °C): m/z (%) = 236 (100) [M
3
3JH,H = 8.3 Hz, 2 H, pTol-H), 7.12–7.19 (m, 2 H, Ar-H), 7.60 (td,
+ H]+, 138 [M – C7H10S]+. HRMS (CI): calcd. for C14H21NS + H
236.1473; found 236.1475.
4
3
3JH,H = 7.6, JH,H = 1.3 Hz, 1 H, Ar-H), 8.59 (d, JH,H = 4.7 Hz,
1 H, Ar-H) ppm. 13C NMR (126 MHz, CDCl3): δ = 20.2 (CH3),
23.1 (CH2), 29.6 (CH2), 40.9 (CH2), 48.6 (CH2), 59.0 (CH), 112.0
(CH), 121.3 (CH), 124.0 (CH), 124.7 (C), 129.8 (CH), 136.3 (CH),
1-tert-Butyl-2-(thiophen-2-ylmethyl)pyrrolidine (34): General Pro-
cedure B was used to synthesize pyrrolidine 34 from alkyne 12 and
tert-butylamine. After purification by flash chromatography (PE/
EtOAc, 10:1 Ǟ 1:1), compound 34 (381 mg, 1.70 mmol, 71%) was
isolated as an orange liquid. 1H NMR (500 MHz, CDCl3): δ = 1.14
(s, 9 H, tBu), 1.49–1.61 (m, 1 H), 1.66–1.83 (m, 3 H), 2.65 (td, JH,H
= 9.4, 6.5 Hz, CHN), 2.81 (dd, 2JH,H = 13.3, 3JH,H = 10.9 Hz, 1 H,
144.8 (C), 149.1 (CH), 159.7 (C) ppm. IR (neat): ν = 3010, 2964,
˜
2924, 2862, 1620, 1589, 1521, 1474, 1435, 1364, 1166, 801,
754 cm–1. GC–MS (EI, 25 °C): m/z (%) = 252 (1) [M]+, 161 (11)
[M – C7H7]+, 160 (100) [M – C6H6N]+, 118 (6) [M – C9H10N]+, 91
(10) [C7H7]+, 43 (8) [C2H5N]+. HRMS (EI): calcd. for C17H20N2
252.1626; found 252.1625.
2
6-H), 2.93 (br. d, JH,H = 14.4 Hz, 1 H, 6-H), 2.97–3.04 (m, 1 H,
CHN), 3.21 (t, JH,H = 8.4 Hz, 1 H, CHN), 6.79 (d, 3JH,H = 3.1 Hz,
3
2-[1-(p-Methoxyphenyl)pyrrolidin-2-ylmethyl]pyridine (31): General
procedure B was used to synthesize pyrrolidine 31 from alkyne 11
and 4-methoxyaniline. After purification by flash chromatography
(PE/EtOAc, 5:1), compound 31 (119 mg, 0.43 mmol, 18%) was iso-
lated as a dark-yellow oil. H NMR (500 MHz, CDCl3): δ = 1.88– 143.1 (C) ppm. IR (neat): ν = 2965, 2869, 1438, 1388, 1364, 1254,
1 H, Ar-H), 6.92 (dd, JH,H = 5.0, 3.4 Hz, 1 H, Ar-H), 7.13 (dd,
3JH,H = 4.8, 4JH,H = 0.9 Hz, 1 H, Ar-H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 24.2 (CH2), 26.7 (CH3), 30.5 (CH2), 39.8 (CH2), 48.5
(CH2), 54.0 (C), 59.4 (CH), 123.3 (CH), 124.8 (CH), 126.5 (CH),
1
˜
2.02 (m, 4 H), 2.81 (m, 1 H), 3.16 (q, JH,H = 8.2 Hz, 1 H), 3.25
1228, 1180, 1125, 1017, 851, 812, 690 cm–1. MS (CI, 25 °C): m/z
2
3
(dd, JH,H = 13.5, JH,H = 3.5 Hz, 1 H, 6-H), 3.46–3.53 (m, 1 H), (%) = 224 (100) [M + H]+, 222 (75) [M – H]+, 210 (10) [M –
3.77 (s, 3 H, OCH3), 4.10–4.18 (m, 1 H), 6.79 (d, JH,H = 8.3 Hz, CH]+, 127 (8) [M – C5H4S]+, 126 (90) [M – C5H5S]+, 89 (30)
3
3
2 H, Ar-H), 6.88 (d, JH,H = 8.9 Hz, 2 H, Ar-H), 7.12–7.20 (m, 2 [C4H9S]. HRMS (CI): calcd. for C13H21NS + H 224.1473; found
H), 7.60 (td, 3JH,H = 7.4, 4JH,H = 0.8 Hz, 1 H, Ar-H), 8.57 (d, 3JH,H 224.1470.
