A practical access to new pyrrolizine carboxylates via KHMDS-catalyzed carbocyclizations

Article abstract of DOI:10.1080/00397911.2018.1563796

Easy and effective preparation of new 1H-pyrrolizine carboxylates was achieved with high efficiency via KHMDS-induced carbocyclization of N-alkynyl proline carboxylates under substantially mild conditions. Meanwhile, some trans-diiodoallylic N-proline carboxylates were obtained from N-propargyl proline carboxylates using molecular I₂ with or without KHMDS. This method is quite feasible in terms of practical and quick access to the pyrrolizines and their derivatives over the formation of carbanions.

Full text of DOI:10.1080/00397911.2018.1563796

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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A practical access to new pyrrolizine carboxylates
via KHMDS-catalyzed carbocyclizations
Muhammet Yildirim & Garba Suleiman
To cite this article: Muhammet Yildirim & Garba Suleiman (2019): A practical access to new
pyrrolizine carboxylates via KHMDS-catalyzed carbocyclizations, Synthetic Communications, DOI:
10.1080/00397911.2018.1563796
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https://doi.org/10.1080/00397911.2018.1563796
A practical access to new pyrrolizine carboxylates via
KHMDS-catalyzed carbocyclizations
a
b
Muhammet Yildirim and Garba Suleiman
a
b
_
Department of Chemistry, Bolu Abant Izzet Baysal University, Bolu, Turkey; Department of Chemistry,
Yobe State University, Damaturu, Yobe State, Nigeria
ABSTRACT
ARTICLE HISTORY
Easy and effective preparation of new 1H-pyrrolizine carboxylates
was achieved with high efficiency via KHMDS-induced carbocycliza-
tion of N-alkynyl proline carboxylates under substantially mild condi-
tions. Meanwhile, some trans-diiodoallylic N-proline carboxylates
were obtained from N-propargyl proline carboxylates using molecu-
Received 11 October 2018
Accepted 20 December 2018
KEYWORDS
5
-endo-dig; A3-coupling;
carbocyclization; L-proline;
sonogashira coupling
lar I with or without KHMDS. This method is quite feasible in terms
2
of practical and quick access to the pyrrolizines and their derivatives
over the formation of carbanions.
GRAPHICAL ABSTRACT
Introduction
Proline is one of the 20 natural proteinogenic amino acids. Using proline and its deriva-
tives or in combination with other compounds as a catalyst enhance cyclizations over
Mannich, enantioselective, heterogeneous, homogeneous, and transition metal-catalyzed
[
1]
[2]
reactions. Besides, it is a good precursor for the synthesis of syn-amino alcohols,
[
3]
[4]
[5]
potential stereoselective catalysts, cyclic dipeptides, neuropathic agents, and a var-
iety of significant natural products.
[
6–9]
The pyrrolizines, which are easily accessible scaffolds from proline derivatives, are the
important members of heterocyclic compounds comprising of two fused five-membered
rings with one nitrogen atom situated at the ring junction. Also, they constitute a prom-
inent group of natural products with a wide range of biological activities, such as anti-
cancer, antimalarial, antimicrobial, analgesic, antiproliferative, antiviral, antitumor,
[
9–14]
antileukemic, anti-inflammatory, and antagonism activities
; hence, they have gained
CONTACT Muhammet Yıldırım
Sciences, Bolu Abant Izzet Baysal University, 14030, Golkoy, Bolu, Turkey.
muhammetyildirim@ibu.edu.tr
Department of Chemistry, Faculty of Arts and
_
€ €
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
M. YILDIRIM AND G. SULEIMAN
Figure 1. Synthetic and natural pyrrolizine derivatives exhibiting biological properties.
[
11,13,15]
significant interest in the field of synthetic chemistry.
For instance, mitomycin
C, an antitumor drug and DNA alkylating agent, was successfully used in treating colon
and breast cancers, upper esophageal carcinoma, and superficial bladder tumors.
Besides, Clazamycin A and B, Licofelone, Ketorolac are the examples of pyrrolizine
[
12–14,16,17]
compounds having antibiotic and anti-inflammatory properties.
zidine alkaloids form the main frame of alkaloids found in over 600 plants.
bases, such as supinidine, retronecine, heliotridine, and crotanecine, belong to this class
Also, pyrroli-
[
18,19]
Necine
[
20]
and they exhibit significant hepatotoxicity.
For instance, heliotridine and crotanecine
are termed as potential insecticides in the field of agriculture due to their strong toxic
[
21]
properties
(Figure 1).
Syntheses of pyrrolizine derivatives are described by a countless number of proce-
[
11,13,14,22,23]
dures in the literature.
Although there are several methods for the construc-
tion of pyrrolizine rings, the most common method used is the addition of 1,3-dipolar
[
8,24,25]
cyclo azomethine ylides to dipolarophiles.
Alternative strategies for the synthesis
of pyrrolizines are: asymmetric cascade aza-Michael–Aldol reaction of (1H-pyrrol-2-yl)-
[
26]
2,2,2-trifluoroethanone with cyclopentene carbaldehyde using organocatalysts,
one-pot multicomponent reactions of 2-(pyrrolidin-2-ylidene)malononitrile with formal-
[
9]
dehyde and morpholine, catalyst-free stereoselective cascade annulation strategy with
[
11]
a,b-unsaturated aldehydes, deactivated olefins, and proline esters.
One of the best methods to access the carbocyclic (or heterocyclic) compounds is car-
bocyclization reaction, in which the ring formation of a system is achieved either in an
intramolecular or intermolecular pattern, over C–C or C-heteroatom bond forma-
[
27,28]
tion.
The molecules bearing alkyne groups usually undergo carbocyclizations with

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3
the aid of Lewis acids such as I and ICl, and transition metal complexes affording poly-
2
[
29]
[30]
[28]
heterocyclic compounds,
and 1H-indene-1,1-dicarboxylates.
minal alkynes afford a variety of heterocycles by the use of alkali bases over carbocycli-
naphthyl ketones,
cyclopentene carboxylic acid esters,
[
31]
Besides, some other precursors having non-ter-
[
32–35]
zations. In some cases, protic–Lewis acid combinations provide methylene
cyclopentanes and azacyclic compounds.
[
36,37]
Although pyrrolizines have been
researched extensively, there are very few findings about pyrrolizine carboxylates in the
recent literature. Herein, we developed and applied a concise synthetic method for the
preparation of new tetrahydro-1H-pyrrolizine carboxylates (6) from different N-alkynyl
proline carboxylates (4) via an alkali base-promoted carbocyclization over two different
routes yielding excellent results. Besides, some diiodo-addition products (5) were pro-
cured through the addition reaction of compound 3 with molecular iodine under very
mild basic conditions.
Results and discussion
The current work comprises a simple and effective synthetic route for the preparation
of new pyrrolizine carboxylates (6) from N-alkynyl proline carboxylates in few steps via
3
esterification, N-substitution, Sonogashira or A -coupling, and base-catalyzed intramo-
lecular carbocyclization reactions.
Preparation of 1-(prop-2-yn-1-yl)pyrrolidine-2-carboxylates (3a–f) and N-alkynyl
proline carboxylates (4a–t)
At the beginning of our work, 1-(prop-2-yn-1-yl)pyrrolidine-2-carboxylates (3a–f) were
prepared in high yields (71–100%) over two steps via Fischer esterification of L-proline
(
1) and S 2 substitution of proline ester salts (2) using propargyl bromide and triethyl-
N
[
38–40]
amine (Scheme 1, conditions a,b).
marily determined by H-NMR and 13C-NMR chemical shifts of acetylenic H (2.2 and
The structures of precursors (3a–f) were pri-
1
73 ppm). Afterwards, Sonogashira coupling reaction was applied to the terminal alkynes
(3a–f) using aryl iodides (1-iodo-4-toluene, 1-iodo-4-anisole, 1-ethoxy-4-iodobenzene)
to generate aryl-substituted N-alkynyl proline carboxylates (4a–i) in the presence of
DIPA. Coupling reactions took place very smoothly and afforded the products (4a–i) in
moderate to good yields (60–82%) under mild conditions (Scheme 1, condition c).
Alternatively, some of the N-alkynyl proline carboxylates (4j–t) were synthesized via
3
A -coupling reactions of L-proline carboxylate salts (2a–f) using formaldehyde and ter-
minal alkynes (phenylacetylene, 1-hexyne, methyl propiolate) in moderate to good yields
[
41,42]
(55–87%).
Only the substitution of formaldehyde with cyclohexanone afforded the
coupling product (4t) in low yield (27%). The formation of coupling products (4a–i)
1
was elucidated by the disappearance of triplet signals of acetylenic H’s (2.2 ppm) in H-
NMR of the products. Also, the structures of the coupling products (4a–t) were deter-
13
mined by the presence of aromatic, acetylenic, C-NMR signals (128–133, 74–85 ppm)
see supplementary file for spectroscopic data of precursors 3a–f and 4a–t).
(

