Stereoselective Heck arylation of a functionalized cyclopentenyl ether using (S)-N-methyl-pyrrolidine as the stereochemical controller

Article abstract of DOI:10.1016/j.tet.2008.06.099

The study of a series of palladium(0)-catalyzed C2-arylations of a 1-cyclopentenyl ether equipped with a chiral (S)-N-methyl-pyrrolidine auxiliary is reported. Stereoselective Heck monoarylations were performed using aryl iodides under classical heating conditions for 1.7-3.0 h at 80 °C and in one case using 30 min of microwave irradiation at 110 °C. To further explore the scope and nature of this stereoselective methodology, aryl bromides were also utilized as arylating agents, using 20 min of microwave processing at 120-130 °C. High to excellent diastereopurities (90-98% de) were obtained according to ¹H NMR and?GC-MS analyses. The prolinol fragment apparently controlled the diastereoselectivity of the Heck reaction by presenting the arylpalladium species from the preferred side of the double bond. By X-ray structure diffraction analysis of an N-quaternized Heck product, the absolute configuration of the new stereocenter was established as (R), supporting a Si-face migratory insertion.

Full text of DOI:10.1016/j.tet.2008.06.099

Tetrahedron 64 (2008) 8746–8751
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective Heck arylation of a functionalized cyclopentenyl ether
using (S)-N-methyl-pyrrolidine as the stereochemical controller
*
Alejandro Trejos, Jonas Sa¨vmarker, Stefanie Schlummer, Gopal K. Datta, Peter Nilsson, Mats Larhed
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University, PO Box 574, SE-751 23 Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 April 2008
Received in revised form 12 June 2008
Accepted 26 June 2008
Available online 28 June 2008
The study of a series of palladium(0)-catalyzed C2-arylations of a 1-cyclopentenyl ether equipped with
a chiral (S)-N-methyl-pyrrolidine auxiliary is reported. Stereoselective Heck monoarylations were per-
formed using aryl iodides under classical heating conditions for 1.7–3.0 h at 80 ꢀC and in one case using
30 min of microwave irradiation at 110 ꢀC. To further explore the scope and nature of this stereoselective
methodology, aryl bromides were also utilized as arylating agents, using 20 min of microwave processing
at 120–130 ꢀC. High to excellent diastereopurities (90–98% de) were obtained according to 1H NMR
and GC–MS analyses. The prolinol fragment apparently controlled the diastereoselectivity of the Heck
reaction by presenting the arylpalladium species from the preferred side of the double bond. By X-ray
structure diffraction analysis of an N-quaternized Heck product, the absolute configuration of the new
stereocenter was established as (R), supporting a Si-face migratory insertion.
Keywords:
Heck reaction
Microwave
Vinyl ether
Palladium catalysis
Stereoselective
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
prolinol vinyl ether 1 with aryl iodides 2 and aryl bromides 6,
followed by subsequent hydrolysis of the Heck product (S,R)-3
Palladium-catalyzed Heck reactions have gained importance
because of their unique capability of forming carbon–carbon bonds
in an atom- and step-economical fashion with high selectivities.1–4
Among the alternative ways to induce stereodifferentiation by Heck
methodology, the most elegant is by means of a chiral catalyst.5–7
Regrettably, in the area of intermolecular Pd(0)-catalyzed Heck
arylations, only a few truly efficient enantioselective examples have
been described.8–11 An alternative strategy relies on the usage of
a chiral palladium(II)-directing auxiliary (chelation-control).12–15 In
this case, the vinyl substrate is equipped with a functionality
designed to establish an initial metal pre-coordination, followed by
a pseudo-intramolecular presentation of the organopalladium
complex for the most favored diastereotopic face of a cyclic olefin.
By choosing the appropriate position, connection, tether length,
geometry, and palladium(II)-coordinating strength of the auxiliary,
it has been possible to control both the stereoselectivity of the
(Scheme 1).16 In this transformation, (S)-N-methyl-pyrrolidine
acted as the organopalladium-directing group and the formed
quaternary carbon center was inert to racemization during the final
acidic hydrolysis.16,17 However, although the optical purities of the
isolated (R)-2-aryl-2-methylcyclopentanones were very satisfying,
we were unable to identify the stereocontrolling reaction step. Was
the transition-state barrier for the migratory insertion determining
the C2-chirality, or alternatively, would the most stable (and
most abundant)
p-complex stereoisomer intermediate undergo
insertion and subsequent
b
-elimination to provide the product
(S,R)-3 in diastereomeric excess? At this stage we initiated a com-
putational investigation18 to clarify the mechanistic features gov-
erning the stereochemical outcome. The work proved difficult and
computationally demanding due to the complexity and number of
putative intermediates. Before finalizing the calculations, a DFT
study on the Heck arylation of 1 with aryl halides was published by
Ming et al.19 Pleasingly, the results from theoretical calculations by
this research group supported the experimental outcome, yielding
the (S,R)-3 product. They concluded that the insertion barrier, and
migratory insertion and the regioselectivity of the following
b-
elimination to afford highly diastereoselective intermolecular Heck
reactions.15
In 2003, we published a chelation-controlled Heck method for
stereoselective generation of (R)-2-aryl-2-methylcyclopentanones
in 90–98% ee and 45–78% overall yield by a Heck arylation of
not the difference in p-complex stability, was the prime factor for
the stereoselection in the directed Heck arylation.