= 4.6 Hz, 1 H, Ar-H) ppm. 13C NMR (126 MHz, CDCl3): δ = 23.1
1-Benzyl-2-(thiophen-2-ylmethyl)pyrrolidine (35): General Pro-
cedure B was used to synthesize pyrrolidine 35 from alkyne 12 and
benzylamine. However, in contrast to the general procedure B, the
(CH2), 29.7 (CH2), 40.6 (CH2), 50.0 (CH2), 55.9 (CH3), 60.4 (CH),
113.9 (CH), 115.2 (CH), 121.4 (CH), 124.2 (CH), 126.8 (C), 136.6
(CH), 140.8 (C), 148.9 (CH), 159.3 (C) ppm. IR (neat): ν = 3043,
2958, 2830, 1588, 1510, 1471, 1434, 1364, 1238, 1179, 1038, 812,
755 cm–1. GC–MS (EI, 25 °C): m/z (%) = 268 (8) [M]+, 177 (16)
[M – C6H5N]+, 176 (100) [M – C6H6N]+, 43 (18) [C2H5N]+. HRMS
(EI): calcd. for C17H20N2O 268.1576; found 268.1572.
˜
amine was added slowly to the reaction mixture over a period of
4 h. After purification by flash chromatography (PE/EtOAc, 10:1
Ǟ 1:1), compound 35 (307 mg, 1.37 mmol, 57%) was isolated as a
yellow liquid. 1H NMR (500 MHz, CDCl3): δ = 1.50–1.80 (m, 3
H), 1.82–1.93 (m, 1 H), 2.20 (td, JH,H = 9.1, 7.6 Hz, 1 H, CHN),
2
3
2-(Thiophen-2-ylmethyl)-1-(p-tolyl)pyrrolidine (32): General Pro- 2.70–2.81 (m, 1 H, CHN), 2.87 (dd, JH,H = 14.4, JH,H = 8.4 Hz,
cedure B was used to synthesize pyrrolidine 32 from alkyne 12 and
p-toluidine. After purification by flash chromatography (PE/
EtOAc, 20:1), compound 32 (445 mg, 1.73 mmol, 72%) was iso-
1 H, 6-H), 2.95 (td, JH,H = 8.2, 2.0 Hz, 1 H, CHN), 3.16 (dd, 2JH,H
3
2
= 14.1, JH,H = 3.7 Hz, 1 H, 6-H), 3.33 (d, JH,H = 12.7 Hz, 1 H,
2
NCH2Ph), 4.09 (d, JH,H = 12.9 Hz, 1 H, NCH2Ph), 6.83 (br. d,
Eur. J. Org. Chem. 2009, 5565–5575
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5573

K. Gräbe, B. Zwafelink, S. Doye
FULL PAPER
3JH,H = 2.8 Hz, 1 H, Ar-H), 6.92 (dd, 3JH,H = 5.2, 3.2 Hz, 1 H, Ar-
0.71 mmol, 91%) as a colorless solid. 1H NMR (500 MHz, CDCl3):
H), 7.14 (dd, 3JH,H = 5.5, 4JH,H = 1.0 Hz, 1 H, Ar-H), 7.24 (t, 3JH,H δ = 1.32–1.36 (m, 2 H), 1.53–1.57 (m, 2 H), 2.35 (s, 3 H, CH3),
3
3
3
= 7.3 Hz, 1 H, Ar-H), 7.32 (t, JH,H = 7.3 Hz, 2 H, Ar-H), 7.37 (d, 7.11 (d, JH,H = 7.9 Hz, 2 H, Ar-H), 7.21 (t, JH,H = 7.3 Hz, 1 H,
3JH,H = 7.5 Hz, 2 H, Ar-H) ppm. 13C NMR (126 MHz, CDCl3): δ Ar-H), 7.32 (t, 3JH,H = 7.9 Hz, 2 H, Ar-H), 7.34 (d, 3JH,H = 8.2 Hz,
= 22.2 (CH2), 30.3 (CH2), 34.7 (CH2), 54.3 (CH2), 58.9 (CH2), 65.1 2 H, Ar-H), 7.41 (d, JH,H = 7.5 Hz, 2 H, Ar-H) ppm. 13C NMR
3
(CH), 123.7 (CH), 125.3 (CH), 126.4 (CH), 126.9 (CH), 128.2
(126 MHz, CDCl3): δ = 16.2 (C), 20.5 (CH2), 21.4 (CH3), 78.4 (C),
(CH), 129.0 (CH), 139.3 (C), 142.1 (C) ppm. IR (neat): ν = 3029, 92.9 (C), 120.6 (C), 125.5 (CH), 126.0 (CH), 128.3 (CH), 128.9