4
M. YILDIRIM AND G. SULEIMAN
Scheme 1. Synthetic route leading to target compounds (5a–f, 6a–r).
Synthesis of 1-(2,3-diiodoallyl)pyrrolidine carboxylates (5a–f)
At first, electrophile-driven (I , ICl) cyclizations of N-propargyl-substituted proline car-
2
boxylates (3a–f) were carried out with the aid of bases (KHMDS, K CO ), but the trials
2
3
were unsuccessful to give any iodocyclization product (7) even in extended reaction
times (1–16 h). These trials of compounds 3a–f with I alone or with KHMDS furnished
2
only diiodo-addition products (5a–f) in DCM at room temperature for overnight
(Scheme 1). Attempts to optimize the reaction conditions failed and low (23–34%) to
moderate (55–57%) reaction yields were obtained for the products (5a–f) (Table 1,
entries 1–6). In structure determination of products (5a–f), singlet peaks at around
13
6
.97–7.00 ppm showed the presence of olefinic =CH proton in proton NMR. The C-
NMR signals around 102 and 81 ppm belonging to I–C=CHI carbons were another evi-
dence of addition products. In addition, the NMR findings were supported by accurate
mass data of the products (5a–f) (see experimental part).
The mechanism for the formation of trans-diiodoallylic proline carboxylates (5a–f)
was proposed to follow a general anti-addition reaction of an electrophile to triple bond
in alkynes. Questioning the formation of the trans-addition product (5) instead of the
iodocyclization product (7), reasonably, the competition of iodo-addition and iodocycli-
zation reactions will be the best explanation. By the formation of cyclic iodonium inter-
mediate as a result of the reaction between iodine and triple bond, the attack of iodine
anion to iodonium will be straightforward and fast to afford stable trans-iodo addition
product (5). In the meantime, carbanion formed from compound 3 by the action of
KHMDS would not react with the iodonium intermediate quite easily and instead, it
will stay in equilibrium with the conjugate acid of KHMDS, hence no iodocyclization
product (7) would form at the end of the reaction.

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Table 1. Formation of trans-diiodo products (5a–f).
a
Entry
R
Product
Yield (%)
1
2
3
4
5
6
a
Ethyl
5a
5b
5c
5d
5e
5f
34
26
31
23
55
57
Propyl
Isopropyl
Butyl
2-Butyl
Methyl
The yields after purification by column chromatography.
Carbocyclizations of N-alkynyl proline carboxylates (4a–t) and formation of title
0
0
compounds (6a–r or 6a –r )
A new series of alkynyl proline carboxylates (4a–t) were subjected to intramolecular
base-catalyzed carbocyclization reactions to explore the formation of cyclization prod-
0
0
ucts (6a–r or 6a –r ). Accordingly, in order to obtain the ideal conditions and optimal
yields, we have tried a comprehensive set of reaction conditions (temperature, base,
solvent, and reaction time) and the reaction completion in each trial was monitored by
TLC analysis. In model cyclization reaction, compound 4l was subjected to cyclizations
with different bases under several conditions. The reaction was first performed in
MeCN with one equivalent of KH at room temperature (Table 2, entry 1), but only the
decomposition of 4l was observed. Similarly, trial experiment using LDA gave only
decomposition products in THF (Table 2, entry 4), whereas the use of KH and KOt-Bu
did not induce the expected cyclization (Table 2, entries 1–3). A strong base, n-BuLi,
was slightly active and gave small amounts of the product 6l in THF under argon, but
any increment in the amount of n-BuLi did not lead to an increase in reaction yields
(Table 2, entries 5–6). Besides, a non-nucleophilic strong base, NaHMDS, in THF
enabled the formation of the target product (6l) in low yields (Table 2, entry 7).
However, the next trials with LiHMDS in THF afforded the expected product 6l in
moderate yields (Table 2, entries 8–9). Lastly, cyclization trial with KHMDS (1.0 equiv.)
in toluene resulted in the formation of product 6l in good yields at room temperature
in 2 hour (Table 2, entry 10). The success in carbocyclization with KHMDS directed us
to alter the reaction conditions. A higher amount of KHMDS (2.0 equiv.) ensured the
completion of cyclization much faster with similar yields (Table 2, entry 11), but the
ꢀ
best condition for the formation of 6l was found as 0.5 equiv. of KHMDS at 0–25 C in
quantitative yields within half an hour (Table 2, entry 12). The use of 0.25 equiv. of
KHMDS in cyclization reaction led to a decrease in reaction yields (Table 2, entry 13).
After assigning the optimized conditions, we subjected other N-alkynyl-substituted
proline carboxylates (4a–t) via KHMDS-mediated carbocyclizations. In general, target
0
compounds were obtained as 5-endo/4-exo isomeric mixtures (6/6 ) in good to excellent
yields at room temperature for 0.5–1 h (Table 3, entries 1–17).

6
M. YILDIRIM AND G. SULEIMAN
Table 2. Optimization of reaction conditions for the synthesis of compound 6l.
a
Reaction conditions
b
Entry
Solvent
Base (equiv.)
Temp.
Time(h)
Yield (%)
1
2
3
4
5
6
7
8
9
MeCN
t-BuOH
t-BuOH
THF
THF
THF
THF
THF
THF
Toluene
Toluene
Toluene
Toluene
KH (1.0)
rt
rt
3
9
8
3
2
16
3
2
2
2
Decomposed
NR
NR
Decomposed
20
25
32
46
55
70
73
KOtBu (1.0)
KOtBu (2.0)
LDA (1.5)
BuLi (1.1)
BuLi (1.5)
NaHMDS (1.0)
LiHMDS (1.0)
LiHMDS (1.5)
KHMDS (1.0)
KHMDS (2.0)
KHMDS (0.5)
KHMDS (0.25)
ꢀ
rt-60 C
ꢀ
–78 C-rt
ꢀ
–78 C-rt
ꢀ
–78 C-rt
ꢀ
0 C-rt
rt
rt
rt
0 C-rt
0 C-rt
1
1
1
1
a
0
1
2
3
ꢀ
1
0.5
0.5
ꢀ
Quantitative
66
ꢀ
0 C-rt
All reactions under inert atmosphere.
b
Yields after column chromatography.
0
0
The structures of carbocyclization products (6a–r and 6a –r ) were fully characterized
1
by using NMR and HRMS analyses. In H-NMR of 5-endo-products (6a–r), the charac-
teristic signals supporting the 5-membered structure were the olefinic CH signals reso-
0
0
nating at around 5.4–6.2 ppm. Besides, olefinic CH signals of 4-exo-products (6a –r )
13
were resonated at around 6.20–6.95 ppm in proton NMR spectra. As for C-NMR of 5-
endo-products (6a–r), basic signals depicting the 5-membered product were of olefinic
quarternary C=C (142–143 ppm) and olefinic=CH carbons (121–124 ppm). Besides, ole-
finic quarternary C=C (160–160.5 ppm) and olefinic=CH (130.7–130.8 ppm) C-NMR
signals supporting the 4-exo-products (6a –r ) were only evident in 13C-NMR spectra of
k and 6n products. In HRMS results of products, molecular ions have been found as
MH accurately by TOF-MS measurements, which were in accordance with calculated
accurate masses of all products (see characterization data in experimental part).
13
0
0
0
0
6
þ
Regarding integral ratio of the relevant protons (=CH, arom. CH or CH of ester
3
groups) in proton NMR spectra, endocyclic pyrrolizine products (6) were found as
major regioisomer in far greater extent (20:1, 10:1, 4:1, 2:1 ratios) in comparison with
0
exocyclic products (6 ) in the mixtures; however, three products 6f–h were obtained as
only the 5-endo-isomers (Table 3, entries 6–8). It is clear that the mechanism of carbo-
cyclizations mostly favored 5-endo-dig fashion rather than a 4-exo-fashion. Since exo-
0
products with a 4-membered ring (6 ) will be more strained and need larger activation
energy to form, this probably slowed down the formation rate of 4-exo-products during
the course of reaction.
In order to understand how the stereochemistry has changed - during the transfor-
mations and carbocyclization reactions, as an example, the specific rotations of L-pro-
line (1), starting compound 4p, and the product 6p were measured at 589 nm and
ꢀ
2
0 C. The specific rotations of the compounds 1, 4p and 6p were found as –0.84, –0.54,
and þ0.03, respectively (Scheme 2). These findings confirmed the retention of

