Diastereoselective Synthesis of Fluorine-Containing Pyrrolizidines via Triphenylcarbenium Tetrafluoroborate-Promoted Carbofluorination of N-3-Arylpropargylpyrrolidine-Tethered Tertiary Allylic Alcohols

Article abstract of DOI:10.1021/acs.joc.5b02025

Inexpensive and air stable triphenylcarbenium tetrafluoroborate efficiently promoted the carbofluorination of N-arylpropargylpyrrolidines bearing a tertiary allylic alcohol tether at the 2-position of the pyrrolidine ring to provide 1-isobutenyl-2-(fluoro(phenyl)methylenylhexahydro-1H-pyrrolizidines in a stereoselective fashion. When subjected to bis(trifluoromethane)sulfonamide, the same substrates underwent cycloisomerization reaction within minutes to generate 1-isobutenyl-2-benzoylhexahydro-1H-pyrrolizidines with excellent stereoselectivity.

Full text of DOI:10.1021/acs.joc.5b02025

Article
pubs.acs.org/joc
Diastereoselective Synthesis of Fluorine-Containing Pyrrolizidines
via Triphenylcarbenium Tetrafluoroborate-Promoted
Carbofluorination of N‑3-Arylpropargylpyrrolidine-Tethered Tertiary
Allylic Alcohols
Ming-Chang P. Yeh,* Hsiao-Feng Chen, Yu-Ya Huang, and Yu-Ting Weng
Department of Chemistry, National Taiwan Normal University, 88 Ding-Jou Road, Section 4, Taipei 11677, Taiwan, Republic of
China
*
S Supporting Information
ABSTRACT: Inexpensive and air stable triphenylcarbenium tetrafluoroborate efficiently promoted the carbofluorination of N-
arylpropargylpyrrolidines bearing a tertiary allylic alcohol tether at the 2-position of the pyrrolidine ring to provide 1-isobutenyl-
2-(fluoro(phenyl)methylenylhexahydro-1H-pyrrolizidines in a stereoselective fashion. When subjected to bis(trifluoromethane)-
sulfonamide, the same substrates underwent cycloisomerization reaction within minutes to generate 1-isobutenyl-2-
benzoylhexahydro-1H-pyrrolizidines with excellent stereoselectivity.
INTRODUCTION
arylpropargylpyrrolidine-tethered tertiary allylic alcohols. It was
suggested that anti-addition of a fluoride and the transient
allylic carbonium ion, generated in situ from the reaction of
tertiary allylic alcohols with the trityl cation, across the
acetylene afforded the fluorinated pyrrolizidine derivatives in
a stereoselective manner and in good yield. Furthermore,
■
The pyrrolizidine ring skeleton is present in a large number of
naturally occurring nacine bases, many of which possess notable
biological and pharmaceutical properties. Many synthetic
1
strategies have been developed for the construction of the
pyrrolizidine ring scaffold including the intramolecular
alkylation of N-chloroethylpyrrolidines with α,β-unsaturated
bis(trifluoromethane)sulfonamide (Tf NH) successfully per-
2
2
3
formed the cycloisomerization reaction of the substrates in
minutes, providing 1-isobutenyl-2-aroylhexahydro-1H-pyrroli-
zine derivatives with excellent stereoselectivity.
esters, the N-alkylation of pyrrolidines with alkyltosylates, or
4
alkylesters, the radical cyclization reaction of N-allylstannane-
5
pyrrolidine-2,5-diones, the reaction of α-acylamino radicals
6
with alkenyl tethers, the SmI -mediated intramolecular ring
2
7
closure of alkyl bromides with ynamides, the Pd(II)-catalyzed
intramolecular 1,2-aminoalkylation of conjugated 1,3-dienes,
RESULTS AND DISCUSSION
■
8
The synthetic route for the preparation of the starting substrate
1a is depicted in Scheme 1. Starting from commercial
(±)-proline 2, an esterification and propargylation sequence,
the 1,3-dipolar cycloaddition of azomethane ylides with
9
acrylates, the [3 + 2]-cycloadditions of cyclic nitrones with
1
0
alkenes and the gold-catalyzed [3 + 2]-cycloaddition-enamine
1
1
followed by reduction of the resulting ester group with LiAlH
gave the corresponding alcohol 3 in 85% yield over the three
4
cyclization of iminoesters with acetylenes and dipolarophiles.
Encouraged by the diverse biological activities of pyrrolizidine
derivatives and to expand our recently developed Lewis acid-
promoted carbohalogenation reactions of alkynes with allylic
13
steps. Following the Sonogashira protocol, coupling the
terminal alkyne of 3 with phenyl iodide afforded the coupling
product 4 in 75% isolated yield. Swern oxidation of 4 provided
1
2
alcohols, we envisioned that N-3-arylpropargylpyrrolidine
containing a tertiary allylic alcohol tether at the 2-position of
the pyrrolidine ring would be a good candidate for a Lewis acid-
assisted carbohalogenation reaction, which may lead to the
formation of halogenated hexahydro-1H-pyrrolizidine deriva-
tives. Herein, we report that triphenylcarbenium tetrafluor-
oborate (Ph CBF ) features both Lewis acid character and the
14
the aldehyde 5, which was used for the next step without
further purification. Next, a Wittig reaction employing 1-
15
(
triphenylphosphoranylidene)propan-2-one with 5, followed
by addition of the methyl Grignard reagent to the resulting
Received: August 31, 2015
3
4
nucleophilic fluoride source for the carbofluorination of N-3-
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02025
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Article
Scheme 1. Synthesis of Starting Substrate 1a
ketone furnished the desired starting substrate 1a in 70% yield
over the last two steps.
Table 1. Optimizing of Reaction Conditions in the
Carbofluorination of 1a with Fluorine-Containing Lewis
Acids
Initially, various Lewis acids were screened for their ability to
promote the carbochlorination of 1a. Chlorine-containing
Lewis acids, including FeCl , InCl , SnCl , AlCl , and TiCl ,
3
3
2
3
4
failed to assist the carbochlorination reaction with 1a.