The intriguing features of this class of auxiliary-controlled Heck
reactions encouraged us to investigate non-C2-methylated olefin 4
as a simplified derivative of 1, using the same chiral pyrrolidine
auxiliary (Scheme 2). The double bond of vinyl ether 4 is only tri-
* Corresponding author. Tel.: þ46 18 471 46 67; fax: þ46 18 471 44 74.
E-mail address: mats.larhed@orgfarm.uu.se (M. Larhed).
substituted and we reasoned that both the
p-complex formation
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.099

A. Trejos et al. / Tetrahedron 64 (2008) 8746–8751
8747
Table 1
O
O
Pd(OAc)2, LiCl
K2CO3, NaOAc
Diastereoselective (S)-N-methyl-pyrrolidine-controlled Heck synthesis of 5 using
aryl iodides
N (S)
N (S)
Ar
(R)
Ar-X
+
Entry
1
Aryl iodide
Time [h] Isolated yielda [%]
deb [%]
98
[a]
D
C2
DMF, Water
2 X=I
1
(S,R)-3
6 X=Br
2a 2.0
2b 2.7
57
60
5a
5b
ꢂ97ꢀ
ꢂ82ꢀ
MeO
I
H
O
2
3
>98
I
N
O
H3O+
Ar
Pd Ar
(R)
2c 3.0
29
5c
96
ꢂ44ꢀ
(R)-2-aryl-2-methyl-
cyclopentanones
(90-98% ee)
I
I
4c
5
2c 0.5
2d 3.0
42
54
5c
94
98
ꢂ43ꢀ
ꢂ73ꢀ
via -complex
5d
Scheme 1. Heck arylation of tetrasubstituted (S)-N-methyl-pyrrolidine-functionalized
vinyl ether 1 and subsequent hydrolysis.
I
6
7
2e 2.2
58
51
5e
5f
96
þ10ꢀ
ꢂ78ꢀ
O
O
O
(S)
(S)
(S)
N
N
N
2 or 6, [Pd]
Ar
(R)
Ar
O
O
or
C2
(S)
(S,S)-5
2f
1.7
>98
I
(S,R)-5
4
8
9
2g 3.0
2h 2.5
45
50
5g
5h
>98
>98
ꢂ73ꢀ
ꢂ76ꢀ
I
Scheme 2. Possible diastereomeric outcomes in Heck arylation of trisubstituted vinyl
ether 4.
Ph
F3C
I
and the insertion rate should increase using 4. Since theoretical DFT
calculations were found problematic, we decided to experimentally
investigate the Heck arylation of olefin 4. In this paper we hereby
report: (1) the synthesis of vinyl ether 4, (2) the identification of
classical and microwave-assisted reaction conditions for mono-
arylation of 4 using either aryl iodides 2 or aryl bromides 6, and (3)
an unambiguous establishment of a Si-insertion process by X-ray
crystallographic analysis of an isolated salt of the (S,R)-5 product.
10
2i
3.0
57
5i
>98
ꢂ94ꢀ
NC
I
a
Reaction conditions: 2a–i (0.30 mmol), 4 (0.33 mmol), Pd(OAc)2 (9
m
mol), NaOAc
(0.36 mmol), LiCl (0.60 mmol), K2CO3 (0.36 mmol), H2O (0.1 mL) in DMF (1.0 mL) at
80 ꢀC; >95% purity according to GC–MS.
b
Determined by GC–MS and 1H NMR of the crude product.
Performed with controlled microwave heating at 110 ꢀC.
c
chromatography on silica. As depicted in Table 1, most aryl iodides
performed well, producing moderate to good isolated yields. A
slightly lower yield was experienced with hindered 2c (29%, entry
3). This was probably due to a slower insertion rate allowing more
pronounced dehalogenation and competing reactions, mainly
homocoupling but also diarylation. Importantly, GC–MS and 1H
NMR analyses of the crude products proved a diastereomeric excess
of more than 96% for all reactions with classical heating regardless
of the electronic properties of the aryl group (Table 1). The high
stereoselectivity elucidates the excellent capability of the pyr-
rolidine auxiliary to control the stereochemical outcome of the
reaction. Despite the possibility for further arylation of the in situ
generated trisubstituted double bond of monoarylated 5, no or very
small amounts of diarylated products (ꢁ4%) were detected using
this protocol. In order to improve the outcome with ortho-
substituted 2c, the reaction was also carried out in sealed vessels
under controlled microwave irradiation22–24 using an identical re-
action system. Full conversion of 2c and an improved yield of 42%
was obtained after merely 30 min of heating at 110 ꢀC (Table 1,
entry 4). Under these conditions, the diastereomeric excess was
reduced to 94%.
2. Results and discussion
An acid-catalyzed transacetalization–elimination process was
utilized in the preparation of vinyl ether 4 from cyclopentanone
and (S)-N-methyl prolinol (Scheme 3). The reaction was found to be
highly moisture sensitive and reversible, cleaving the product and
reforming cyclopentanone if dry conditions were not established.
Continuous azeotropic distillation with toluene and subsequent
addition of small amounts of chloroform to remove formed meth-
anol provided a residue, which was purified by silica-chromato-
graphy, yielding 45% of pure product 4.
1) PTSA, HC(OMe)3
OH
, H+
O
2)
O
(S)
N
(S)
N
3) Distillation
4
Scheme 3. Synthesis of vinyl ether 4.