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0
0
Table 3. Formation of pyrrolizine carboxylates 6a–r and isomers (6a –r ) and reaction yields.
ENTRY PRECURSOR
PRODUCT(S)
6:6’ RATIOa YIELD (%)b TIME
(
MIN)
1
2
3
4
4a
4b
4c
4d
10:1
10:1
10:1
10:1
76
81
30
30
35
40
QUANT.
90
5
6
4e
4f
10:1
QUANT.
30
40
SINGLE
ISOMER
90
6f
SINGLE
ISOMER
7
8
4g
4h
86
88
40
50
6
6
g
h
SINGLE
ISOMER
(continued)

8
M. YILDIRIM AND G. SULEIMAN
9
4i
4j
20:1
10:1
92
69
60
30
1
0
11
12
13
4k
4l
2:1
69
quant.
74
45
45
60
10:1
20:1
4m
1
4
4n
4:1
95
45
1
5
6
4o
4p
10:1
10:1
72
76
50
50
1
1
7
4r
10:1
74
60
1
8
9
4s
6s
6t
-
-
decomp.
NR
5
c
1
4t
120
a
Endo/exo ratio of regioisomers were principally determined by comparing the integrals of olefinic protons in proton
NMR of the products.
Yields after column chromatography.
Cyclohexanone was used instead of formaldehyde in preparation of 4t.
b
c

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9
0
Scheme 2. Proposed mechanism for the formation of products (6 or 6 ).
configuration from L-proline (1) to starting compounds (4), and also confirmed the for-
0
mation of an almost racemic mixture of products (6:6 ) during KHMDS-catalyzed car-
bocyclization reactions.
When the precursors 4s and 4t were subjected to KHMDS-induced carbocyclization
reactions, no product was obtained in both reactions. By the introduction of compound
4
s, decomposition took place less than5 minutes, likely, the electron-withdrawing effect
of C=O group made the b-carbon more positive and also due to keto-enol tautomeriza-
tion, the formation of products was not possible. Under similar conditions, no change
was observed in the reaction of compound 4t with KHMDS when monitored on TLC.
Arguably, the presence of bulky cyclohexane moiety (a to CꢁC bond) in compound 4s
blocked the formation of any cyclic product which would be very unstable due to ring
strain after formation.
Conclusion
In summary, we demonstrated an efficient synthesis of new tetrahydro-1H-pyrrolizine
carboxylates as 5-endo-isomers along with the trace amount of 4-exo-isomers in good to
excellent yields via KHMDS-mediated carbocyclization of N-alkynyl-substituted proline
carboxylates under very mild conditions. In addition, some trans-diiodoallylic proline
carboxylates were prepared from N-propargyl proline carboxylates via the addition reac-
tion of molecular I alone or with the aid of KHMDS to the terminal alkynes under
2
mild conditions. The present route provides an easy, practical, and impactful access to
bioactive pyrrolizines bearing different carboxylate groups through the use of very small
quantities of alkali base within minutes in excellent yields. Further studies to get new
pyrrolizine scaffolds via electrophile-catalyzed cyclizations are underway.

1
0
M. YILDIRIM AND G. SULEIMAN
Experimental section
General
All the reactions were carried out under inert atmophere in flame-dried reaction flasks
and monitored with TLC precoated plates (60, F254, Merck 5735 and 5554). The precur-
sors and the products were purified by CC using silica gel 60 (Merck-109385) or neutral
alumina (Merck-101077), and the eluent was the mixtures of ethyl acetate (EA) and
hexanes (H). All reagents and solvents of analytical grade were purchased from com-
1
13
mercial suppliers (Merck, Sigma-Aldrich, TCI) and used as received. H-NMR and C-
NMR spectra were recorded on VARIAN NMR spectrometers (400 MHz for proton and
100 MHz for carbon) and a JEOL-ECS400 Delta2 NMR spectrometer (400 MHz for pro-
ton and 100 MHz for carbon) at ambient temperature. All chemical shifts (d) are
reported in parts per million (ppm) downfield from TMS and J values are given in Hz.
The abbreviations used for NMR signals are: s=singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, quint ¼ quintet, sep ¼ septet, hep ¼ heptet, m ¼ multiplet, dd ¼ doublet of
doublets, dq ¼ doublet of quartets, td ¼ triplet of doublets, qd ¼ quartet of doublets,
ddd ¼ doublet of doublet of doublets, dtd ¼ doublet of triplet of doublets, tdt ¼ triplet of
doublet of triplets, and dddd ¼ doublet of doublet of doublet of doublets. IR spectra
were recorded on a SHIMADZU FTIR-8400S instrument using KBr or NaCl discs.
HRMS were run on a Waters Lct Premier XE oa-TOF Mass Spectrometer. Specific rota-
tions were run by a Rudolph Research Analytical Autopol I Automatic polarimeter.
Melting points were determined on a MELTEMP apparatus and are uncorrected.
Typical procedure for the preparation of diiodo addition products (5a–f)
ꢀ
A solution of compound 3 (1.0 mmol) in DCM (10 mL) at 0 C was stirred for
15 minutes and only iodine (3.0 equiv.) or iodine (2.0 equiv.) and 0.5 M KHMDS (1.0
equiv.) were added into the solution successively under inert atmosphere. The resulting
solution was warmed up to room temperature and progress of the reaction was con-
trolled by TLC until the starting material was completely consumed. The reaction mix-
ture was treated with a saturated solution Na S O and extracted with DCM
2
2 3
(
3 ꢂ 15 mL). Combined organic phases were washed with brine (15 mL). After drying
over Na SO , the solvent was rotaevaporated and the residue was purified through a sil-
2
4
ica column using EtOAc:hexane (1:7) as an eluent to afford compound 5.
Typical procedure for the synthesis of carbocyclization products (6a–r)
A solution of 0.5 M KHMDS (0.25 mmol) in toluene was added dropwise to a solution
of N-propargyl proline ester (0.5 mmol) in dry toluene (5 mL) under an inert atmos-
ꢀ
phere. First, the resulting solution was stirred at 0 C, then at room temperature until
the starting material was completely consumed (about 0.5–1 h). The solvent was rotae-
vaporated under reduced pressure and the residue was purified through a neutral alu-
mina column using EtOAc:hexane mixture as an eluent.