Delightfully, the use of 2.0 equiv of BF ·OEt in 0.1 M of
3
2
dichloromethane (DCM) with 1a completed the carbofluori-
nation reaction in 10 min, generating 1-isobutenyl-2-(fluoro-
a
yield (%)
(
phenyl)methylenylhexahydro-1H-pyrrolizidine (7a) in 46%
yield together with the cycloisomerization product 1-
isobutenyl-2-benzoyl-hexahydro-1H-pyrrolizidine (8a) in 17%
yield and a trace amount of the dehydration product 9a (Table
loading
(equiv)
entry
1
reagent
BF ·OEt
solvent
time
7a
8a
9a
2
0.1 M
DCM
10 min
46
17
1
3
2
1
, entry 1). Importantly, both compounds 7a and 8a were
isolated as the only stereomer. The relative stereochemistry of
a and 8a as depicted were determined on the basis of NOESY
2
3
4
5
6
BF ·OEt2
3
2
0.01 M
DCM
5 min
30 min
24 h
47
54
−
24
−
−
12
8
8
7
BF ·OEt2
3
2
0.0025 M
DCM
3
experiments (see Supporting Information for details). As shown
in Figure 1, for 7a, the cis relationship between H-8 and the
isobutenyl group was established since the NOE correlation is
observed between H-8 and H-9. For 8a, the NOE correlations
between H-8 and H-9, and between H-8 and H-2 supports the
trans relationship between H-8 and H-1 and the cis relationship
BF ·OEt2
3
2
0.1 M
20
−
5
CH CN
3
3
Ph CBF4
2
0.1 M
DCM
5 min
25 min
6.5 h
2.5 h
24 h
41
85
43
79
52
−
Ph CBF4
3
2
0.01 M
DCM
b
between H-8 and H-2. In the transformation of 1a into 7a, BF3·
7
Ph CBF
3
2
0.01 M
DCM
8
2
4
OEt acts as both the Lewis acid character and the nucleophilic
2
16
8
9
Ph CBF4
2
0.0025 M
DCM
13
19
4
−
7
fluoride source in the carbofluorination of the acetylene. The
relative stereochemistry may derive from anti-addition of the
transient allylic carbonium ion from the less hindered β-face
and the fluoride source across the acetylene. On the other hand,
3
Ph CBF4
3
1.2
2
0.01 M
DCM
1
0
Ph CPF6
3
0.0025 M
DCM
20 h
30
the minor product 8a may arise from addition of BF OH and
2
a
b
the allylic carbonium ion across the acetylene followed by an
Yields obtained from column chromatography over silica gel. The
aqueous workup (Scheme 2).
reaction was performed at 0 °C.
Next, substrate 1a was subjected to fluorine-containing Lewis
acids, including BF ·OEt , Ph CBF , and Ph CPF , to search
3
2
3
4
3
6
for optimal conditions for the carbofluorination reaction. The
results are summarized in Table 1. Decreasing the concen-
tration of 1a to 0.01 or 0.0025 M in DCM with BF ·OEt did
3
2
not affect the cyclization reaction significantly and the desired
product 7a was isolated in 47% and 54% yield, respectively,
(Table 1, entries 2 and 3). Switching the solvent from DCM to
CH CN failed to provide the desired fluorination product 7a
3
and the dehydration product 9a was isolated in 20% yield
Figure 1. NOE interactions for 7a and 8a.
(Table 1, entry 4). Changing the Lewis acid and the fluoride
source to Ph CBF (2.0 equiv) in DCM at 0.1 M concentration,
3
4
B
DOI: 10.1021/acs.joc.5b02025
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Scheme 2. Suggested Reaction Paths for the Formation of
and the nucleophilic fluoride source in numerous organic
23
7
a, 8a, and 9a from 1a with BF ·OEt
transformations have been extensively studied. It is worthy to
mention that the fluorinated pyrrolizidines may have potential
applications in medicinal chemistry since many monofluor-
3
2
24
oalkenes play an important role in pharmaceuticals.
With optimized reaction conditions in hand, the scope of the
carbofluorination reaction was investigated employing various
aryl substituted alkynes using the standard reaction conditions.
As can be seen from Table 2, substrates 1a−d having an
Table 2. Ph CBF -Promoted Carbofluorination of 1
3
4
yield
a
entry
Ar
substrate
time
product
(%)
1
2
3
4
5
6
7
8
9
phenyl
1a
1b
1c
1d
1e
1f
25 min
30 min
45 min
40 min
2.0 h
7a
7b
7c
7d
−
85
71
50
40
3-methylphenyl
4-methylphenyl
4-biphenyl
1
a gave 7a and 8a in 5 min and in 41 and 12% yield,
respectively (Table 1, entry 5). Delightly, the use of 2.0 equiv of
Ph CBF at a concentration of 0.01 M in DCM completed the
reaction within 30 min and afforded 7a in 85% yield and the
side products 8a and 9a in 8 and 5% yield, respectively (Table
3
4
b
1-naphthyl
−
3-methoxyphenyl
4-methoxyphenyl
3-trifluoromethylphenyl
3-carbethoxyphenyl
4-carbethoxyphenyl
3-nitrophenyl
10 min
25 min
2.0 h
7f
52
c
1g
1h
1i
−
7h
−
1, entry 6). Conducting the reaction at 0 °C (Table 1, entry 7)
55
52
48
50
58
60
66
or lowering the concentration of 1a (Table 1, entry 8) did not
improve the yield of 7a. Furthermore, the use of 1.2 equiv of
Ph CBF at 0.01 M in DCM required a longer reaction time
1.0 h
7i
10
11
12
13
14
15
16
17
18
1j
1.5 h
7j
3
4
1k
1l
1.5 h
7k
7l
(
24 h) to afford a 52% yield of the desired product 7a (Table 1,
4-nitrophenyl
1 h
entry 9). Unfortunately, switching the trityl cation source from
Ph CBF to Ph CPF (Table 1, entry 10) gave predominantly
4-chlorophenyl
4-bromophenyl
2-bromophenyl
2-nitrophenyl
1m
1n
1o
1p
1q
1r
20 min
1.0 h
7m
7n
−
−
−
3
4
3
6
the dehydration product 9a in 30% yield and a trace amount of
the cycloisomerization product 8a. Therefore, the use of
Ph CBF (2.0 equiv) with 1a at 0.01 M concentration in DCM
under nitrogen (Table 1, entry 5) was the most efficient and
was employed as the standard reaction conditions. It is
d
30 min
4.5 h
−
−
−
3
4
e
2-carbethoxyphenyl
3-thienyl
2 h
40 min
7r
14
a
Isolated yields obtained from column chromatography over silica gel.
Ketone 8e was isolated in 40% yield. Ketone 8g was isolated in 52%
yield. Ketone 8o was Isolated in 14% yield. Lactone 11 was isolated
in 46% yield.
important to state that reports on the use of the trityl cation
b
c
+
(
Ph C ) to promote organic transformations have been limited
3
d
e
1
7
18
to Mukaiyama aldol reactions, Diels−Alder reactions,
Michael additions, hydride abstractions from metal-alkene
19
20
and -diene complexes, dehydrogenation of polycyclic hydro-
aromatics, and deprotection of ketone acetals. Our current
study reveals that Ph CBF can behave as both the Lewis acid
and the fluoride source in the carbofluorination of the N-3-
arylpropargylpyrrolidine-tethered tertiary allylic alcohols, pro-
viding the fluorine-containing pyrrolizidine derivatives under
mild reaction conditions in good yield and with high
stereoselectivity (Scheme 3). Moreover, the use of the stable
Ph CBF powder is operationally easier than our previous
2
1
22
electron-neutral aryl group on the acetylene afforded
pyrrolizidine derivatives 7a−d in 40−85% yields within a
period of 45 min (Table 2, entries 1−4). Substrate 1e, bearing a
naphthyl-substituted alkyne, failed to produce any fluorinated
pyrrolizidine but instead the cycloisomerization product 8e was
isolated as the major product in 40% yield (Table 2, entry 5).