2.1. Aryl iodides as coupling partners
2.2. Aryl bromides as coupling partners
Utilizing previous experiences on Heck arylations of non-cyclic
vinyl ethers,12 straightforward phosphine-free conditions20,21 were
selected for arylation of 4 using Pd(OAc)2 (2 mg, 9 mmol) as pre-
catalyst, aryl iodides 2a–i (0.30 mmol), 4 (60 mg, 0.33 mmol),
NaOAc (31 mg, 0.38 mmol), LiCl (25 mg, 0.60 mmol), K2CO3 (50 mg,
0.36 mmol), H2O (0.1 mL), and DMF (1.0 mL). The reactions were
performed in a sealed vessel using a heating-block set at 80 ꢀC.
After full conversion of yield-determining 2a–i (1.7–3.0 h), arylated
products (S,R)-5a–i were isolated (>95% purity) using column
The productive reaction conditions for aryl iodides were found
to be insufficient for activation of the cheaper but more sluggish
aryl bromides (6a–i). In addition, hydrolysis of the starting vinyl
ether, competing diarylation, and dehalogenation of starting ma-
terial complicated both product generation and isolation of the
desired product. These difficulties were solved using controlled
microwave heating and trans-di-m-acetatobis[2-(di-o-tolylphos-
phino)benzyl]dipalladium(II) (Herrmann’s palladacycle)25–27/2-
(di-tert-butylphosphino)biphenyl (JohnPhos)28 as a thermostable

8748
A. Trejos et al. / Tetrahedron 64 (2008) 8746–8751
catalytic system, resulting in both faster reactions and higher yields
of products 5a–i.29,30 All the microwave reactions were performed
under an atmosphere of air in septum sealed reaction vials charged
with 6a–i (0.30 mmol), 4 (60 mg, 0.33 mmol), Herrmann’s palla-
methylated by stirring the compound in methyl iodide (2 mL) for
2 h at 40 ꢀC (Scheme 4).
dacycle (8 mg, 9.0 mmol), JohnPhos (8 mg, 27.0 mmol), NaOAc
+
O
O
N
N
(29 mg, 0.36 mmol), LiCl (25 mg, 0.60 mmol), K2CO3 (50 mg,
0.36 mmol), H2O (0.1 mL), and DMF (1.0 mL). The reaction mixtures
were irradiated for 20 min at 120 ꢀC or 130 ꢀC using a single-mode
reactor with temperature control. At higher reaction temperature,
the diarylation process becomes more competitive, partly due to
reduced steric requirements of the ArPdBr complex, set against the
alternative ArPdI intemediate.12 In comparison, reactions using aryl
iodides 2a and 2c at 120 ꢀC did not provide the diarylated product
at all. The preparative results with aryl bromides using our opti-
mized conditions are summarized in Table 2, showing identical
or slightly improved yields compared with the corresponding
reactions with aryl iodides 2a–i, except for the case of electron-rich
4-bromoanisole 6a. In this case, rapid homocoupling of 6a,
producing the bianisyl side-product and rapid diarylation of 4,
competed with the formation of the desired monoarylated product
5a. Despite the higher reaction temperature, the diastereomeric
selectivity remained virtually intact (90–98% de), although
diarylation was slightly more pronounced using aryl bromides
instead of the iodo counterparts. Thus, the efficiency of the
catalyst-presenting (S)-N-methyl-pyrrolidine remained high also
in the presence of the Pd(II)-coordinating phosphine ligand
JohnPhos.
CH3I
-
I
(S,R)-5b
(S,R)-7b
Scheme 4. Synthesis of the quarternary ammonium salt (S,R)-7b.
2.3. X-ray diffraction analysis
To determine the absolute configuration of the Heck arylation
products, (S,R)-5b (27 mg, 0.10 mmol) was selected and N-
Figure 1. Ortep plot of C2-arylated N,N-dimethyl vinyl ether ammonium iodide salt
(S,R)-7b. Probability level 40%. Hydrogens are fixed with a radius of 0.30 Å. Please note
that the cyclopentenyl ring is slightly disordered with large thermal displacements at
C2 and C4.
Table 2
Diastereoselective (S)-N-methyl-pyrrolidine-controlled Heck synthesis of 5 using
aryl bromides
The resulting quaternary ammonium salt 7b was thereafter
recrystallized in i-PrOH. X-ray crystallography analysis based on
the known (S)-stereocenter of the prolinol moiety revealed that the
(S,R)-C2-isomer was formed, confirming a Si-face insertion to the
Entry
Aryl bromide
Temperature [ꢀC] Isolated yielda [%] deb [%]
[a]
D
ꢂ97ꢀ
ꢂ79ꢀ
cyclopentene
p-system (Fig. 1).
1
2
6a 130
6b 120
35
68
5a
5b
98
94
MeO
Br
Br
3. Conclusion
In summary, palladium(0)-catalyzed Heck methods for highly
diastereoselective syntheses of monoarylated cyclopentenyl
ethers (S,R)-5a–i have been developed by the use of a palladium-
presenting pyrrolidine auxiliary. Chelation-controlled C2-arylations
proceeded smoothly and with high to excellent diaster-
eoselectivities (90–98% de) using nine different aryl iodides and the
corresponding aryl bromides as arylating agents. Best results with
aryl bromides were obtained under controlled microwave heating
using a phosphine ligand based catalytic system. Investigated (S)-N-
methyl-pyrrolidine-functionalized 1-cyclopentenyl ether un-
dergoes Si-face insertion, providing(R)-configuration of the arylated
C2-carbon. The absolute configuration was unambiguously estab-
lished using X-ray crystallographic analysis of a quaternary ammo-
nium salt prepared from the corresponding isolated Heck product
(S,R)-5b.