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0
0
Spectroscopic data for the products (5a–f, 6a–r, and 6a –r )
(
E)-ethyl 1-(2,3-diiodoallyl)pyrrolidine-2-carboxylate (5a): Yield: 148 mg, 34%.
ꢃ1
Viscous dark green oil. R : 0.67 (15% hexane/EA). IR (KBr): ꢀmax/cm = 3066 (olef.
f
CH), 2974–2804 (alip. CH), 1728 (ester C=O), 1589, 1442 (olefinic C=C), 1180–1145
ꢃ1
1
(
C–O) cm ; H-NMR (400 MHz, CDCl ) d 7.00 (s, olefinic CH, 1H), 4.20–4.14 (qd,
3
2
1
1
1
1
H, J ¼ 7.1, 2.0 Hz), 3.65–3.49 (d, 1H, J ¼ 14.0 Hz), 3.54–3.46 (m, 2H), 3.12–3.10 (td,
H, J ¼ 8.1, 3.9 Hz), 2.67–2.63 (dd, 1H, J ¼ 16.3, 7.7 Hz), 2.16–2.13 (ddd, 1H, J ¼ 16.0,
1
3
2.4, 8.9 Hz), 2.09–1.79 (m, 3H), 1.27 (t, 3H, J ¼ 7.1 Hz); C-NMR (100 MHz, CDCl ) d
3
73.5 (ester C=O), 101.9 (I–C=, olefinic), 81.2 (=CHI), 80.5, 64.5, 60.8, 52.1, 29.3, 23.4,
4.5. m/z (TOF-MS APCI ) 435 (100, MH ), 436 (25); HRMS (TOF-MS APCI ):
þ
þ
þ
þ
MH , found: 435.9287. C H I NO requires 435.9270.
1
0
16 2
2
(
E)-propyl 1-(2,3-diiodoallyl)pyrrolidine-2-carboxylate (5b): Yield: 115 mg, 26%.
1
Viscous dark green oil. R : 0.68 (15% hexane/EA). H-NMR (400 MHz, CDCl ) d 6.98
f
3
(
2
s, olefinic CH, 1H), 4.12–4.01 (m, 2H), 3.64–3.60 (d, 1H, J ¼ 14.0 Hz), 3.52–3.47 (m,
H), 3.12–3.07 (td, 1H, J ¼ 8.1, 4.0 Hz), 2.66–2.60 (dd, 1H, J ¼ 16.0, 7.8 Hz), 2.20–2.11
(
ddd, 1H, J ¼ 16.1, 12.3, 8.7 Hz), 2.03–1.79 (m, 3H), 1.71–1.62 (m, 2H), 0.93 (t, 3H,
1
3
J ¼ 7.4 Hz); C-NMR (100 MHz, CDCl ) d 173.9 (ester C=O), 102.0 (I–C=, olefinic),
3
þ
8
1.1 (=CHI), 79.8, 66.4, 64.3, 52.7, 29.4, 23.7, 22.4, 10.9. m/z (TOF-MS ES ) 449 (100,
þ
þ
þ
MH ), 152 (3); HRMS (TOF-MS ES ): MH , found: 449.9440. C H I NO
2
11
18 2
requires 449.9427.
E)-isopropyl 1-(2,3-diiodoallyl)pyrrolidine-2-carboxylate (5c): Yield: 279 mg, 31%.
(
1
Dark brown oil. R : 0.66 (15% hexane/EA). H-NMR (400 MHz, CDCl ) d 6.97 (s, ole-
f
3
finic CH, 1H), 5.07–4.97 (hept, 1H, J ¼ 6.3 Hz), 3.61–3.58 (dd, 1H, J ¼ 13.9, 1.1 Hz),
.51–3.40 (m, 2H), 3.12–3.01 (m, 1H), 2.66–2.55 (m, 1H), 2.17–2.03 (m, 1H), 2.00–1.73
3
1
3
(
m, 3H), 1.24 (dd,6H, J ¼ 6.3, 4.0 Hz); C-NMR (100 MHz, CDCl ) d 173.2 (ester
3
C=O), 102.6 (I–C=, olefinic), 80.8 (=CHI), 79.9, 67.7, 64.6, 52.4, 29.3, 23.4, 22.1, 22.0.
þ
þ
þ
þ
m/z (TOF-MS ES ) 449 (100, MH ), 450 (20); HRMS (TOF-MS ES ): MH , found:
49.9416. C H NO requires 449.9405.
4
1
6
28
2
(
E)-butyl 1-(2,3-diiodoallyl)pyrrolidine-2-carboxylate (5d): Yield: 108 mg, 23%.
1
Viscous dark green oil. R : 0.72 (15% hexane/EA). H-NMR (400 MHz, CDCl ) d 7.04
f
3
(
2
(
s, olefinic CH, 1H), 4.19–4.08 (m, 2H), 3.70–3.67 (d, 1H, J ¼ 14.0 Hz), 3.62–3.52 (m,
H), 3.17–3.15 (td, 1H, J ¼ 8.1, 4.1 Hz), 2.73–2.69 (dd, 1H, J ¼ 15.8, 7.6 Hz), 2.26–2.13
m, 1H), 2.08–1.83 (m, 3H), 1.70–1.57 (m, 2H), 1.46–1.33 (m, 2H), 0.92 (t, 3H,
1
3
J ¼ 7.4 Hz); C-NMR (100 MHz, CDCl ) d 173.4 (ester C=O), 101.2 (I–C=, olefinic),
3
þ
8
4
1.8 (=CHI), 81.2, 64.8, 63.7, 52.5, 30.7, 29.3, 23.3, 19.3, 13.8. m/z (TOF-MS APCI )
þ
þ
þ
63 (100, MH ), 464 (20); HRMS (TOF-MS APCI ): MH , found: 463.9603.
C H I NO requires 463.9583.
1
2
20 2
2
(
E)-sec-butyl 1-(2,3-diiodoallyl)pyrrolidine-2-carboxylate (5e): Yield: 255 mg, 55%.
1
Viscous dark green oil. R : 0.70 (15% hexane/EA). H-NMR (400 MHz, CDCl ) d 7.01
f
3
(
s, olefinic CH, 1H), 4.94–4.84 (m, 1H), 3.68–3.63 (ddd, 1H, J ¼ 14.0, 4.7, 0.9 Hz),
3
3
1
.56–3.48 (m, 2H), 3.14–3.09 (td, 1H, J ¼ 7.6, 3.8 Hz), 2.69–2.63 (qd, 1H, J ¼ 7.6,
.5 Hz), 2.24–2.13 (tt, 1H, J ¼ 11.9, 7.4 Hz), 2.05–1.80 (m, 3H), 1.72–1.49 (m, 2H),
13
.25–1.23 (dd, 3H, J ¼ 6.3, 3.2 Hz), 0.93–0.89 (td, 3H, J ¼ 7.5, 2.9 Hz); C-NMR
(100 MHz, CDCl ) d 173.2 (ester C=O), 102.2 (I–C=, olefinic), 80.5 (=CHI), 72.7, 64.6,
3