˜
2965, 2914, 2790, 1496, 1455, 1442, 1357, 1120, 1076, 1031, 851,
822, 737, 695 cm–1. GC–MS (CI, 25 °C): m/z (%) = 258 (43) [M +
H]+, 256 (17) [M – H]+, 161 (19) [M – C5H5S]+, 160 (100) [M –
C5H6S]+, 91 (12) [C7H7]+. HRMS (EI): calcd. for C16H19NS
257.1238; found 257.1241.
(CH), 131.6 (CH), 137.7 (C), 142.0 (C) ppm. IR (neat): ν = 3086,
˜
3027, 2920, 2236, 1905, 1602, 1509, 1496, 1097, 1028, 955, 815,
752, 695 cm–1. MS (CI, 25 °C): m/z (%) = 233 (60) [M + H]+, 232
(100) [M]+, 231 (20) [M – H]+, 217 (35) [M – CH3]+, 202 (13) [M –
C2H6]+, 105 (17) [C8H9]+. HRMS (CI): calcd. for C18H16 + H
233.1330; found 233.1327.
2-[1-(p-Tolyl)pyrrolidin-2-ylmethyl]thiazole (36): General procedure
B was used to synthesize pyrrolidine 36 from alkyne 13 and p-
toluidine. After purification by flash chromatography (PE/EtOAc,
40:1 Ǟ EtOAc), compound 36 (532 mg, 2.06 mmol, 86%) was iso-
2-(4-Methylbenzyl)-3-phenyl-1-(p-tolyl)pyrrolidine (47): A Schlenk
tube equipped with a Teflon stopcock and a magnetic stirring bar
was charged with alkyne 45 (558 mg, 2.40 mmol), p-toluidine
(282 mg, 2.64 mmol), [Ind2TiMe2] (74 mg, 0.24 mmol, 10.0 mol-%),
and toluene (1.0 mL). The resulting mixture was heated at 160 °C
for 48 h. After cooling to room temperature, NH4Cl (65 mg,
1.20 mmol, 50 mol-%) was added, and the mixture was heated at
145 °C for 8 h. Then the mixture was cooled to room temperature,
and a mixture of NaBH3CN (302 mg, 4.80 mmol) and ZnCl2
(326 mg, 2.40 mmol) in MeOH (10 mL) was added. After this mix-
ture had been stirred at 25 °C for 20 h, CH2Cl2 (50 mL) and a
saturated Na2CO3 solution (20 mL) were added. The resulting mix-
ture was filtered, and the solid residue was washed with CH2Cl2
(50 mL). The organic layer was separated, and the aqueous layer
was extracted with CH2Cl2 (6ϫ50 mL) and the combined organic
layers were dried with Na2SO4. After concentration under vacuum,
the residue was purified by flash chromatography (SiO2, PE/
EtOAc, 40:1) to give 47 (387 mg, 1.15 mmol, 48%) as a mixture of
two diastereomers. The diastereomeric ratio was determined by GC
to be 54:46. In addition, it was possible to recover unconsumed
alkyne 45 (240 mg, 1.03 mmol, 43%). 1H NMR (500 MHz, CDCl3,
mixture of two diastereomers): δ = 1.85–1.94 (m, 1 H), 2.09–2.19
(m, 2 H), 2.22 (s, 3 H, CH3), 2.25 (s, 3 H, CH3), 2.26–2.34 (m, 2
1
lated as a brown oil. H NMR (500 MHz, CDCl3): δ = 1.87–2.04
(m, 4 H), 2.29 (s, 3 H, CH3), 3.06 (dd, 2JH,H = 14.7, 3JH,H = 9.1 Hz,