While 1f, with an electron-donating methoxy group at the 3-
position of the phenyl ring, afforded the desired product 7f in
3
4
3
4
1
0 min in 52% yield (Table 2, entry 6), compound 1g, with a
method employing BF ·OEt for the carbofluorinaton of
enynols.
including tetrafluoroborates been used both as a promotor
3
2
1
2b
C4-methoxyphenyl-substituted alkyne, cycloisomerized to the
corresponding ketone 8g in 52% yield and none of the desired
fluorination product was isolated (Table 2, entry 7). The
formation of 8g from 1g was suggested in Scheme 4. The initial
formed tertiary allylic carbonium ion was attacked by the
electron-rich (p-methoxyphenyl)alkynyl group to give the
allenyl intermediate 10. Addition of the tetrafluoroborate
anion at the allenyl carbon center failed. Hydrolysis of the
intermediate 10 provided ketone 8g. Substrates possessing an
electron withdrawing group, including a trifluoromethyl, ester,
and nitro group on the phenyl ring (1h−l), were also effective
in the carbofluorination and generated the fluorinated
Recently, various fluorine-containing reagents
Scheme 3. Ph CBF -Promoted Formation of 7a from 1a
3
4
C
DOI: 10.1021/acs.joc.5b02025
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The Journal of Organic Chemistry
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Scheme 4. Mechanism for the Formation of 8g from 1g
Inspired by the work of Yamamoto on the TfOH-catalyzed
cycloisomerization reaction of alkyne-tetherd tertiary alco-
hols, we then concentrated our effort on searching for a
suitable Brønsted acid and optimal reaction conditions in
obtaining ketone 8a from 1a. The screening of the cyclo-
isomerization reaction was carried out by treating 1a with
26
TfOH and Tf NH. The results are summarized in Table 3.
2
Table 3. Optimization of Cycloisomerization of 1a to 8a
pyrrolizidines (7h−l) in 48−58% yields (Table 2, entries 8−
1
2). Moreover, the presence of a halogen atom at the 4-
position of the phenyl ring, 1m and 1n, did not influence the
pyrrolizidines formation and the desired products, 7m and 7n,
were isolated in 60 and 66% yield, respectively (Table 2, entries
1
3−14). Unfortunately, a substituent at the 2-position of the
phenyl ring, (1o−p), inhibited the carbofluorination reaction
Table 2, entries 15−16). Compound 1o gave the cyclo-
a
(
yield (%)
isomerization product 8o in only 14% isolated yield and 1p
gave a mixture of unidentified compounds. Apparently, the
presence of a substituent at the C-2 position of the phenyl ring
prevents BF4− from attacking at the acetylene carbon. This
steric effect is consistent with that of the pyrrolidine-tethered
naphthyl-substituted alkyne 1e, which did not produce any
desired fluorinated pyrrolizidine (Table 2, entry 5). Interest-
ingly, substrate 1q (Figure 2) bearing a carbethoxy group at the
entry
acid (equiv)
solvent
temp. (°C)
time
24 h
8a
9a
1
2
3
4
5
6
7
TfOH (0.1)
TfOH (0.1)
TfOH (2.0)
DCE
50
28
28
28
28
28
28
28
0
−
−
−
−
−
10
7
DCM
DCM
DCM
DCM
DCM
DCE
24 h
10 min
1 min
6 h
Tf NH (2.0)
2
45
39
29
48
21
32
35
8
Tf NH (1.2)
2
7
Tf NH (3.0)
2
1 min
50 min
24 h
−
9
Tf NH (2.0)
2
b
8
Tf NH (2.0)
2
DCM
DCM
DCM
Ether
THF
19
5
9
Tf NH (2.0)
2
5 min
1 min
10 h
10
11
12
13
Tf NH (2.0)
2
40
28
28
28
−
72
58
−
Tf NH (2.0)
2
Tf NH (2.0)
2
40 h
−
−
Tf NH (2.0)
2
Toluene
24 h
a
b
Yield obtained from column chromatography over silica gel. Three
drops of water were added.
Substrate 1a was first treated with TfOH employing
Yamamoto’s protocol (0.1 equiv of TfOH in DCE), at 50
and 28 °C. After 24 h, only starting material 1a was recovered
without any evidence for the formation of 8a at both
temperatures (Table 3, entries 1−2). Increasing the amount
of TfOH up to 2.0 equiv, 1a gave the dehydration product 9a in
Figure 2. Structures of 8e, 8g, 8o, 11−12, 1s, and 7s.
1
0% yield (Table 3, entry 3). While employing 2.0 equiv of
Tf NH in DCM delivered 8a instantaneously in 45% isolated
2
yield (Table 1, entry 4), the use of 1.2 equiv of Tf NH required
2
2
1
-position of the phenyl group afforded the azabicyclic lactone
1 in 46% isolated yield under the standard reaction conditions.
longer reaction time (6 h) and gave only a 39% yield of 8a
(Table 3, entry 5). In both cases, the dehydration product 9a
was isolated in 7% yield in each case. It is important to state
that, in this simple operation, three carbon stereocenters of 8a
are created; however, only the single stereoisomer shown was
isolated. Moreover, the relative stereochemistry does not erode
In this process, anti-addition of the transient allylic carbonium
ion and the proximal ester group across the acetylene afford the
pyrrolizidine-tethered lactone 11. The 3-thienyl-substituted
alkyne 1r also gave the desired cyclized product 7r, albeit in
only 14% yield (Table 2, entry 18). Attempts to carry out the
carbofluorination of substrate 12 (Figure 2), bearing a
secondary allyic alcohol, failed. Instead the oxidation product
ketone 6 (Scheme 1) was isolated in 80% yield. The formation
of the ketone from 12 is consistent with those of literature
reports on oxidation of secondary allylic alcohols with trityl
cations. Unfortunately, attempts to synthesize a substrate
bearing an n-butyl-substituted alkyne failed. Moreover, the
tertiary allylic alcohol 1s, substituted with a methyl and an ethyl
group at the carbinol carbon, was subjected to the standard
reaction conditions to give 7s in 60% yield as a mixture of Z
and E isomers (Figure 2).
in this high acidic condition. Increasing Tf NH loading (Table
2
3 entry 6), changing the solvent system to dicholoroethane
(DCE) (Table 3, entry 7) or addition of a small amount of
water (Table 3, entry 8) into the reaction mixture did not
improve the cycloisomerization reaction. No improvements
were observed when the reaction was conducted in DCM at 0
or 40 °C (Table 3, entries 9−10). The use of ether gave 8a in
8% yield (Table 3, entries 11). Furthermore, no desired
product was obtained in THF or toluene (Table 3, entry 12−
2
5
13). Therefore, the use of 2.0 equiv of Tf NH in DCM at 0.1 M
2
concentration was chosen as the optimal conditions for
transformation of 1 into ketone 8.
D
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With the optimized reaction conditions in hand (Table 3,
entry 3), we further investigated the substrate scope of this
with 400 and 500 MHz spectrometers. Chemical shifts are given in
parts per million (ppm) relative to Me Si (0.00 ppm) with either
4
Me Si or the solvent residual peak (CHCl , 7.26 ppm) as internal
cycloisomerization of 1a using 2.0 equiv of Tf NH in DCM at
4
3
2
standard. Coupling patterns are described by the following
room temperature. In general, substrates substituted with an
electron-neutral or -rich aryl group at the alkyne were capable
of transforming 1 into ketone 8 in minutes, albeit in 15−45%
yields (Table 4, entries 1−6). Unfortunately, substrates 1i−j,
abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), m
13
(
multiplet). Coupling costants (J) are given in Herz (Hz). C NMR
spectra were recorded with 100 and 125 MHz spectrometers using
solvent CDCl (77.0 ppm) as internal standard. Mass spectra were
3
determined by using a spectrometer at a 70 eV ionization potential.