3
4
6c 130
6d 120
56
65
5c
90
92
ꢂ42ꢀ
ꢂ70ꢀ
Br
Br
Br
5d
5
6
6e 120
6f 120
46
44
5e
5f
92
98
þ9ꢀ
O
O
ꢂ78ꢀ
Br
7
8
6g 120
6h 130
56
57
5g
5h
>98
>98
ꢂ73ꢀ
ꢂ76ꢀ
Br
Ph
F3C
Br
Br
9
6i 120
57
5i
98
ꢂ94ꢀ
NC
4. Experimental
a
Reaction conditions: 6a–i (0.30 mmol), 4 (0.33 mmol), Herrmann’s palladacycle
mol), JohnPhos (27 mol), NaOAc (0.36 mmol), LiCl (0.60 mmol), K2CO3
4.1. General comments
(9
m
m
(0.36 mmol), H2O (0.1 mL), and DMF (1.0 mL). Microwave heating in a sealed vessel
1H and 13C NMR spectra were obtained in CDCl3 solution at
for 20 min; >95% purity according to GC–MS.
Determined by GC–MS and 1H NMR of the crude product.
400 MHz and 100 MHz, respectively. Chemical shifts for 1H and 13
C
b

A. Trejos et al. / Tetrahedron 64 (2008) 8746–8751
8749
are referenced toTMS via the solvent signals (1H, CHCl3 at 7.26 ppm;
4.4. General procedure for Heck arylation using aryl iodides,
Table 1, entries 1–3, 5–9
13C, CDCl3 at 77.0 ppm). Low resolution mass spectra were recorded
on a GC–MS instrument equipped with a Varian Chrompack Capil-
lary column CP-SIL 8 CB Low Bleed/MS (30 mꢃ0.22 mm, 0.25
mm)
The reactants were added to a reaction vial in the following
order: aryl iodide 2 (0.30 mmol), 4 (60 mg, 0.33 mmol), Pd(OAc)2
and utilizing an ion generation potential of 70 eV. The oven tem-
perature was 40–300 ꢀC (gradient 30 ꢀC/min), 70–320 ꢀC (gradient
16 ꢀC/min), or 90–300 ꢀC (gradient 8 ꢀC/min). Diastereomeric excess
was measured by GC–MS and 1H NMR of the crude product; the
different diastereomers were assumed to give equal response factor
on GC–MS. HRMS experiment was performed on a 7-tesla hybrid ion
trap (LTQ) FT mass spectrometer modified with a nanospray ion
source. Elemental analyses were performed by MikroKemi AB,
Uppsala, Sweden or Analytische Laboratorien, Lindlar, Germany.
Conventionally heated reactions were performed in thick-walled
tubes fitted with Teflon-lined screw caps. Optical rotations were
obtained on a Perkin–Elmer 241 polarimeter using dichloromethane
as solvent (c¼10 mg/mL) at ambient temperature (20–22 ꢀC). Mi-
crowave heating was carried out using an automatic Smith single-
mode synthesizer from Biotage, Sweden, producing a radiation
frequency of 2450 MHz. Microwave reaction vessels in Pyrex (5 mL,
code no 351520, Smith process vial) with silicon septum were also
supplied by Biotage. Analytical TLC was performed using Merck
glass-backed 0.2 mm silica-gel 60 F-254 plates. Visualization was
performed by ultraviolet light and/or by staining with phospho-
molybdic acid (12 g) in ethanol (250 mL). Flash column chroma-
tography was performed using commercially available silica (Merck
grade 9385, 230–400 mesh, 60 Å) or aluminum oxide (Aldrich, ac-
tivated, neutral, STD grade, 150 mesh, 58 Å).
(2 mg,
9 mmol), NaOAc (29 mg, 0.36 mmol), LiCl (25 mg,
0.60 mmol), K2CO3 (50 mg, 0.36 mmol), DMF (1 mL), and water
(0.1 mL). The tube was closed and the contents were magnetically
stirred and heated for 1.7–3 h at 80 ꢀC. The reaction was stopped
when GC–MS analysis showed complete conversion of 2. The re-
action mixture was diluted with dichloromethane and thereafter
filtered through a plug of Celite. The filtrate was washed using 0.1 M
NaOH (aq) (25 mL). The aqueous layer was thereafter extracted
with dichloromethane (3ꢃ25 mL). The organic phases were com-
bined, dried with K2CO3 (s), concentrated, and purified by column
chromatography on silica-gel affording pure products (S,R)-5a–i.
4.5. Microwave procedure for Heck arylation using 2-iodo-
toluene, Table 1, entry 4
The reactants were added to a 0.5–2.0 mL process vial in the
following order: 2-iodo-toluene (65 mg, 0.30 mmol), 4 (60 mg,
0.33 mmol), Pd(OAc)2 (2 mg, 9 mmol), NaOAc (29 mg, 0.36 mmol),
LiCl (25 mg, 0.60 mmol), K2CO3 (50 mg, 0.36 mmol), DMF (1 mL),
and water (0.1 mL). The vial was sealed and the contents were
magnetically stirred and microwave-heated for 30 min at 110 ꢀC.
The reaction mixture was diluted with dichloromethane and
thereafter filtered through a plug of Celite. The filtrate was washed
using 0.1 M NaOH (aq) (25 mL). The aqueous layer was thereafter
extracted with dichloromethane (3ꢃ25 mL). The organic phases
were combined, dried with K2CO3 (s), concentrated, and purified
by column chromatography on silica-gel affording pure product
(S,R)-5c.