3
1 H, 6-H), 3.14–3.22 (m, 1 H, CHN), 3.41 (dd, 2JH,H = 14.7, JH,H
= 3.0 Hz, 1 H, 6-H), 3.44–3.52 (m, 1 H, CHN), 4.06–4.19 (m, 1 H,
3
3
CHN), 6.64 (d, JH,H = 8.5 Hz, 2 H, pTol-H), 7.10 (d, JH,H
=
3
8.5 Hz, 2 H, pTol-H), 7.24 (d, JH,H = 3.4 Hz, 1 H, Ar-H), 7.73 (d,
3JH,H = 3.3 Hz, 1 H, Ar-H) ppm. 13C NMR (126 MHz, CDCl3): δ
= 20.2 (CH3), 23.0 (CH2), 30.0 (CH2), 36.3 (CH2), 48.8 (CH2), 58.7
(CH), 112.0 (CH), 118.7 (CH), 125.0 (C), 129.9 (CH), 142.4 (CH),
144.6 (C), 167.7 (C) ppm. IR (neat): ν = 3010, 2963, 2920, 2860,
˜
2223, 1618, 1518, 1361, 1343, 1179, 1049, 938, 800, 721 cm–1. MS
(EI, 25 °C): m/z (%)
=
258 (8) [M]+, 161 (12)
[C12H15]+, 160 (100) [C12H16]+, 91 (10) [C7H7]+. HRMS (EI): calcd.
for C15H18N2S 258.1191; found 258.1188.
2-[1-(p-Methoxyphenyl)pyrrolidin-2-ylmethyl]thiazole (40): General
procedure B was used to synthesize pyrrolidine 40 from alkyne 13
and 4-methoxyaniline. After purification by flash chromatography
(PE/EtOAc, 5:1), compound 40 (230 mg, 0.84 mmol, 35%) was iso-
1
lated as a brown oil. H NMR (500 MHz, CDCl3): δ = 1.84–2.03
2
2
3
H), 2.29 (s, 3 H, CH3), 2.31 (s 3 H, CH3), 2.55 (dd, JH,H = 14.0,
(m, 4 H), 3.04 (dd, JH,H = 14.6, JH,H = 9.0 Hz, 1 H, 6-H), 3.11–
3
3JH,H = 3.0 Hz, 1 H), 2.72 (dd, 2JH,H = 13.5, JH,H = 5.6 Hz, 1 H),
2
3
3.29 (m, 1 H, CHN), 3.39 (dd, JH,H = 14.6, JH,H = 3.0 Hz, 1 H,
6-H), 3.43–3.49 (m, 1 H, CHN), 3.76 (s, 3 H, OCH3), 4.07–4.25
(m, 1 H, CHN), 6.62–6.67 (m, 2 H, Ar-H), 6.86–6.90 (m, 2 H, Ar-
H), 7.22 (d, JH,H = 3.3 Hz, 1 H, Ar-H), 7.73 (d, JH,H = 3.3 Hz,
1 H, Ar-H) ppm. 13C NMR (126 MHz, CDCl3): δ = 23.2 (CH2),
30.2 (CH2), 36.5 (CH2), 49.3 (CH2), 56.0 (CH3), 59.1 (CH), 112.9
(CH), 115.3 (CH), 118.7 (CH), 141.7 (C), 142.4 (CH), 151.2 (C),
2
3
2
2.76 (dd, JH,H = 13.8, JH,H = 9.0 Hz, 1 H), 3.05 (d, JH,H
=
13.8 Hz, 1 H), 3.29 (q, JH,H = 8.7 Hz, 2 H), 3.35 (d, JH,H = 8.3 Hz,
1 H), 3.36–3.44 (m, 1 H), 3.50 (t, JH,H = 7.4 Hz, 1 H), 3.52–3.60
3
3
3
(m, 1 H), 4.11 (br. d, JH,H = 8.3 Hz, 1 H), 4.32 (m, 1 H), 6.50 (d,
3
3JH,H = 7.8 Hz, 2 H, Ar-H), 6.55 (d, JH,H = 7.6 Hz, 2 H, Ar-H),
3
3
6.66 (d, JH,H = 7.3 Hz, 2 H, Ar-H), 6.83 (d, JH,H = 7.7 Hz, 2 H,
Ar-H), 6.96 (d, 3JH,H = 7.8 Hz, 2 H, Ar-H), 7.01 (d, 3JH,H = 8.0 Hz,
2 H, Ar-H), 7.05–7.14 (m, 6 H, Ar-H), 7.17 (d, JH,H = 7.3 Hz, 2
H, Ar-H), 7.20 (d, JH,H = 8.0 Hz, 2 H, Ar-H), 7.23 (t, JH,H
167.7 (C) ppm. IR (neat): ν = 3076, 2949, 2830, 1735, 1618, 1509,
˜
3
1461, 1363, 1238, 1178, 1037, 810, 723 cm–1. MS (CI, 25 °C): m/z
3
3
(%) = 275 (40) [M + H]+, 274 (60) [M]+, 176 (100) [M – C7H10]+.