Peaks are listed according to their mass/charge (m/e) value with
percent relative abundance. High-resolution mass spectra were
obtained with a double-focusing mass spectrometer.
Table 4. Tf NH-Promoted Cycloisomerization of 1 to 8
2
Representative Procedure for the Synthesis of Starting
Compound 1. To a solution of (±)-proline 2 (3.45 g, 30.00 mmol)
in dried MeOH (30 mL), thionyl chloride (3.93 g, 33.00 mmol) was
added dropwise at 0 °C. The reaction mixture was stirred for 1 h under
refluxing condition and then allowed to cool to room temperature.
The solvent was removed in vacuo to afford a crude methyl
pyrrolidine-2-carboxylate (5.02 g, 30.00 mmol, 95%). To a solution
of methyl pyrrolidine-2-carboxylate (5.02 g, 30.00 mmol) in toluene
a
entry
Ar
substrate time (min) product yield (%)
1
2
3
4
5
6
7
8
9
phenyl
1a
1b
1c
1e
1f
1
8a
8b
8c
8e
8f
45
36
36
20
30
15
−
3-methylphenyl
4-methylphenyl
1-naphthyl
1
(
30 mL) were added Et N (9.2 mL) and propargyl bromide (4.64 g,
3
1
3
9.00 mmol). The reaction mixture was heated at 50 °C for 18 h
5
before it was cooled to room temperature and quenched with aqueous
3-methoxyphenyl
4-methoxyphenyl
4-carbethoxyphenyl
4-nitrophenyl
10
1
NaHCO solution (90 mL). The mixture was extracted with toluene
3
1g
1j
8g
−
−
(90 mL × 3). The combined organic extracts were washed with water
(200 mL × 2) and brine (200 mL × 2). The organic layer was dried
10
5
over MgSO4 (15 g) and filtered. Solvent were evaporated under
reduced pressure. The crude mixture was purified by flash column
chromatography over silica gel (EtOAc/hexanes 1:3) to afford the
corresponding methyl-1-(prop-2-yn-1-yl)- pyrrolidine-2-carboxylate
1l
−
4-chlorophenyl
4-bromophenyl
2-bromophenyl
3-thienyl
1m
1n
1o
1r
5
8m
8n
8o
8r
45
38
32
25
10
11
12
5
10
1
(4.34 g, 25.96 mmol, 91%). To a 250 mL round-bottom flask,
equipped with a stirring bar and a dropping funnel, under nitrogen at 0
a
Isolated yields obtained from column chromatography over silica gel.
°C were added lithium aluminum hydride (LAH, 1.97 g, 51.92 mmol)
and dry Et O (130 mL). The methyl-1-(prop-2-yn-1-yl)pyrrolidine-2-
2
carboxylate (4.34 g, 25.96 mmol) was added dropwise to the reaction
at 0 °C. The reaction mixture was stirred at room temperature for 4 h.
The solution was added a mixture of NH Cl (10 mL) and NH3(aq)
bearing an electron-withdrawing group on the phenyl ring,
decomposed when subjected to Tf NH under the same
2
4
(aq)
reaction conditions. (Table 4, entries 7−8). Moreover,
substrates 1m−o, bearing a bromine or chlorine atom on the
phenyl ring, were also successfully transformed into the
corresponding ketones 8m−o in 32−45%, respectively (Table
(
20 mL) to obtain a buffer solution (pH 8). The suspension was
filtered through a bed of Celite, and the solid residue was washed with
Et O. The filtrate was dried over MgSO (15 g) and concentrated
2
4
under reduced pressure in vacuo to afford the corresponding (1-(prop-
-yn-1-yl)pyrrolidin-2-yl)methanol 3 (3.61 g, 25.96 mmol, 98%). To a
two-neck flask equipped with a stirring bar were added CuI (0.19 g,
.04 mmol), PhI (6.36 g, 31.15 mmol), Pd(PPh ) (0.06 g, 0.52
2
4
, entries 9−11). The 3-theinyl-substituted alkyne 1r also
reacted with Tf NH to afford the corresponding ketone 8r in
2
1
3
4
2
5% isolated yield (Table 4, entry 12).
In conclusion, a carbofluorination reaction of N-arylpropar-
mmol) and Et N (26 mL) under nitrogen. The mixture was allowed to
3
stir at room temperature for 30 min followed by addition of (1-(prop-
gylpyrrolidine- tethered tertiary allylic alcohols to afford
fluorinated pyrrolizidines in an excellent stereoselective fashion
is described. The procedure employs the inexpensive and air
stable triphenylcarbenium tetrafluoroborate instead of the
strong Lewis acid (BF ·OEt ). Furthermore, 2-alkenyl-3-
2
-yn-1-yl)pyrrolidin-2-yl)methanol 3 (3.61 g, 25.96 mmol). The
reaction mixture was stirred at room temperature for 8 h before
quenching with aqueous NH Cl solution (30 mL). The resulting
4
solution was extracted with CH Cl (30 mL × 3). The combined
2
2
organic extracts were washed with water (70 mL × 2) and brine (70
3
2
mL × 2). The organic layer was dried over MgSO (15 g) and filtered.
aroylpyrrolizidine derivatives are available with excellent
stereoselectivity via cycloisomerization of the substrates
employing bis(trifluoromethane)sulfonamide. Further studies
on the extension of the present methods to the construction of
other nitrogen-containing heterocycles are currently underway
in our laboratory.
4
Solvent was evaporated under reduced pressure. The crude mixture
was purified by flash column chromatography over silica gel (EtOAc/
hexanes 1:1) to afford the corresponding product (1-(3-phenylprop-2-
yn-1-yl)pyrrolidin-2- yl)methanol 4 (4.19 g, 19.47 mmol, 75%). Oxalyl
chloride (2.77 g, 21.81 mmol) was added dropwise to a solution of
dimethyl sulfoxide (DMSO, 3.41 g, 43.62 mmol) in CH Cl (73 mL)
2
2
at −78 °C. The reaction was allowed to stir at −78 °C for 15 min
followed by addition of (1-(3-phenylprop-2-yn-1-yl)pyrrolidin-2-yl)-
methanol 4 (3.1317 g, 14.54 mmol). After being stirred for 30 min, the
EXPERIMENTAL SECTION
■
General Considerations. All reactions were conducted in
carefully dried glassware in an atmosphere of nitrogen. The addition
of anhydrous solvents or liquid (regents) was performed with an oven-
dried syringe or cannula through a septum. Solids were added under
gentle stream of nitrogen. Solvents were predried by molecular sieves
and then by passing through an Al O column. Melting points were
reaction was allowed to warm to −50 °C followed by addition of Et N
3
(14.2 mL). The reaction mixture was stirred at room temperature for 2
h before quenching with brine (30 mL). The resulting solution was
extracted with CH Cl (30 mL × 3). The combined organic extracts
2 2
were washed (70 mL × 2) with water and brine (70 mL × 2). The
2
3
measured in open glass capillaries with an electronic apparatus and
were uncorrected. Chromatographic purification was performed with
flash column chromatography using silica P60, 40−63 m (230−400
filtrate was dried over MgSO (15 g) and concentrated under reduced
4
pressure in vacuo to afford the corresponding 1-(3-phenylprop-2-yn-1-
yl)pyrrolidine-2-carbaldehyde 5 (3.10 g, 14.54 mmol, 98%). To a
solution of 1-(3-phenylprop-2-yn-1-yl)pyrrolidine- 2-carbaldehyde 5
1
mesh). H nuclear magnetic resonance (NMR) spectra were recorded
E
DOI: 10.1021/acs.joc.5b02025
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
(
3.10 g, 14.54 mmol) in CH Cl2 (73 mL) was added 1-
triphenylphosphoranylidene)propan-2-one (6.94 g, 21.81 mmol).