4.2. Materials
Palladium(II)acetate and Herrmann’s precatalyst (trans-di-
m-acetatobis[2-(di-o-tolylphosphino)benzyl]dipalladium(II)) were
obtained from Strem Chemicals. 2-(Di-tert-butylphosphino)biphenyl,
cyclopentanone, trimethylorthoformate and (S)-(ꢂ)-1-methyl-
2-pyrrolidine-methanol were purchased from Sigma–Aldrich and
used as received. All other reagents obtained from commercial
sources were used as received. Spectral and analytical properties of
all products synthesized using method A are summarized below.
All products were obtained as colorless viscous oils. Compounds 4,
5a–i, and 7b are all novel structures.
4.6. General procedure for Heck arylation using aryl
bromides, Table 2, entries 1–9
The reactants were added to a 0.5–2.0 mL process vial in the
following order: aryl bromide 2 (0.30 mmol), 4 (60 mg, 0.33 mmol),
Herrmann’s palladacycle (8.4 mg, 9
mmol), 2-(di-tert-butylphos-
phino)biphenyl (8.1 mg, 27 mol), NaOAc (29 mg, 0.36 mmol), LiCl
m
(25 mg, 0.60 mmol), K2CO3 (50 mg, 0.36 mmol), DMF (1 mL), and
water (0.1 mL). The vial was sealed and the contents were mag-
netically stirred and microwave-heated for 20 min at 120–130 ꢀC.
The reaction mixture was diluted with dichloromethane and
thereafter filtered through a plug of Celite. The filtrate was washed
using 0.1 M NaOH (aq) (25 mL). The aqueous layer was thereafter
extracted with dichloromethane (3ꢃ25 mL). The organic phases
were combined, dried with K2CO3 (s), concentrated, and purified
by column chromatography on silica-gel affording pure products
(S,R)-5a–i.
4.3. Preparation of (S)-2-(cyclopent-1-enyloxymethyl)-1-
methyl-pyrrolidine (4)
1,1-Dimethoxy-cyclopentane (1.6 g, 13.0 mmol), prepared as
described by Nilsson et al.,16 and (S)-(ꢂ)-1-methyl-2-pyrrolidine-
methanol (1.5 g, 13.0 mmol) were dissolved in 4 mL toluene. HCl/
ether was slowly added until all amine was precipitated. Sub-
sequently, chloroform (4 mL) was added to increase the solubility.
The slurry was transferred to a distillation device and heated at
100 ꢀC overnight. The oil-bath temperature was raised to 115 ꢀC
and chloroform (4 mL) was added twice a day. The distillation was
interrupted when GC–MS analysis of the residue showed complete
consumption of 1,1-dimethoxy-cyclopentane. Addition of sodium
hydroxide (0.1 M, 25 mL) and subsequent extraction with diethyl
ether (3ꢃ25 mL) provided a red-brown crude product after drying
(K2CO3(s)) and concentration of the combined etheral phases.
Purification by column chromatography on silica-gel using 96:4 iso-
4.7. Experimental data and characterization of compounds 4
and (S,R)-5a–i
4.7.1. (S)-2-[(R)-5-(4-Methoxy-phenyl)-cyclopent-1-enyloxy-
methyl]-1-methyl-pyrrolidine (5a)
Using method A, compound 5a was obtained in 98% de and 57%
yield after purification by column chromatography on silica-gel
(iso-hexane/diethyl ether/triethylamine, 70:25:5). Using method C,
compound 5a was obtained in 98% de and 35% yield after purifi-
cation by column chromatography on silica-gel (iso-hexane/ethyl-
hexane/triethylamine provided pure 4 (1.0 g, 45%). 1H NMR
d 4.44–
4.41 (m, 1H), 3.74 (dd, J¼5.0, 9.7 Hz,1H), 3.63 (dd, J¼6.0, 9.7 Hz,1H),
3.08–3.03 (m, 1H), 2.52–2.45 (m, 1H), 2.40 (s, 3H), 2.37–2.18 (m,
5H), 2.02–1.57 (m, 5H); 13C NMR
d
160.1, 93.9, 71.8, 64.4, 57.7, 41.5,
acetate/triethylamine, 80:16:4). 1H NMR
d
7.11 (dd, J¼2.1, 6.6 Hz,
31.9, 29.0, 28.7, 22.9, 21.3; MS (70 eV) m/z (relative intensity) 181
(Mþ, 2), 98 (5), 84 (100), 42 (8). Anal. Calcd for C11H18NO: C, 72.88;
H, 10.56. Found: C, 72.85; H, 10.55.