1
2
M. YILDIRIM AND G. SULEIMAN
þ
þ
6
3.5, 52.3, 29.4, 28.8, 23.3, 19.6, 9.8. m/z (TOF-MS ES ) 463 (100, MH ), 464 (15);
þ
þ
HRMS (TOF-MS ES ): MH , found: 463.9572. C H I NO requires 463.9584.
12
20 2
2
(
E)-methyl 1-(2,3-diiodoallyl)pyrrolidine-2-carboxylate (5f): Yield: 240 mg, 57%.
1
Viscous dark green oil. R : 0.65 (15%hexane/EA). H-NMR (400 MHz, CDCl ) d 6.99 (s,
f
3
olefinic CH, 1H), 3.72 (s, 3H), 3.63–3.59 (d, 1H, J ¼ 14.1 Hz), 3.54–3.45 (m, 2H),
3
1
.14–3.09 (td, 1H, J ¼ 8.1, 3.9 Hz), 2.67–2.61 (dd, 1H, J ¼ 16.1, 7.9 Hz), 2.12–2.09 (m,
1
3
H), 2.05–1.78 (m, 3H); C-NMR (100 MHz, CDCl ) d 174.3 (ester C=O), 102.3 (I–C=,
3
þ
olefinic), 80.4 (=CHI), 64.3, 63.8, 52.5, 51.9, 29.4, 23.5. m/z (TOF-MS ES ) 421 (100,
MH ), 143 (2); HRMS (TOF-MS ES ): MH , found: 421.9102. C H I NO
2
þ
þ
þ
9
12 2
requires 421.9114.
Mixture of endo/exo isomers (10:1 ratio): Ethyl 7-(4-methoxyphenyl)-2,3,5,7a-tet-
rahydro-1H-pyrrolizine-7a-carboxylate (6a) and (E)-ethyl 6-(4-methoxy benzylidene)-
0
1
(
6
3
-azabicyclo[3.2.0]heptane-5-carboxylate (6a ): Yield: 110 mg, 76%. Yellow oil. R : 0.32
f
1
15% hexane/EA). H-NMR (400 MHz, CDCl ) d 7.32–7.30 (d, arom H, 2H, J ¼ 8.9 Hz),
3
.85–6.82 (d, arom H, 2H, J ¼ 8.9 Hz), 6.08 (t, –C=CH, 1H, J ¼ 2.0 Hz), 4.22–4.05 (m,
H), 3.79 (s,OCH , 3H), 3.52–3.48 (dd, 1H, J ¼ 16.3, 2.4 Hz), 3.32–3.27 (ddd, 1H,
3
J ¼ 8.7, 6.0, 2.6 Hz), 2.90–2.85 (ddd, 1H, J ¼ 12.3, 6.9, 2.6 Hz), 2.55–2.48 (ddd, 1H,
J ¼ 10.3, 9.0, 5.4 Hz), 2.01–1.89 (dddd, 2H, J ¼ 12.9, 10.5, 6.9, 5.1 Hz), 1.86–1.81 (m,
13
2
(
H), 1.74–1.66 (ddd, 1H, J ¼ 12.4, 10.8, 7.1 Hz), 1.14 (t, 3H, J ¼ 7.1 Hz); C-NMR
100 MHz, CDCl ) d 174.4 (ester C=O), 159.0, 141.8 (olef. C=C), 128.6, 127.5, 125.9,
3
1
21.8 (C=CH, olefinic), 114.3, 113.8, 83.1, 61.2, 57.4, 55.2, 33.1, 26.5, 13.9. m/z (TOF-
þ
þ
þ
þ
MS ES ) 288 (100, MH ), 286 (5), 275 (1); HRMS (TOF-MS ES ): MH , found:
88.1596. C H NO requires 288.1600.
2
1
7
22
3
Mixture of endo/exo isomers (10:1 ratio): Ethyl 7-(p-tolyl)-2,3,5,7a-tetrahydro-1H-
pyrrolizine-7a-carboxylate (6b) and (E)-ethyl 6-(4-methylbenzylidene)-1-azabicy-
0
clo[3.2.0]heptane-5-carboxylate (6b ): Yield: 110 mg, 81%. Red oil. R : 0.35 (15% hex-
f
1
ane/EA). H-NMR (400 MHz, CDCl ) d 7.27–7.25(d, 2H, J ¼ 8.2 Hz), 7.12–7.10 (d, 2H,
3
J ¼ 8.0 Hz,), 6.17–6.16 (t, 1H, J ¼ 2.1 Hz), 4.22–4.04 (m, 3H), 3.53–3.49 (dd, 1H, J ¼ 16.4,
2
2
1
.4 Hz), 3.32–3.28 (ddd, 1H, J ¼ 8.8, 6.1, 2.5 Hz), 2.91–2.85 (ddd, 1H, J ¼ 12.3, 6.9,
.6 Hz), 2.55–2.49 (ddd, 1H, J ¼ 10.1, 9.1, 5.4 Hz), 2.32 (s, 3H), 2.02–1.89 (m, 1H),
.87–1.78 (m, 1H), 1.73–1.66 (ddd, 1H, J ¼ 12.4, 10.8, 7.1 Hz), 1.14 (t, 3H, J ¼ 7.1 Hz);
1
3
C-NMR (100 MHz, CDCl ) d 174.4 (ester C=O), 142.7 (olef. C=C), 137.3, 130.3, 129.6,
3
1
29.1, 126.9, 126.1, 123.0 (C=CH, olefinic), 120.2, 83.0, 61.2, 57.4, 33.0, 26.3, 21.2, 13.9.
þ
þ
þ
þ
m/z (TOF-MS ES ) 272 (100, MH ), 270 (1), 258 (1); HRMS (TOF-MS ES ): MH ,
found: 272.1657. C H NO requires 272.1651.
1
7
22
2
Mixture of endo/exo isomers (10:1 ratio): Isopropyl 7-(4-methoxyphenyl)-2,3,5,7a-
tetrahydro-1H-pyrrolizine-7a-carboxylate (6c) and (E)-isopropyl 6-(4-methoxybenzy-
0
lidene)-1-azabicyclo[3.2.0]heptane-5-carboxylate (6c ): Yield: 160 mg, quantitative.
1
Yellow oil. R : 0.43 (15% hexane/EA). H-NMR (400 MHz, CDCl ) d 7.31–7.29 (d, arom
f
3
H, 2H, J ¼ 8.8 Hz), 6.84–6.82 (d, arom H, 2H, J ¼ 8.8 Hz), 6.06 (t, –C=CH, 1H,
J ¼ 2.1 Hz), 5.00–4.91 (hept, 1H, J ¼ 6.3 Hz), 4.11–4.06 (dd, 1H, J ¼ 16.3, 1.7 Hz), 3.79 (s,
3
2
1
H), 3.51–3.46 (dd, 1H, J ¼ 16.3, 2.4 Hz), 3.32–3.27 (ddd, 1H, J ¼ 8.7, 6.1, 2.5 Hz),
.88–2.82 (ddd, 1H, J ¼ 12.3, 6.9, 2.4 Hz), 2.54–2.46 (m, 1H), 2.03–1.88 (m, 2H),
.84–1.80 (tdt, 1H, J ¼ 9.9, 5.2, 2.5 Hz), 1.74–1.64 (m, 1H), 1.21–1.19 (d, 3H,
1
3
J ¼ 6.3 Hz),1.09–1.07 (d, 3H, J ¼ 6.3 Hz); C-NMR (100 MHz, CDCl ) d 173.9 (ester
3

V
R
SYNTHETIC COMMUNICATIONS
13
C=O), 158.9, 142.0 (olef. C=C), 127.5, 126.1, 121.8 (C=CH, olefinic), 113.7, 83.2, 68.4,
þ
þ
6
1.2, 57.4, 55.2, 32.9, 26.0, 21.6, 21.4. m/z (TOF-MS ES ) 302 (100, MH ), 300 (5);
þ
þ
HRMS (TOF-MS ES ): MH , found: 302.1757. C H NO requires 302.1756.
18
23
3
Mixture of endo/exo isomers (10:1 ratio): Isopropyl 7-(p-tolyl)-2,3,5,7a-tetrahydro-
1
H-pyrrolizine-7a-carboxylate (6d) and (E)-isopropyl 6-(4-methylbenzylidene)-1-aza-
0
bicyclo[3.2.0]heptane-5-carboxylate (6d ): Yield: 129 mg, 90%. Pale yellow oil. R : 0.45
f
1
(
7
(
15% hexane/EA). H-NMR (400 MHz, CDCl ) d 7.24–7.26 (d, arom H, 2H, J ¼ 8.0 Hz),
3
.10(d, 2H, J ¼ 8.0 Hz), 6.15 (t, –C ¼ CH, 1H, J ¼ 2.1 Hz), 5.01–4.91 (m, 1H), 4.11–4.07
dd, 3H, J ¼ 16.4, 1.7 Hz), 3.51–3.47 (dd, 1H, J ¼ 16.4, 2.4 Hz), 3.31–3.27 (ddd, 1H,
J ¼ 8.6, 6.1, 2.5 Hz), 2.88–2.82 (ddd, 1H, J ¼ 12.4, 6.9, 2.5 Hz), 2.53–2.47 (ddd, 1H,
J ¼ 10.3, 9.0, 5.3 Hz), 2.32 (s, 3H), 2.02–1.85 (m, 1H), 1.85–1.76 (m, 1H), 1.72–1.64
(
ddd, 1H, J ¼ 12.4, 10.8, 7.1 Hz), 1.20–1.19 (d, 3H, J ¼ 6.3 Hz), 1.09–1.07 (d, 3H,
13
J ¼ 6.2 Hz); C-NMR (100 MHz, CDCl ) d 173.8 (ester C=O), 142.4 (olef. C=C), 137.1,
3
1
2
30.5, 129.0, 126.1, 123.0 (C=CH, olefinic), 121.2, 83.1, 68.4, 61.2, 57.4, 32.9, 26.3, 21.6,
1.4, 21.1. m/z (TOF-MS ES ) 286 (100, MH ), 284 (20), 276 (1); HRMS (TOF-MS
þ
þ
þ
þ
ES ): MH , found: 286.1810. C H NO requires 286.1807.
1
8
24
2
Mixture of endo/exo isomers (10:1 ratio): Isopropyl 7-(4-ethoxyphenyl)-2,3,5,7a-
tetrahydro-1H-pyrrolizine-7a-carboxylate (6e) and (E)-isopropyl 6-(4-ethoxybenzyli-
0
dene)-1-azabicyclo[3.2.0]heptane-5-carboxylate (6e ): Yield: 170 mg, quantitative. Pale
1
yellow oil, R : 0.43 (15% hexane/EA). H-NMR (400 MHz, CDCl ) d 7.29–7.27 (d, arom
f
3
H, 2H, J ¼ 9.9 Hz), 6.82–6.80 (d, 2H, J ¼ 8.9 Hz), 6.05 (t, –C=CH, 1H, J ¼ 2.1 Hz),
5
3
.00–4.89 (m, 1H), 4.10–4.05 (dd, 1H, J ¼ 16.1, 2.0 Hz), 4.04–3.98 (q, 1H, J ¼ 7.0 Hz),
.50–3.45 (dd, 1H, J ¼ 16.3, 2.4 Hz), 3.31–3.26 (ddd, 1H, J ¼ 8.5,5.9,2.4 Hz), 2.87–2.82
(
1
ddd, 1H, J ¼ 12.3, 6.9, 2.5 Hz), 2.52–2.46 (ddd, 1H, J ¼ 10.4, 9.0, 5.3 Hz), 2.00–1.87 (m,
H), 1.85–1.76 (m, 1H), 1.72–1.65 (ddd, 1H, J ¼ 12.3, 10.8, 7.1 Hz), 1.39 (t, 3H,
13
J ¼ 7.0 Hz), 1.20–1.18 (d, 3H, J ¼ 6.3 Hz), 1.08–1.06 (d, 3H, J ¼ 6.2 Hz); C-NMR
(
100 MHz, CDCl ) d 173.9 (ester C=O), 158.3, 142.0 (olef. C=C), 127.5, 125.9,
3
1
21.7(C=CH, olefinic), 114.6, 83.6, 68.4, 63.3, 61.2, 57.4, 33.0, 26.3, 21.6, 21.4, 14.8. m/z
þ
þ
þ
þ
(TOF-MS ES ) 316 (100, MH ), 314 (5), 307 (1); HRMS (TOF-MS ES ): MH , found:
3
16.1910. C H NO requires 316.1913.
1
9
26
3
Propyl
7-(4-methoxyphenyl)-2,3,5,7a-tetrahydro-1H-pyrrolizine-7a-carboxylate
1
(
6f): Yield: 271 mg, 90%. Light brown oil. R : 0.48 (15% hexane/EA). H-NMR
f
(
–
400 MHz, CDCl ) d 7.30–7.28 (d, 2H, J ¼ 8.7 Hz), 6.82–6.80 (d, 2H, J ¼ 8.8 Hz), 6.06 (s,
3
C=CH, 1H), 4.10–4.05 (m, 2H), 3.98–3.92 (m, 1H), 3.77 (d, 3H, J ¼ 1.3 Hz), 3.51–3.46
(
2
1
dd, 1H, J ¼ 16.3, 2.2 Hz), 3.29–3.26 (t, J ¼ 6.3 Hz), 2.89–2.84 (dd, 1H, J ¼ 12.1, 6.8 Hz),
.52–2.46 (td, 1H, J ¼ 9.6, 5.4 Hz), 2.02–1.88 (m, 1H),1.84–1.78 (m, 1H), 1.71–1.66 (m,
13
H), 1.57–1.47 (m, 2H), 0.75 (t, 3H, J ¼ 7.4 Hz); C-NMR (100 MHz, CDCl ) d 174.5
3
(
6
(
ester C=O), 158.8, 141.8 (olef. C=C), 127.6, 125.9, 121.8 (C ¼ CH, olefinic), 113.8, 83.2,
þ
þ
6.7, 61.2, 57.5, 55.2, 33.2, 26.4, 21.9, 10.2. m/z (TOF-MS ES ) 302 (100, MH ), 143
þ
þ
5); HRMS (TOF-MS ES ): MH , found: 302.1765. C H NO requires 302.1756.
18 24 3
Propyl 7-(p-tolyl)-2,3,5,7a-tetrahydro-1H-pyrrolizine-7a-carboxylate (6g): Yield:
1
2
7
45 mg, 86%. Yellow oil. R : 0.53 (15% hexane/EA). H-NMR (400 MHz, CDCl ) d
f
3
.26–7.24 (d, 2H, J ¼ 7.1 Hz), 7.10–7.08 (d, 2H, J ¼ 7.7 Hz), 6.16 (d, –C=CH, 1H,
J ¼ 1.4 Hz), 4.11–4.04 (m, 2H), 3.99–3.93 (dtd, 1H, J ¼ 8.1, 6.6, 1.4 Hz), 3.52–3.48 (d,
1
H, J ¼ 16.4 Hz), 3.30–3.26 (t, 1H, J ¼ 7.3 Hz), 2.90–2.85 (dd, 1H, J ¼ 12.3, 6.8 Hz),