2.74 (q, J = 8.8 Hz, 1H), 2.27 (s, 3H), 2.13−2.02 (m, 1H), 2.00−1.89
2
1
3
1
(m, 1H), 1.89−1.80 (m, 1H), 1.78−1.67 (m, 1H); C{ H} NMR
The reaction mixture was stirred for 24 h under refluxing condition
(100 MHz, CDCl ) δ 198.5, 148.7, 132.0, 131.7 (2C), 128.2 (2C),
3
before it cooled to room temperature, quenched with saturated brine
128.1, 123.0, 85.2, 84.3, 63.5, 52.6, 41.6, 31.8, 26.7, 22.7; IR (CH Cl )
2
2
−1
(
50 mL) and extracted with CH Cl (50 mL × 3). The combined
2924, 2368, 2346, 1677, 1357, 1255, 978, 757 cm ; MS (ESI) m/e
2
2
+
organic extracts were washed with water (70 mL × 2) and saturated
brine (70 mL × 2). The filtrate was dried over MgSO4 and
concentrated under reduced pressure. The crude mixture was purified
by flash column chromatography over silica gel (EtOAc/hexanes 1:3)
to afford the corresponding (E)-4-(1-(3-phenylprop-2-yn-1-yl)-
pyrrolidin-2-yl)but-3-en-2-one 6 (3.20 g, 12.64 mmol, 88%).
Methylmagnesium bromide (38 mL of a 1.0 M solution in THF,
(%) 254.2 ([M + H] , 100); HRMS (ESI) calcd. for C H NO [M +
1
7
20
+
H] 254.1542, found 254.1545.
(E)-2-Methyl-4-(1-(3-(m-tolyl)prop-2-yn-1-yl)pyrrolidin-2-yl)but-
1
3-en-2-ol (1b). (0.26 g, 0.95 mmol, 70%). A yellow oil: H NMR (400
MHz, CDCl ) δ 7.27−7.21 (m, 2H), 7.18 (t, J = 7.5 Hz, 1H), 7.11 (d,
3
J = 7.5 Hz, 1H), 5.84 (d, J = 15.6 Hz, 1H), 5.52 (dd, J = 15.5, 8.5 Hz,
1H), 3.70 (d, J = 16.7 Hz, 1H), 3.48 (d, J = 17.0 Hz, 1H), 3.13 (td, J =
8.8, 2.8 Hz, 1H), 3.03 (q, J = 8.2 Hz, 1H), 2.74−2.55 (m, 2H), 2.32 (s,
3H), 2.04−1.95 (m, 1H), 1.92−1.83 (m, 1H), 1.82−1.73 (m, 1H),
37.91 mmol) was added dropwise over 30 min to a stirred solution of
4
-(1-(3-phenylprop-2-yn-1-yl)pyrrolidin-2-yl)but-3-en-2-one 6 (3.20
13
1
g, 12.64 mmol) in dried THF (126 mL) at −78 °C under an nitrogen
atmosphere. The mixture was stirred at room temperature for 1 h.
After which time, the reaction mixture was quenched with water (30
mL) and extracted with EtOAc (30 mL × 3). The combined organic
extracts were washed with water (70 mL × 2) and saturated brine (70
1.70−1.60 (m, 1H), 1.33 (s, 3H), 1.33 (s, 3H); C{ H} NMR (100
MHz, CDCl ) δ 141.4, 137.8, 132.2, 128.8, 128.7, 128.1, 127.7, 123.0,
3
85.1, 84.2, 70.4, 64.4, 52.0, 40.9, 31.6, 29.8, 29.6, 22.0, 21.1; IR
(CH Cl ) 3369, 2970, 2926, 2346, 2224, 1945, 1602, 1459, 1361,
2
2
−1
+
1234, 1153, 974, 891 cm ; MS (APCI) m/e (%) 284.2 ([M + H] ,
100); HRMS (APCI) calcd. for C H NO [M + H] 284.2014, found
+
mL × 2). The filtrate was dried over MgSO and concentrated under
4
19 26
reduced pressure. The crude mixture was purified by flash column
chromatography over silica gel (EtOAc/hexanes 1:1) to afford the
284.2018.
(E)-2-Methyl-4-(1-(3-(p-tolyl)prop-2-yn-1-yl)pyrrolidin-2-yl)but-3-
en-2-ol (1c). (0.22 g, 0.77 mmol, 90%). A yellow oil: H NMR (400
MHz, CDCl ) δ 7.32 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H),
1
corresponding (E)-2-methyl-4-(1-(3-phenylprop- 2-yn-1-yl)pyrolidin-
1
2
-yl)but-3-en-2-ol (1a) (2.72 g, 10.11 mmol, 80%) as a yellow oil: H
3
NMR (400 MHz, CDCl ) δ 7.46−7.40 (m, 2H), 7.32−7.27 (m, 3H),
5.85 (d, J = 15.5 Hz, 1H), 5.53 (dd, J = 15.6, 8.5 Hz, 1H), 3.72 (d, J =
16.7 Hz, 1H), 3.48 (d, J = 17.0 Hz, 1H), 3.17 (td, J = 8.9, 2.8 Hz, 1H),
3.04 (q, J = 8.2 Hz, 1H), 2.67 (q, J = 8.9 Hz, 1H), 2.49 (br s., 1H),
2.34 (s, 3H), 2.04−1.94 (m, 1H), 1.93−1.84 (m, 1H), 1.83−1.73 (m,
3
5
1
3
1
3
.84 (d, J = 15.6 Hz, 1H), 5.52 (dd, J = 15.6, 8.4 Hz, 1H), 3.71 (d, J =
7.0 Hz, 1H), 3.46 (d, J = 17.0 Hz, 1H), 3.15 (td, J = 8.6, 2.8 Hz, 1H),
.00 (q, J = 8.2 Hz, 1H), 2.63 (q, J = 8.9 Hz, 1H), 2.04−1.94 (m, 1H),
.92−1.84 (m, 1H), 1.82−1.74 (m, 1H), 1.69−1.62 (m, 1H), 1.34 (s,
1
3
1
1H), 1.71−1.62 (m, 1H), 1.34 (s, 3H), 1.33 (s, 3H); C{ H} NMR
H), 1.34 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ 141.2, 131.6
1
(100 MHz, CDCl ) δ 141.7, 138.0, 131.5 (2C), 128.9 (2C), 127.2,
3
3
(
3
2
2C), 128.1 (2C), 128.0, 127.9, 123.2, 84.9, 84.7, 70.3, 64.4, 52.2, 41.0,
119.9, 85.1, 83.5, 70.3, 64.5, 51.9, 40.8, 31.5, 29.7, 29.5, 22.0, 21.3; IR
(CH Cl ) 3373, 2969, 2924, 2233, 1904, 1671, 1509, 1460, 1361,
1.7, 29.7, 29.7, 22.0; IR (CH Cl ) 3369, 2970, 2928, 2818, 2346,
2 2
2
2
−1
−1
+
373, 1675, 1598, 1459, 1363, 1153, 974, 756 cm ; MS (ESI) m/e
%) 270.2 ([M + H] , 100), 262.2 (10); HRMS (ESI) calcd. for
1331, 1152, 974, 816 cm ; MS (APCI) m/e (%) 284.2 ([M + H] ,
+
+
(
100), 194.2 (5); HRMS (APCI) calcd. for C H NO [M + H]
19
26
+
C H NO [M + H] 270.1858, found 270.1859.