2H), 6.82 (dd, J¼2.1, 6.6 Hz, 2H), 4.65 (dt, J¼1.5, 2.3 Hz,1H), 3.81 (dd,
J¼5.7, 9.5 Hz, 1H), 3.79 (s, 3H), 3.75–3.68 (m, 1H), 3.56 (dd, J¼6.8,
9.5 Hz,1H), 2.99 (ddd, J¼2.2, 7.0, 9.1 Hz,1H), 2.50–2.25 (m, 4H), 2.33

8750
A. Trejos et al. / Tetrahedron 64 (2008) 8746–8751
(s, 3H), 2.19 (ddd, J¼7.1, 9.1, 9.9 Hz, 1H), 1.88–1.60 (m, 4H), 1.46–1.36
(m, 1H); 13C NMR
161.2, 158.1, 136.8, 128.5, 113.8, 95.5, 73.4, 63.9,
chromatography on silica-gel (iso-hexane/ethylacetate/triethyl-
amine, 70:25:5). 1H NMR
d
d
8.10 (ddd, J¼1.1, 2.0, 8.3 Hz, 1H), 7.87–
57.8, 55.4, 49.5, 41.9, 32.7, 29.2, 27.6, 23.41; MS (70 eV) m/z (relative
7.83 (m, 1H), 7.71 (dt, J¼1.1, 8.2 Hz, 1H), 7.52–7.44 (m, 2H), 7.41 (dd,
J¼7.1, 8.2 Hz, 1H), 7.28 (dd, J¼1.6, 7.1 Hz, 1H), 4.85 (dt, J¼1.3, 2.4 Hz,
1H), 3.92 (dd, J¼5.4, 9.5 Hz, 1H), 3.68 (dd, J¼6.9, 9.5 Hz, 1H),
3.00 (ddd, J¼2.0, 7.2, 11.5 Hz, 1H), 2.66–2.55 (m, 1H), 2.52–2.36 (m,
3H), 2.34 (s, 3H), 2.19 (dt, J¼7.23, 9.68 Hz, 1H), 1.89–1.60 (m, 5H),
intensity) 287 (Mþ, 2), 98 (50), 84 (100). Anal. Calcd for C18H25NO2:
22
C, 75.22; H, 8.77; N, 4.87. Found: C, 75.10; H, 8.79; N, 4.80. [a]
D
ꢂ97ꢀ.
4.7.2. (S)-1-Methyl-2-((R)-5-p-tolyl-cyclopent-1-enyloxymethyl)-
1.53–1.44 (m, 1H); 13C NMR
d 160.2. 139.9, 134.2, 132.2, 128.8, 126.7,
pyrrolidine (5b)
125.7, 125.7, 125.3, 124.0, 123.8, 97.1, 73.3, 64.1, 57.7, 46.3, 41.8, 32.1,
Using method A, compound 5b was obtained in >98% de and
60% yield after purification by column chromatography on silica-gel
(iso-hexane/triethylamine, 96:4). Using method C, compound 5b
was obtained in 94% de and 68% yield after purification by column
chromatography on silica-gel (iso-hexane/ethylacetate/triethyl-
29.4, 27.6, 23.1; MS (70 eV) m/z (relative intensity) 307 (Mþ, 7), 98
(24), 84 (100). Anal. Calcd for C21H25NO: C, 82.04; H, 8.20; N, 4.56.
20
Found: C, 82.28; H, 8.29; N, 4.45. [
a]
þ10ꢀ.
D
4.7.6. 1-{4-[(R)-2-((S)-1-Methyl-pyrrolidin-2-ylmethoxy)-
cyclopent-2-enyl]-phenyl}-ethanone (5f)
amine, 80:16:4). 1H NMR
3.83 (dd, J¼5.7, 9.6 Hz, 1H), 3.77–3.70 (m, 1H), 3.58 (dd, J¼6.6,
9.6 Hz, 1H), 3.00 (m, 1H), 2.56–2.35 (m, 3H), 2.34 (s, 3H), 2.32 (s,
3H), 2.26–2.14 (m, 1H),1.92–1.59 (m, 5H), 1.51–1.40 (m, 1H); 13C
d
7.08 (s, 4H), 4.66 (dt, J¼2.3, 1.4 Hz, 1H),
Using method A, compound 5f was obtained in >98% de and 51%
yield after purification by column chromatography on silica-gel
(iso-hexane/diethyl ether/triethylamine, 70:25:5). Using method C,
compound 5f was obtained in 98% de and 44% yield after purifi-
cation by column chromatography on silica-gel (iso-hexane/diethyl
NMR
d 161.1, 141.5, 135.6, 129.1, 127.5, 95.7, 73.2, 63.9, 57.8, 49.9,
41.8, 32.7, 29.2, 27.6, 23.1, 21.2; MS (70 eV) m/z (relative intensity)
271 (Mþ, 2), 98 (12), 84 (100). Anal. Calcd for C18H252N2 O: C, 79.66; H,
ether/triethylamine, 70:25:5). 1H NMR
d
7.88 (dd, J¼1.9, 6.5 Hz, 2H),
9.28; N, 5.16. Found: C, 79.39; H, 9.09; N, 5.08. [
a
]
ꢂ82ꢀ.
7.28 (dd, J¼1.9, 6.5 Hz, 2H), 4.71 (dt, J¼1.4, 2.3 Hz, 1H), 3.87–3.80
(m, 1H), 3.81 (dd, J¼5.7, 9.5 Hz, 1H), 3.56 (dd, J¼6.7, 9.5 Hz, 1H), 2.99
(ddd, J¼2.3, 6.8, 9.2 Hz, 1H), 2.58 (s, 3H), 2.49–2.31 (m, 4H), 2.32 (s,
3H), 2.18 (ddd, J¼7.3, 9.1, 9.7 Hz, 1H), 1.85–1.60 (m, 4H), 1.44–1.35
D
4.7.3. (S)-1-Methyl-2-((R)-5-o-tolyl-cyclopent-1-enyloxymethyl)-
pyrrolidine (5c)
Using method A, compound 5c was obtained in 96% de and 29%
yield after purification by column chromatography on silica-gel
(iso-hexane/diethyl ether/triethylamine, 70:25:5). Using method B,
compound 5c was obtained in 94% de and 42% yield after purifi-
cation by column chromatography on silica-gel (iso-hexane/ethyl-
acetate/triethylamine, 90:6:4). Using method C, compound 5c was
obtained in 90% de and 56% yield after purification by column
chromatography on silica-gel (iso-hexane/ethylacetate/triethyl-
(m, 1H); 13C NMR
d 198.1, 160.2, 150.5, 135.4, 128.6, 127.9, 96.3, 73.5,
63.9, 57.8, 50.4, 41.9, 32.4, 29.2, 27.7, 26.7, 23.1; MS (70 eV) m/z
(relative intensity) 299 (Mþ, 1), 98 (8), 84 (100). Anal. Calcd for
C
19H25NO2: C, 76.22; H, 8.42; N, 4.68. Found: C, 76.08; H, 8.61; N,
20
4.64. [
a]
ꢂ78ꢀ.