1
4
M. YILDIRIM AND G. SULEIMAN
2
1
.53–2.47 (m, 1H), 2.30 (s, 3H), 2.02–1.89 (m, 1H),1.84–1.78 (m, 1H), 1.71–1.64 (m,
H), 1.59–1.46 (m, 2H), 0.78–0.74 (td, 3H, J ¼ 7.4, 1.4 Hz); C-NMR (100 MHz, CDCl3)
13
d 174.6 (ester C=O), 142.3 (olef. C=C), 137.4, 130.3, 129.2, 126.1, 123.2 (C=CH, ole-
finic), 83.0, 66.7, 61.3, 57.5, 33.3, 26.4, 21.9, 21.2, 10.1. m/z (TOF-MS ES ) 286 (100,
MH ), 285 (5); HRMS (TOF-MS ES ): MH , found: 286.1803. C H NO
2
þ
þ
þ
þ
18
24
requires 286.1807.
Butyl 7-(4-methoxyphenyl)-2,3,5,7a-tetrahydro-1H-pyrrolizine-7a-carboxylate (6h):
1
Yield: 270 mg, 88%. Pale yellow oil. R : 0.46 (15% hexane/EA). H-NMR (400 MHz,
f
CDCl ) d 7.30–7.28 (d, 2H, J ¼ 8.8 Hz), 6.83–6.81 (d, 2H, J ¼ 8.8 Hz), 6.06 (t, –C=CH,
3
1
3
H, J ¼ 2 Hz), 4.16–4.05 (m, 2H), 4.02–3.96 (dt, 1H, J ¼ 10.9, 6.7 Hz), 3.78 (s, 3H),
.51–3.47 (dd, 1H, J ¼ 16.3, 2.3 Hz), 3.30–3.26 (ddd, 1H, J ¼ 8.6, 6.0, 2.4 Hz), 2.90–2.84
(
1
ddd, 1H, J ¼ 12.2, 6.8, 2.3Hz), 2.53–2.47 (m, 1H), 2.01–1.88 (m, 1H), 1.85–1.78 (m,
H), 1.73–1.65 (m, 1H), 1.54–1.41 (m, 2H), 0.92 (s, 1H), 1.26–1.13 (m, 7H), 0.78 (t, 3H,
1
3
J ¼ 7.4 Hz); C-NMR (100 MHz, CDCl ) d 174.6 (ester C=O), 159.2, 141.8 (olef. C=C),
3
1
2
27.5, 126.0, 121.8 (C=CH, olefinic), 113.8, 83.1, 65.0, 61.4, 57.5, 55.3, 33.2, 30.6, 29.6,
6.6, 19.1, 13.6. m/z (TOF-MS ES ) 316 (100, MH ), 143 (5); HRMS (TOF-MS ES ):
þ
þ
þ
þ
MH , found: 316.1927. C H NO requires 316.1913.
1
9
26
3
Mixture of endo/exo isomers (20:1 ratio): Butyl 7-(p-tolyl)-2,3,5,7a-tetrahydro-1H-
pyrrolizine-7a-carboxylate (6i) and (E)-butyl 6-(4-methylbenzylidene)-1-azabicy-
0
clo[3.2.0]heptane-5-carboxylate (6i ): Yield: 67 mg, 92%. Yellow oil. R : 0.52 (15% hex-
f
1
ane/EA). H-NMR (400 MHz, CDCl ) d 7.25–7.24 (d, 2H, J ¼ 7.9 Hz), 7.10–7.08 (d, 2H,
3
J ¼ 8.0 Hz), 6.15 (s, –C=CH, 1H), 4.15–4.07 (m, 2H), 4.02–3.96 (m, 1H, J ¼ 8.1, 6.6,
1
.4 Hz), 3.51–3.47 (d, 1H, J ¼ 16.4 Hz), 3.28 (t, 1H, J ¼ 7.4 Hz), 2.89–2.84 (dd, 1H,
J ¼ 12.3, 6.9 Hz), 2.53–2.47 (td, 1H, J ¼ 9.6, 5.6 Hz), 2.30 (s, 3H), 2.00–1.88 (m, 1H),
1
(
.84–1.78 (dtd, 1H, J ¼ 9.6, 5.1, 2.4 Hz), 1.72–1.64 (td, 1H, J ¼ 11.9, 7.1 Hz), 1.54–1.41
13
m, 2H), 1.24–1.11(m, 2H),0.77 (t, 3H, J ¼ 7.1 Hz); C-NMR (100 MHz, CDCl ) d 174.9
3
(
6
3
ester C=O), 142.2 (olef. C=C), 137.5, 130.3, 129.3, 126.2, 123.1 (C=CH, olefinic), 83.2,
þ
þ
5.0, 61.4, 57.6, 33.0, 30.6, 26.7, 21.2, 18.9, 13.7. m/z (TOF-MS ES ) 300 (100, MH ),
01 (20); HRMS (TOF-MS ES ): MH , found: 300.1986. C H NO requires 300.1963.
þ
þ
19
26
2
Mixture of endo/exo isomers (10:1 ratio): Ethyl 7-phenyl-2,3,5,7a-tetrahydro-1H-
pyrrolizine-7a-carboxylate (6j) and (E)-ethyl 6-benzylidene-1-azabicyclo[3.2.0] hept-
0
ane-5-carboxylate (6j ): Yield: 151 mg, 69%. Yellow-green oil. R : 0.39 (15% hexane/
f
ꢃ1
EA). IR (KBr): ꢀmax/cm
C=O), 1600 (arom. C=C), 1496 (olefinic C=C), 1446, 1269–1234 (C–O) cm ; H-
= 3055 (arom. CH), 2974–2816 (alip. CH), 1724 (ester
ꢃ1
1
NMR (400 MHz, CDCl ) d 7.43–7.24 (m, arom. H, 5H), 6.25 (t, –C=CH, 1H,
3
J ¼ 2.0 Hz), 4.24–4.06 (m, 3H), 3.57–3.52 (dd, 1H, J ¼ 16.6, 2.4 Hz), 3.33–3.28 (ddd,
1
1
H, J ¼ 8.9, 6.1, 2.7 Hz), 2.92–2.85 (ddd, 1H, J ¼ 16.6, 6.9, 2.6 Hz), 2.56–2.50(ddd,
H, J ¼ 10.2, 9.1, 5.4 Hz), 2.02–1.91 (m, 1H), 1.87–1.80 (m, 2H), 1.75–1.68 (ddd, 1H,
13
J ¼ 12.4, 10.7, 7.1 Hz), 1.47 (t, 3H, J ¼ 7.2 Hz); C-NMR (100 MHz, CDCl ) d 174.0
3
(ester C=O), 142.1 (olef. C=C), 132.9, 128.1, 127.2, 125.9, 123.8 (C=CH, olefinic),
þ
þ
1
2
21.2, 82.7, 60.9, 57.1, 32.7, 26.0, 13.6. m/z (TOF-MS ES ) 258 (100, MH ),
þ
þ
56 (1), 246 (1); HRMS (TOF-MS ES ): MH , found: 258.1483. C H NO
16 20 2
requires 258.1494.
Mixture of endo/exo isomers (2:1 ratio): Propyl 7-phenyl-2,3,5,7a-tetrahydro-1H-
pyrrolizine-7a-carboxylate (6k) and Propyl 6-benzylidene-1-azabicyclo