284.2014, found 284.2021.
18
24
(
1-(Prop-2-yn-1-yl)pyrrolidin-2-yl)methanol (3). (3.61 g, 25.96
(E)-4-(1-(3-([1,1′-Biphenyl]-4-yl)prop-2-yn-1-yl)pyrrolidin-2-yl)-2-
1
1
mmol, 98%). A colorless oil: H NMR (400 MHz, CDCl ) δ 3.64 (dd,
methylbut-3-en-2-ol (1d). (0.20 g, 0.59 mmol, 39%). A yellow oil: H
3
J = 11.0, 3.5 Hz, 1H), 3.53 (dd, J = 17.3, 2.3 Hz, 1H), 3.48−3.38 (m,
NMR (400 MHz, CDCl ) δ 7.60−7.57 (m, 2H), 7.54 (dd, J = 6.2, 2.0
3
2
1
1
7
7
H), 3.07−2.99 (m, 1H), 2.89−2.82 (m, 1H), 2.69 (q, J = 8.5 Hz,
Hz, 2H), 7.50 (dd, J = 6.6, 2.1 Hz, 2H), 7.44 (t, J = 7.2 Hz, 2H), 7.38−
7.33 (m, 1H), 5.86 (d, J = 15.5 Hz, 1H), 5.53 (dd, J = 15.6, 8.5 Hz,
1H), 3.74 (d, J = 17.0 Hz, 1H), 3.49 (d, J = 17.0 Hz, 1H), 3.18 (td, J =
9.0, 2.8 Hz, 1H), 3.02 (q, J = 8.1 Hz, 1H), 2.65 (q, J = 8.9 Hz, 1H),
2.05−1.96 (m, 1H), 1.94−1.85 (m, 1H), 1.85−1.74 (m, 1H), 1.71−
H), 2.44−2.29 (br s., 1H), 2.20 (t, J = 2.4 Hz, 1H), 1.98−1.84 (m,
13
1
H), 1.84−1.68 (m, 4H); C{ H} NMR (100 MHz, CDCl ) δ 79.1,
3
2.5, 62.3, 61.8, 53.2, 41.0, 27.5, 23.1; IR (CH Cl ) 3491, 2970, 1230,
2
2
−1
+
80, 699 cm ; MS (ESI) m/e (%) 140.1 ([M + H] , 100), 120.1 (25);
HRMS (ESI) calcd. for C H NO [M + H] 140.0998, found
40.0997.
+
13
1
1.61 (m, 2H), 1.35 (s, 3H), 1.35 (s, 3H); C{ H} NMR (100 MHz,
CDCl ) δ 141.4, 140.8, 140.4, 132.1 (2C), 128.8 (2C), 127.9, 127.6,
127.0 (2C), 126.9 (2C), 122.1, 85.4, 84.8, 70.5, 64.6, 52.2, 41.1, 31.7,
29.8, 29.7, 22.1; IR (CH Cl ) 3372, 2968, 2358, 2632, 1366, 1120,
8
14
1
3
(1-(3-Phenylprop-2-yn-1-yl)pyrrolidin-2-yl)methanol (4). (3.61 g,
1
2
7
=
2
1
1
5.96 mmol, 75%). A yellow oil: H NMR (400 MHz, CDCl ) δ
2
2
3
−1
+
.48−7.38 (m, 2H), 7.36−7.27 (m, 3H), 3.78−3.68 (m, 2H), 3.65 (d, J
975, 843, 764, 698 cm ; MS (ESI) m/e (%) 346.2 ([M + H] , 100),
342.1 (5), 304.1 (5); HRMS (ESI) calcd. for C H NO [M + H]
+
17.3 Hz, 1H), 3.47 (dd, J = 11.0, 2.8 Hz, 1H), 3.14−3.06 (m, 1H),
24
28
.98−2.91 (m, 1H), 2.78 (q, J = 8.5 Hz, 1H), 1.97−1.90 (m, 1H),
346.2171, found 346.2169.
13
1
.87−1.73 (m, 4H); C{ H} NMR (100 MHz, CDCl ) δ 131.7 (2C),
(E)-2-Methyl-4-(1-(3-(naphthalen-1-yl)prop-2-yn-1-yl)pyrrolidin-
3
1
28.3 (2C), 128.1, 123.1, 84.9, 84.8, 62.1, 61.9, 53.5, 41.8, 27.8, 23.5;
2-yl)but-3-en-2-ol (1e). (0.64 g, 2.02 mmol, 80%). A yellow oil: H
−1
IR (CH Cl ) 3376, 2948, 1599, 1459, 1328 cm ; MS (ESI) m/e (%)
16.1 ([M + H] , 100); HRMS (ESI) calcd. for C H NO [M + H]
NMR (400 MHz, CDCl ) δ 8.33 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 8.1
3
2
2
+
+
2
2
Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.67 (dd, J = 7.1, 0.9 Hz, 1H),
7.58−7.54 (m, 1H), 7.52−7.48 (m, 1H), 7.40 (t, J = 7.7 Hz, 1H), 5.90
(d, J = 15.5 Hz, 1H), 5.58 (dd, J = 15.6, 8.6 Hz, 1H), 3.88 (d, J = 17.1
Hz, 1H), 3.68 (d, J = 17.1 Hz, 1H), 3.21 (td, J = 8.8, 2.8 Hz, 1H), 3.15
(q, J = 8.2 Hz, 1H), 2.78 (q, J = 8.8 Hz, 1H), 2.05−1.96 (m, 1H),
14
18
16.1388, found 216.1385.