=
8.5 Hz, 2 H, Ar-H), 7.30 (t, JH,H = 7.1 Hz, 2 H, Ar-H) ppm. 13C
NMR (126 MHz, CDCl3, mixture of two diastereomers): δ = 20.2
(CH3), 20.3 (CH3), 20.9 (CH3), 21.0 (CH3), 26.7 (CH2), 31.2 (CH2),
35.0 (CH2), 37.8 (CH2), 47.1 (CH2), 47.4 (CH), 47.7 (CH2), 47.7
(CH), 63.2 (CH), 65.9 (CH), 111.6 (CH), 112.1 (CH), 124.5 (C),
124.7 (C), 126.5 (CH), 126.8 (CH), 128.2 (CH), 128.4 (CH), 128.5
(CH), 128.7 (CH), 129.1 (CH), 129.4 (CH), 129.5 (CH), 129.7
(CH), 130.0 (CH), 134.9 (C), 135.7 (C), 135.8 (C), 136.3 (C), 139.2
(C), 144.2 (C), 145.3 (C), 145.4 (C) ppm. IR (neat, mixture of two
3
HRMS (CI): calcd. for C15H18N2SO
275.1220.
+ H 275.1218; found
1-Phenyl-1-(p-tolylethynyl)cyclopropane (45): A 1.6  solution of
nBuLi in hexanes (0.90 mL, 1.41 mmol) was added to a solution of
1-cyclopropyl-2-(p-tolyl)acetylene (9; 182 mg, 1.17 mmol) in THF
(3.0 mL) at –78 °C. After warming to room temperature and stir-
ring for 1 h, a solution of dry ZnCl2 (534 mg, 2.37 mmol) in THF
(12 mL) was added. Then the mixture was stirred for 25 min, and
[Pd(PPh3)4] (45 mg, 0.039 mmol, 5 mol-%) and iodobenzene (1, diastereomers): ν = 3025, 2919, 2858, 1619, 1518, 1362, 1188, 1165,
˜
87 µL, 0.78 mmol) were added. After the mixture had been stirred
at room temperature for an additional 14 h, a saturated aqueous
NH4Cl solution (3 mL) was added. The mixture was then extracted
with Et2O (6ϫ2 mL), and the combined organic layers were dried
with MgSO4. After concentration under vacuum, the residue was
907, 799, 729, 698 cm–1. GC–MS (CI, 25 °C): First diastereomer:
m/z (%) = 342 (44) [M + H]+, 341 (37) [M]+, 236 (100) [M –
C8H9]+, 89 (57) [C7H5]+; second diastereomer: m/z (%) = 342 (46)
[M + H]+, 341 (41) [M]+, 236 (100) [M – C8H9]+, 89 (82)
[C7H5]+. HRMS (EI, mixture of two diastereomers): calcd. for
purified by flash chromatography (SiO2, PE) to give 45 (165 mg, C25H27N 341.2143; found 341.2146.
5574 Eur. J. Org. Chem. 2009, 5565–5575
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of N-Substituted 2-(Arylmethyl)pyrrolidines
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synthesized compounds.
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We thank the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie for financial support of our research.
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Received: May 8, 2009
Published Online: October 7, 2009
Publication delayed on authors’ request
Eur. J. Org. Chem. 2009, 5565–5575
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5575