V
R
SYNTHETIC COMMUNICATIONS
15
0
3.2.0]heptane-5-carboxylate (6k ): Yield: 320 mg, 69%. Yellow oil. R : 0.43 (15% hex-
f
[
1
ane/EA). H-NMR (400 MHz, CDCl ) d 7.39–7.34 (m, arom H, 3H), 7.51–7.49 (m,
3
arom H, 3H), 7.30–7.26 (t, arom H, 2H, J ¼ 7.6 Hz), 7.23–7.19 (t, arom H, 2H,
J ¼ 7.2 Hz), 6.22 (t, –C=CH, 1H, J ¼ 2.1 Hz), 6.35 (s, –C=CH, 1H), 4.13–4.05 (m, 2H),
4
8
2
1
.03–3.90 (m, 2H), 3.53–3.49 (dd, 1H, J ¼ 16.6, 2.4 Hz), 3.71–3.64 (dt, 1H, J ¼ 11.4,
.3 Hz), 2.91–2.85 (ddd, 1H, J ¼ 12.4, 6.9, 2.6 Hz), 3.00–2.94 (ddd, 1H, J ¼ 12.4, 7.3,
.3 Hz), 2.54–2.48 (m, 1H), 2.46–2.36 (m, 1H), 2.35–2.26 (m, 1H), 2.02–1.90 (m, 1H),
.86–1.78 (m, 1H), 1.74–1.65 (m, 1H), 1.58–1.35 (m, 3H), 0.75 (t, 3H, J ¼ 7.4 Hz), 0.66
1
3
(
1
t, 3H, J ¼ 7.4 Hz; C-NMR (100 MHz, CDCl ) d 175.5, 174.2 (ester C=O), 170.3, 160.5,
3
42.4 (olef. C=C), 133.1, 130.7, 130.3, 129.0, 128.4, 127.4, 127.0, 126.2, 123.9 (C ¼ CH,
olefinic), 121.0, 82.6, 78.3, 67.6, 66.7, 61.2, 60.1, 57.4, 33.0, 32.0, 28.4, 26.4, 21.8, 21.6,
1
MH , found: 272.1671. C H NO requires 272.1650.
þ
þ
þ
0.2, 9.94. m/z (TOF-MS APCI ) 272 (100, MH ), 273 (20); HRMS (TOF-MS APCI ):
þ
1
7
22
2
Mixture of endo/exo isomers (10:1 ratio): Isopropyl 7-phenyl-2,3,5,7a-tetrahydro-
1
H-pyrrolizine-7a-carboxylate (6l) and (E)-isopropyl 6-benzylidene-1-azabicyclo
0
[
3.2.0]heptane-5-carboxylate (6l ): Yield: 141 mg, quantitative. Yellow-green oil. R : 0.41
f
1
(15% hexane/EA). H-NMR (400 MHz, CDCl ) d 7.37–7.21 (m, arom H, 5H), 6.21 (t,
3
–
C=CH, 1H, J ¼ 2.0 Hz), 5.01–4.90 (quint, 1H, J ¼ 6.4 Hz), 4.13–4.08 (dd, 1H, J ¼ 12.8,
2
2
1
.4 Hz), 3.53–3.49 (dd, 1H, J ¼ 12.4, 6.0 Hz), 3.33–3.27 (ddd, 1H, J ¼ 8.8, 6.1, 2.6 Hz),
.89–2.83 (ddd, 1H, J ¼ 9.2, 7.2, 2.4 Hz), 2.54–2.48 (m, 1H), 2.02–1.90 (m, 1H),
.83–1.81 (m, 1H), 1.73–1.66 (ddd, 1H, J ¼ 12.4, 10.8, 7.1 Hz), 1.19–1.18 (d, 3H,
1
3
J ¼ 6.4 Hz), 1.08–1.06 (d, 3H, J ¼ 6.4 Hz); C-NMR (100 MHz, CDCl ) d 173.7 (ester
3
C=O), 142.6 (olef. C=C), 133.4, 128.4, 127.4, 126.3, 124.1 (C=CH, olefinic), 121.1, 83.1,
þ
þ
68.5, 61.2, 57.5, 33.0, 21.6, 21.4. m/z (TOF-MS ES ) 272 (100, MH ), 270 (5), 254 (1);
þ
þ
HRMS (TOF-MS ES ): MH , found: 272.1658. C H NO requires 272.1651.
17
22
2
Mixture of endo/exo isomers (20:1 ratio): Butyl 7-phenyl-2,3,5,7a-tetrahydro-1H-
pyrrolizine-7a-carboxylate (6m) and (E)-butyl 6-benzylidene-1-azabicyclo[3.2.0]hep-
0
tane-5-carboxylate (6m ): Yield: 798 mg, 74%. Yellow-green oil. R : 0.51 (15% hexane/
f
1
EA). H-NMR (400 MHz, CDCl ) d 7.38–7.35 (d, arom H, 2H, J ¼ 7.2 Hz), 7.31–7.20
3
(
m, arom H, 3H), 6.22 (t, –C=CH, 1H, J ¼ 2.1 Hz), 4.17–4.09 (m, 2H), 4.04–3.98 (dt,
1
2
1
1
H, J ¼ 10.8, 66 Hz), 3.54–3.49 (dd, 1H, J ¼ 16.6, 2.4 Hz), 3.31–3.27 (ddd, 1H, J ¼ 8.9,6.1,
.6 Hz), 2.92–2.86 (ddd, 1H, J ¼ 12.4, 6.9, 2.6 Hz), 2.55–2.49 (m, 1H), 2.02–1.91 (m,
H), 1.85–1.82 (m, 1H), 1.75–1.67 (ddd, 1H, J ¼ 12.4, 10.7, 7.1 Hz), 1.55–1.41 (m, 2H),
1
3
.24–1.14 (m, 2H), 0.78 (t, 3H, J ¼ 7.4 Hz); C-NMR (100 MHz, CDCl ) d 174.5 (ester
3
C=O), 142.7 (olef. C ¼ C), 133.2, 128.4, 127.4, 126.2, 124.1(C=CH, olefinic), 83.0, 64.9,
þ
þ
6
1.3, 57.4, 33.1, 30.5, 26.4, 18.8, 13.5. m/z (TOF-MS APCI ) 286 (100, MH ), 287 (20);
þ
þ
HRMS (TOF-MS APCI ): MH , found: 286.1809. C H NO requires 286.1807.
18
24
2
Mixture of endo/exo isomers (4:1 ratio): Sec-butyl 7-phenyl-2,3,5,7a-tetrahydro-
1
H-pyrrolizine-7a-carboxylate (6n) and sec-butyl 6-benzylidene-1-azabicyclo[3.2.0]-
0
heptane-5-carboxylate (6n ): Yield: 272 mg, 95%. Yellow oil. R : 0.50 (15% hexane/EA).
f
1
H-NMR (400 MHz, CDCl ) d 7.38–7.33 (m, arom H, 3H), 7.51–7.48 (m, arom H, 3H),
3
7
.28–7.24 (t, arom H, 2H, J ¼ 7.4 Hz), 7.21–7.18 (t, arom H, 2H, J ¼ 7.8 Hz), 6.20–6.18
(
1
dt, –C=CH, 1H, J ¼ 4.3, 2.1 Hz), 6.33–6.32 (d, –C=CH, 1H, J ¼ 2.9 Hz), 4.83–4.73 (m,
H), 4.11–4.05 (ddd, 1H, J ¼ 16.5, 3.9, 1.8 Hz), 3.52–3.46 (dt, 1H, J ¼ 16.5, 2.9 Hz),
.71–3.64 (dt, 1H, J ¼ 11.3, 8.3 Hz), 3.30–3.24 (tt, 1H, J ¼ 11.4, 4.3 Hz), 3.00–2.93 (ddd,
3