D
4.7.7. {4-[(R)-2-((S)-1-Methyl-pyrrolidin-2-ylmethoxy)-cyclopent-
2-enyl]-phenyl}-phenyl-methanone (5g)
amine, 90:6:4). 1H NMR
d
7.16–7.06 (m, 4H), 4.73 (dt, J¼1.4, 2.4 Hz,
Using method A, compound 5g was obtained in >98% de and
45% yield after purification by column chromatography on silica-gel
(iso-hexane/diethyl ether/triethylamine, 70:25:5). Using method C,
compound 5g was obtained in >98% de and 56% yield after
purification by column chromatography on silica-gel (iso-hexane/
1H), 3.99 (dddd, J¼1.4, 2.7, 5.0, 10.3 Hz, 1H), 3.85 (dd, J¼5.5, 9.4 Hz,
1H), 3.60 (dd, J¼6.9, 9.5 Hz, 1H), 3.00 (dd, J¼2.3, 6.9 Hz, 1H), 2.49–
2.30 (m, 4H), 2.35 (s, 3H), 2.34 (s, 3H), 2.27–2.16 (m, 1H), 1.91–1.60
(m, 4H), 1.51–1.43 (m, 1H); 13C NMR
d 160.7, 142.6, 136.1, 130.2,
126.5, 126.0, 125.9, 96.4, 73.3, 64.0, 57.8, 46.7, 41.9, 31.4, 29.4, 27.4,
diethyl ether/triethylamine, 70:25:5). 1H NMR
d
7.79 (dd, J¼1.3,
23.1, 19.7; MS (70 eV) m/z (relative intensity) 271 (Mþ, 3), 98 (30),
8.3 Hz, 2H), 7.75 (d, J¼8.5 Hz, 2H), 7.57 (ddt, J¼1.3, 6.6, 7.3 Hz, 1H),
7.48–7.43 (m, 2H), 7.29 (d, J¼8.3 Hz, 2H), 4.71 (dt, J¼1.4, 2.3 Hz, 1H),
3.88–3.84 (m, 1H), 3.81 (dd, J¼5.8, 9.6 Hz, 1H), 3.57 (dd, J¼6.7,
9.5 Hz, 1H), 2.99 (ddd, J¼2.2, 6.9, 9.2 Hz, 1H), 2.49–2.33 (m, 4H),
2.32 (s, 3H), 2.18 (ddd, J¼7.4, 9.1, 9.5 Hz, 1H), 1.87–1.76 (m, 2H),
84 (100). Anal. Calcd for C18H25NO: C, 79.66; H, 9.28; N, 5.16. Found:
C, 79.21; H, 9.41; N, 5.20. [
20
a
]
ꢂ44ꢀ.
D
4.7.4. (S)-1-Methyl-2-((R)-5-phenyl-cyclopent-1-enyloxymethyl)-
pyrrolidine (5d)
1.75–1.60 (m, 2H), 1.45–1.36 (m, 1H); 13C NMR
d 169.7, 160.3, 149.9,
Using method A, compound 5d was obtained in 98% de and 54%
yield after purification by column chromatography on silica-gel
(iso-hexane/triethylamine, 96:4). Using method C, compound 5d
was obtained in 92% de and 65% yield after purification by column
chromatography on silica-gel (iso-hexane/ethylacetate/triethyl-
138.1, 135.6, 132.3, 130.4, 130.1, 128.3, 127.6, 96.4, 73.5, 63.9, 57.8,
50.4, 41.9, 32.4, 29.2, 27.8, 23.1; MS (70 eV) m/z (relative intensity)
362 (Mþ, 5), 98 (18), 84 (100). Anal. Calcd for C24H27NO2: C, 79.74;
20
H, 7.53; N, 3.87. Found: C, 79.49; H, 7.28; N, 3.73. [
a
]
ꢂ73ꢀ.
D
amine, 80:16:4). 1H NMR
d
7.29 (ddd, J¼0.9, 1.9, 7.2 Hz, 2H), 7.22–
4.7.8. (S)-1-Methyl-2-[(R)-5-(4-trifluoromethyl-phenyl)-cyclopent-
1-enyloxymethyl]-pyrrolidine (5h)
7.15 (m, 3H), 4.68 (dt, J¼1.5, 2.2 Hz, 1H), 3.82 (dd, J¼5.7, 9.5 Hz, 1H),
3.79–3.74 (m, 1H), 3.57 (dd, J¼6.7, 9.5 Hz, 1H), 2.99 (ddd, J¼2.2, 7.1,
9.3 Hz, 1H), 2.50–2.34 (m, 3H), 2.32 (s, 3H), 2.22–2.15 (m, 1H), 1.88–
Using method A, compound 5h was obtained in >98% de and
50% yield after purification by column chromatography on silica-gel
(iso-hexane/diethyl ether/triethylamine, 90:6:4). Using method C,
compound 5h was obtained in >98% de and 57% yield after puri-
fication by column chromatography on silica-gel (iso-hexane/
1.59 (m, 5H), 1.48–1.35 (m, 1H); 13C NMR
d 160.9, 144.6, 128.3, 127.6,
126.1, 95.8, 73.4, 63.9, 57.8, 50.3, 41.9, 32.6, 29.2, 27.7, 23.1; MS
(70 eV) m/z (relative intensity) 257 (Mþ, 2), 98 (24), 84 (100).