-(3-Phenylprop-2-yn-1-yl)pyrrolidine-2-carbaldehyde (5). (3.10
1
1
g, 14.54 mmol, 98%). A yellow oil: H NMR (400 MHz, CDCl ) δ
3
9
(
1
3
(
2
.59 (d, J = 3.3 Hz, 1H), 7.46−7.38 (m, 2H), 7.34−7.27 (m, 3H), 3.72
d, J = 1.1 Hz, 2H), 3.26 (ddd, J = 9.3, 6.2, 3.4 Hz, 1H), 3.22−3.13 (m,
1.95−1.85 (m, 1H), 1.85−1.76 (m, 1H), 1.73−1.64 (m, 1H), 1.35 (s,
3H), 1.34 (s, 3H); 13C{ H} NMR (100 MHz, CDCl
1
) δ 141.7, 133.3,
H), 2.76 (q, J = 8.5 Hz, 1H), 2.13−2.02 (m, 1H), 2.00−1.84 (m,
3
H); 13C{ H} NMR (100 MHz, CDCl ) δ 202.5, 131.6 (2C), 128.2
1
133.1, 130.5, 128.4, 128.2, 127.5, 126.6, 126.3, 126.0, 125.1, 120.8,
89.4, 83.0, 70.4, 64.5, 52.0, 41.1, 31.6, 29.8, 29.6, 22.0; IR (CH Cl )
2
3
2C), 128.2, 122.8, 85.2, 84.4, 69.7, 53.3, 43.0, 26.9, 24.0; IR (CH Cl )
2
2
2
−1
965, 2716, 1727, 1598, 1490 cm ; MS (ESI) m/e (%) 214.1 ([M +
3365, 3058, 2969, 2935, 2816, 2227, 1932, 1812, 1689, 1586, 1507,
+
−1
H] , 40), 166.7 (45), 148.8 (12), 102.1 (61), 91.0 (3); HRMS (ESI)
1424, 1395, 1359, 1330, 1153, 973, 799, 774 cm ; MS (ESI) m/e (%)
+
+
calcd. for C H NO [M + H] 214.1232, found 214.1232.
320.2 ([M + H] , 100), 284.2 (5), 266.2 (5); HRMS (ESI) calcd. for
14
16
+
(
E)-4-(1-(3-Phenylprop-2-yn-1-yl)pyrrolidin-2-yl)but-3-en-2-one
C H NO [M + H] 320.2014, found 320.2012.
2
2
26
1
(
6). (3.20 g, 12.64 mmol, 88%). A yellow oil: H NMR (400 MHz,
(E)-4-(1-(3-(3-Methoxyphenyl)prop-2-yn-1-yl)pyrrolidin-2-yl)-2-
1
CDCl ) δ 7.46−7.39 (m, 2H), 7.34−7.27 (m, 3H), 6.66 (dd, J = 16.0,
.0 Hz, 1H), 6.22 (d, J = 15.9 Hz, 1H), 3.71 (d, J = 17.2 Hz, 1H), 3.52
methylbut-3-en-2-ol (1f). (0.19 g, 0.64 mmol, 70%). A yellow oil: H
3
8
NMR (400 MHz, CDCl ) δ 7.21 (t, J = 7.9 Hz, 1H), 7.03 (d, J = 7.6
3
(
d, J = 17.1 Hz, 1H), 3.27 (q, J = 8.0 Hz, 1H), 3.21−3.12 (m, 1H),
Hz, 1H), 6.99−6.95 (m, 1H), 6.86 (dd, J = 8.2, 2.6 Hz, 1H), 5.85 (d, J
F
DOI: 10.1021/acs.joc.5b02025
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
=
=
15.4 Hz, 1H), 5.54 (dd, J = 15.5, 8.5 Hz, 1H), 3.80 (s, 3H), 3.73 (d, J
17.2 Hz, 1H), 3.48 (d, J = 17.0 Hz, 1H), 3.18 (td, J = 8.9, 2.7 Hz,
(E)-2-Methyl-4-(1-(3-(3-nitrophenyl)prop-2-yn-1-yl)pyrrolidin-2-
1
yl)but-3-en-2-ol (1k). (0.40 g, 1.28 mmol, 85%). A yellow oil: H
1
1
1
1
5
1
H), 3.03 (q, J = 8.1 Hz, 1H), 2.66 (q, J = 8.8 Hz, 1H), 2.03−1.97 (m,
NMR (400 MHz, CDCl ) δ 8.27 (s, 1H), 8.18−8.11 (m, 1H), 7.73 (d,
3
H), 1.93−1.85 (m, 1H), 1.82−1.75 (m, 1H), 1.72−1.65 (m, 1H),
J = 7.7 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 5.84 (d, J = 15.7 Hz, 1H),
5.52 (dd, J = 15.6, 8.4 Hz, 1H), 3.75 (d, J = 17.1 Hz, 1H), 3.47 (d, J =
17.1 Hz, 1H), 3.18 (td, J = 8.6, 2.7 Hz, 1H), 2.97 (q, J = 8.2 Hz, 1H),
2.61 (q, J = 8.8 Hz, 1H), 2.07−1.97 (m, 1H), 1.94−1.85 (m, 1H),
1.83−1.76 (m, 1H), 1.71−1.64 (m, 1H), 1.35 (s, 3H), 1.35 (s, 3H);
.34 (s, 3H), 1.34 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ 159.2,
41.3, 129.3, 127.9, 124.2, 124.2, 116.6, 114.5, 84.7, 84.7, 70.5, 64.6,
5.2, 52.2, 41.1, 31.7, 29.8, 29.7, 22.1; IR (CH Cl ) 3364, 2969, 2366,
1
3
2
2
−1
603, 1463, 1360, 1318, 1288, 1203, 1162, 1045, 976 cm ; MS (ESI)
+
13
1
m/e (%) 300.2 ([M + H] , 100); HRMS (ESI) calcd. for C H NO
C{ H} NMR (100 MHz, CDCl ) δ 148.1, 141.3, 137.4, 129.2, 128.0,
3
19
26
2
+
[
M + H] 300.1964, found 300.1964.
126.5, 125.1, 122.7, 88.2, 82.5, 70.6, 64.8, 52.5, 41.1, 31.8, 29.9, 29.7,
22.1; IR (CH Cl ) 2256, 2967, 2944, 1981, 1531, 1351, 1155, 1105,
(
E)-4-(1-(3-(4-Methoxyphenyl)prop-2-yn-1-yl)pyrrolidin-2-yl)-2-
2
2
1
−1
+
methylbut-3-en-2-ol (1g). (0.20 g, 0.68 mmol, 43%). A yellow oil: H
NMR (400 MHz, CDCl ) δ 7.37 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8
Hz, 2H), 5.84 (d, J = 15.6 Hz, 1H), 5.52 (dd, J = 15.5, 8.4 Hz, 1H),
974, 736 cm ; MS (ESI) m/e (%) 315.2 ([M + H] , 100); HRMS
(ESI) calcd. for C H N O [M + H] 315.1709, found 315.1705.