1
6
M. YILDIRIM AND G. SULEIMAN
1
H, J ¼ 11.6, 6.8, 3.3 Hz), 2.90–2.81 (tdd, 1H, J ¼ 14.5, 7.0, 2.4 Hz), 2.52–2.46 (td, 1H,
J ¼ 9.0, 5.5 Hz), 2.43–2.26 (m, 1H), 2.00–1.88 (m, 1H), 1.83–1.77 (m, 1H), 1.73–1.64 (m,
1
H), 1.57–1.24 (m, 3H), 1.16–1.14 (d, 3H, J ¼ 6.3 Hz), 1.04–1.02 (d, 3H, J ¼ 6.3 Hz), 0.83
(
t, 3H, J ¼ 7.4 Hz), 0.76 (t, 3H, J ¼ 7.4 Hz), 0.63 (t, 3H, J ¼ 7.5 Hz), 0.48 (t, 3H,
1
3
J ¼ 7.4 Hz); C-NMR (100 MHz, CDCl ) d 175.6, 173.9 (ester C=O), 169.6, 160.6, 142.6
3
(olef. C=C), 133.3, 130.8, 130.3, 128.8, 128.3, 127.4, 127.0, 126.2, 124.0 (C=CH, olefinic),
1
9
21.0, 83.1, 78.5, 74.4, 72.9, 61.2, 57.4, 41.8, 33.0, 31.9, 28.5, 28.3, 26.4, 19.1, 18.8, 9.4,
.2, 9.0. m/z (TOF-MS ES ) 286 (100, MH ), 287 (20); HRMS (TOF-MS ES ): MH ,
þ
þ
þ
þ
found: 286.1793. C H NO requires 286.1807.
1
8
24
2
Mixture of endo/exo isomers (10:1 ratio): Ethyl 7-butyl-2,3,5,7a-tetrahydro-1H-pyr-
rolizine-7a-carboxylate (6o) and (E)-ethyl 6-pentylidene-1-azabicyclo[3.2.0] heptane-
0
5
(
(
-carboxylate (6o ): Yield: 170 mg, 72%. Pale yellow oil. R : 0.41 (15% hexane/EA). IR
f
ꢃ1
KBr): ꢀmax/cm = 3059 (olef. CH), 2958–2870 (alip. CH), 1728 (ester C=O), 1458
olefinic C=C), 1265–1230 (C–O) cm ; H-NMR (400 MHz, CDCl ) d 5.40–5.38 (m,
ꢃ1
1
3
–
C ¼ CH, 1H), 4.24–4.15 (m, 1H), 4.13–4.05 (dq, 1H, J ¼ 10.8, 7.1 Hz), 3.96–3.91 (ddd,
1
H, J ¼ 15.3, 4.3, 2.5 Hz), 3.33–3.28 (dq, 1H, J ¼ 15.3, 2.2 Hz), 3.26–3.22 (ddd, 1H,
J ¼ 9.4, 5.9, 3.7 Hz), 2.50–2.42 (m, 2H), 2.01–1.95 (dtd, 1H, J ¼ 12.9, 4.4, 1.9 Hz),
1
1
.86–1.68 (m, 2H), 1.66–1.58 (ddd, 1H, J ¼ 12.3, 9.9, 6.9 Hz), 1.52–1.42 (m, 2H),
13
.38–1.28 (m, 2H), 1.23 (t, 3H, J ¼ 7.1 Hz), 0.89 (t, 3H, J ¼ 7.3 Hz); C-NMR (100 MHz,
CDCl ) d 174.6 (ester C=O), 143.3 (olef. C=C), 128.4, 126.5, 121.0 (C=CH, olefinic),
3
þ
þ
84.9, 60.9, 57.4, 32.8, 29.8, 26.7, 25.6, 13.9. m/z (TOF-MS ES ) 238 (100, MH ), 236
þ
þ
(1), 224 (1); HRMS (TOF-MS ES ): MH , found: 238.1810 C H NO
14 24 2
requires 238.1807.
Mixture of endo/exo isomers (10:1 ratio): Isopropyl 7-butyl-2,3,5,7a-tetrahydro-
H-pyrrolizine-7a-carboxylate (6p) and (E)-isopropyl 6-pentylidene-1-azabicyclo
1
[
0
4
2
0
20
3.2.0]heptane-5-carboxylate (6p ): Yield: 385 mg, 76%. Yellow oil. ½aꢄ ¼ þ0:03: R :
5
89
f
1
.45 (15% hexane/EA). H-NMR (400 MHz, CDCl ) d 5.39–5.37 (m, –C=CH, 1H),
3
.99–4.93 (dt, 1H, J ¼ 12.5, 6.3 Hz), 3.95–3.91 (dd, 1H, J ¼ 15.2, 1.7 Hz), 3.32–3.23 (m,
H), 2.49–2.37 (m, 2H), 2.02–1.94 (m, 2H), 1.82–1.68 (m, 2H), 1.66–1.59 (ddd, 1H,
J ¼ 12.3, 9.8, 6.9 Hz), 1.50–1.43 (tdd, 2H, J ¼ 8.9, 6.9, 2.5 Hz), 1.41 (s, 1 H), 1.38–1.30
1
3
(
1
2
m, 2H), 1.24–1.19 (m, 10H), 0.89 (t, 3H, J ¼ 7.3 Hz); C-NMR (100 MHz, CDCl ) d
3
73.9 (ester C=O), 143.3 (olef. C=C), 120.9 (C=CH, olefinic), 85.2, 68.7, 68.1, 61.3, 29.9,
9.8, 26.8, 25.7, 22.7, 21.8, 21.7, 14.0. m/z (TOF-MS ES ) 252 (100, MH ), 253 (15);
HRMS (TOF-MS ES ): MH , found: 252.1964 C H NO requires 252.1963.
þ
þ
þ
þ
15
26
2
Mixture of endo/exo isomers (10:1 ratio): Butyl 7-butyl-2,3,5,7a-tetrahydro-1H-
pyrrolizine-7a-carboxylate (6r) and (E)-butyl 6-pentylidene-1-azabicyclo[3.2.0] hept-
0
ane-5-carboxylate (6r ): Yield: 376 mg, 74%. Pale yellow oil. R : 0.37 (15% hexane/EA).
f
1
H-NMR (400 MHz, CDCl ) d 5.38 (d, –C=CH, 1H, J ¼ 1.2 Hz), 4.19–4.12 (dtd, 1H,
3
J ¼ 7.6, 6.7, 1.1 Hz), 4.04–3.90 (m, 2H), 3.32–3.23 (m, 2H), 2.47–2.41 (m, 2H), 1.96–1.94
(
m, 2H), 1.83–1.69 (m, 2H), 1.62–1.56 (m, 2H), 1.49–1.42 (m, 2H), 1.37–1.28 (m, 4H),
1
3
1
1
2
.23 (m, 2H), 0.88 (t, 6H, J ¼ 7.3 Hz); C-NMR (100 MHz, CDCl ) d 174.8 (ester C=O),
3
43.4 (olef. C=C), 120.9 (C=CH, olefinic), 85.1, 64.9, 61.6, 32.9, 30.7, 29.8, 26.8, 25.8,
þ
þ
2.7, 19.1, 14.0, 13.7. m/z (TOF-MS ES ) 266 (100, MH ), 267 (15); HRMS (TOF-MS
ES ): MH , found: 266.2126 C H NO requires 266.2120.
þ
þ
1
6
28
2

V
R
SYNTHETIC COMMUNICATIONS
17
Funding
_
This study was funded by Bolu Abant Izzet Baysal University, Scientific Research
Projects Division (BAP grant no. 2015.03.03.931).
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