Anal. Calcd for C17H23NO: C, 79.33; H, 9.01. Found: C, 79.1; H, 8.9.
ethylacetate/triethylamine, 70:25:5). 1H NMR
d
7.53 (dd, J¼0.8,
20
[
a]
ꢂ73ꢀ.
8.6 Hz, 2H), 7.29 (dd, J¼0.7, 8.6 Hz, 2H), 4.71 (dt, J¼1.4, 2.4 Hz, 1H),
3.86–3.81 (m, 1H), 3.81 (dd, J¼5.8, 9.5 Hz, 1H), 3.57 (dd, J¼6.6,
9.5 Hz, 1H), 2.99 (ddd, J¼2.2, 6.8, 9.4 Hz, 1H), 2.49–2.31 (m, 4H),
2.32 (s, 3H), 2.19 (ddd, J¼7.3, 9.2, 9.8 Hz, 1H), 1.87–1.61 (m, 4H),
D
4.7.5. (S)-1-Methyl-2-((R)-5-naphthalen-1-yl-cyclopent-1-
enyloxymethyl)-pyrrolidine (5e)
Using method A, compound 5e was obtained in 96% de and 58%
yield after purification by column chromatography on silica-gel
(iso-hexane/triethylamine, 96:4). Using method C, compound 5e
was obtained in 92% de and 46% yield after purification by column
1.45–1.36 (m, 1H); 13C NMR
d
160.2, 148.8 (q, J4 ¼1.3 Hz), 128.47
C–F
(q, J2 ¼32.3 Hz), 128.0, 125.30 (q, J3 ¼3.8 Hz), 124.6 (q, J1
¼
C–F
C–F
C–F
271.3 Hz), 96.4, 73.6, 63.9, 57.8, 50.2, 41.9, 32.4, 29.2, 27.7, 23.1; MS
(70 eV) m/z (relative intensity) 326 (Mþ, 8), 98 (31), 84 (100). Anal.

A. Trejos et al. / Tetrahedron 64 (2008) 8746–8751
8751
Calcd for C18H22F3NO: C, 66.45; H, 6.82; N, 4.30. Found: C, 66.58; H,
www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@
ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223
336033. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.06.099.
20
6.86; N, 4.41. [
a
]
D
ꢂ76ꢀ.
4.7.9. 4-[(R)-2-((S)-1-Methyl-pyrrolidin-2-ylmethoxy)-cyclopent-
2-enyl]-benzonitrile (5i)
Using method A, compound 5i was obtained in >98% de and 57%
yield after purification by column chromatography on silica-gel
(iso-hexane/ethylacetate/triethylamine, 80:15:5). Using method C,
compound 5i was obtained in 98% de and 57% yield after purifi-
cation by column chromatography on silica-gel (iso-hexane/ethyl-
References and notes
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acetate/triethylamine, 80:15:5). 1H NMR
d
7.56 (d, J¼8.4 Hz, 2H),
7.28 (d, J¼8.4 Hz, 2H), 4.70 (dt, J¼1.5, 2.5 Hz, 1H), 3.84–3.79 (m, 1H),
3.80 (dd, J¼5.8, 9.5 Hz, 1H), 3.55 (dd, J¼6.6, 9.5 Hz, 1H), 2.99 (ddd,
J¼2.4, 6.9, 9.3 Hz,1H), 2.47–2.31 (m, 4H), 2.30 (s, 3H), 2.19 (dt, J¼7.5,
9.5 Hz, 1H), 1.86–1.60 (m, 4H), 1.42–1.33 (m, 1H); 13C NMR
d 159.7,
150.3, 132.2, 128.5, 119.4, 110.0, 96.7, 73.6, 63.9, 57.8, 50.5, 41.9, 32.2,
29.2, 27.7, 23.1; MS (70 eV) m/z (relative intensity) 283 (Mþ, 10), 98
(33), 84 (100). Anal. Calcd for C18H22N2O: C, 76.56; H, 7.85; N, 9.92.
20
Found: C, 76.35; H, 7.94; N, 9.98. [
a]
ꢂ94ꢀ.
D
4.8. Preparation of (S)-1,1-dimethyl-2-((R)-5-o-tolyl-
cyclopent-1-enyloxymethyl)-pyrrolidine (7b)
14. Buezo, N. D.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc. 1998, 120, 7129–7130.
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Compound (S,R)-5b (27.1 mg, 0.10 mmol) was stirred with
methyl iodide (2 mL) for 2 h at 40 ꢀC. The solvent was removed in
vacuo furnishing a yellow oil in quantitative yield. The product was
then crystallized in i-PrOH providing white crystals of 7b, which
were used for X-ray crystallography. CCDC 683362. LC–MS, m/z¼
286 [Mþ]; HRMS [Mþ] 286.2166, C19H18NOþ requires 286.2171.
Acknowledgements
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We acknowledge the financial support from the Swedish
Research Council and the Knut and Alice Wallenberg’s Foundation.
¨
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Supplementary data
¨
M. Chem.dEur. J. 1997, 3, 1357–1364.
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1808–1812.
GC–MS and NMR data of products 4 and 5a–i, and crystallo-
graphic and LC–MS data of the salt 7b can be found in the online
version. CCDC 683362 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via