+
3
18 23
2
3
(E)-2-Methyl-4-(1-(3-(4-nitrophenyl)prop-2-yn-1-yl)pyrrolidin-2-
1
3.81 (s, 3H), 3.70 (d, J = 16.9 Hz, 1H), 3.45 (d, J = 17.0 Hz, 1H), 3.16
yl)but-3-en-2-ol (1l). (0.42 g, 1.35 mmol, 90%). A yellow oil: H
(
td, J = 8.9, 2.7 Hz, 1H), 3.01 (q, J = 8.2 Hz, 1H), 2.63 (q, J = 8.9 Hz,
NMR (400 MHz, CDCl ) δ 8.17 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.7
3
1
1
H), 2.23 (br s., 1H), 2.03−1.95 (m, 1H), 1.92−1.83 (m, 1H), 1.81−
Hz, 2H), 5.84 (d, J = 15.5 Hz, 1H), 5.52 (dd, J = 15.6, 8.4 Hz, 1H),
3.76 (d, J = 17.2 Hz, 1H), 3.47 (d, J = 17.2 Hz, 1H), 3.18 (td, J = 8.9,
2.6 Hz, 1H), 2.96 (q, J = 8.2 Hz, 1H), 2.59 (q, J = 8.9 Hz, 1H), 2.06−
1.96 (m, 1H), 1.94−1.85 (m, 1H), 1.84−1.76 (m, 1H), 1.71−1.58 (m,
13
1
.74 (m, 1H), 1.70−1.63 (m, 1H), 1.34 (s, 3H), 1.33 (s, 3H); C{ H}
NMR (100 MHz, CDCl ) δ 159.3, 141.6, 133.0 (2C), 127.4, 115.2,
3
1
2
1
13.7 (2C), 84.7, 82.9, 70.2, 64.4, 55.1, 51.9, 40.9, 31.5, 29.7, 29.5,
2H), 1.35 (s, 3H), 1.34 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ
1
1.9; IR (CH Cl ) 3374, 2968, 2932, 2872, 2838, 2228, 1607, 1509,
2
2
3
−1
291, 1248, 1152, 1033, 832 cm ; MS (ESI) m/e (%) 300.2 ([M +
147.0, 141.4, 132.4 (2C), 130.2, 128.0, 123.5 (2C), 91.2, 83.1, 70.6,
64.9, 52.5, 41.3, 31.8, 29.9, 29.7, 22.1; IR (CH Cl ) 3354, 2968, 2875,
+
H] , 100), 284.2 (15), 279.3 (5), 246.2 (10); HRMS (ESI) calcd. for
C H NO [M + H] 300.1964, found 300.1956.
2
2
+
−1
2828, 2360, 2232, 1966, 1594, 1518, 1343, 1107, 854, 750 cm ; MS
(ESI) m/e (%) 315.2 ([M + H] , 100); HRMS (ESI) calcd. for
C H N O [M + H] 315.1709, found 315.1700.
19
26
2
+
(
E)-2-Methyl-4-(1-(3-(3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)-
+
pyrrolidin-2-yl)but-3-en-2-ol (1h). (1.13 g, 4.29 mmol, 87%). A
yellow oil: H NMR (400 MHz, CDCl ) δ 7.68 (s, 1H), 7.59 (d, J =
18
23
2
3
1
3
(E)-4-(1-(3-(4-Chlorophenyl)prop-2-yn-1-yl)pyrrolidin-2-yl)-2-
1
7
.7 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 5.84 (d,
J = 15.6 Hz, 1H), 5.52 (dd, J = 15.6, 8.5 Hz, 1H), 3.73 (d, J = 17.2 Hz,
H), 3.45 (d, J = 17.1 Hz, 1H), 3.17 (td, J = 8.7, 2.8 Hz, 1H), 2.98 (q,
methylbut-3-en-2-ol (1m). (0.95 g, 3.09 mmol, 72%). A yellow oil: H
NMR (400 MHz, CDCl ) δ 7.35 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.6
3
1
Hz, 2H), 5.83 (d, J = 15.5 Hz, 1H), 5.51 (dd, J = 15.6, 8.4 Hz, 1H),
3.70 (d, J = 17.0 Hz, 1H), 3.43 (d, J = 17.0 Hz, 1H), 3.15 (td, J = 8.7,
2.7 Hz, 1H), 2.96 (q, J = 8.2 Hz, 1H), 2.59 (q, J = 8.8 Hz, 1H), 2.04−
1.95 (m, 1H), 1.92−1.83 (m, 1H), 1.82−1.73 (m, 1H), 1.69−1.61 (m,
J = 8.2 Hz, 1H), 2.61 (q, J = 8.9 Hz, 1H), 2.05−1.96 (m, 1H), 1.93−
1
1
.84 (m, 1H), 1.84−1.75 (m, 1H), 1.72−1.61 (m, 2H), 1.35 (s, 3H),
.34 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ 141.3, 134.8, 130.9
1
3
1H), 1.34 (s, 3H), 1.33 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ
1
(
q, J = 32.6 Hz),128.8, 128.5 (q, J = 3.7 Hz), 128.1, 124.5 (q, J = 3.7
3
Hz), 124.2, 123.7 (q, J = 272.4 Hz), 86.9, 83.3, 70.6, 64.7, 52.4, 41.1,
141.2, 133.9, 132.9 (2C), 128.5 (2C), 128.1, 121.7, 86.1, 83.6, 70.5,
64.7, 52.4, 41.2, 31.7, 29.8, 29.7, 22.1; IR (CH Cl ) 3357, 2968, 2875,
3
1.8, 29.8, 29.7, 22.1; 19F NMR (376 MHz, CDCl ) δ −63.9; IR
3
2
2
−1
(
9
CH Cl ) 3372, 2970, 2826, 2961, 1638, 1334, 1166, 1129, 1094, 974,
2827, 2901, 2644, 1489, 1363, 1151, 1091, 827, 754, 740 cm ; MS
2
2
−1
+
+
+
02, 801, 696 cm ; MS (ESI) m/e (%) 338.2 ([M + H] , 100), 330.2
(ESI) m/e (%) 306.1 ([M + 2 + H] , 30), 304.1 ([M + H] , 100),
+
+
(
5), 284.1 (5); HRMS (ESI) calcd. for C H NOF [M + H]
296.1 (5), 264.1 (5); HRMS (ESI) calcd. for C H NOCl [M + H]
19
23
3
18 23
3
38.1732, found 338.1723.
304.1468, found 304.1463.
(
E)-Ethyl 3-(3-(2-(3-hydroxy-3-methylbut-1-en-1-yl)pyrrolidin-1-
(E)-4-(1-(3-(4-Bromophenyl)prop-2-yn-1-yl)pyrrolidin-2-yl)-2-
1
yl)prop-1-yn-1- yl)benzoate (1i). (0.26 g, 0.75 mmol, 50%). A yellow
methylbut-3-en-2-ol (1n). (0.93 g, 2.66 mmol, 93%). A yellow oil: H
1
oil: H NMR (400 MHz, CDCl ) δ 8.10 (t, J = 1.8 Hz, 1H), 7.97 (dt, J
NMR (400 MHz, CDCl ) δ 7.43 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4
3
3
=
1
(
1
7.8, 1.3 Hz, 1H), 7.60 (dt, J = 7.7, 1.2 Hz, 1H), 7.37 (t, J = 7.8 Hz,
H), 5.85 (d, J = 15.5 Hz, 1H), 5.52 (dd, J = 15.5, 8.4 Hz, 1H), 4.38
q, J = 7.0 Hz, 2H), 3.72 (d, J = 17.0 Hz, 1H), 3.46 (d, J = 17.0 Hz,
H), 3.15 (td, J = 8.8, 2.7 Hz, 1H), 2.99 (q, J = 8.2 Hz, 1H), 2.62 (q, J
Hz, 2H), 5.83 (d, J = 15.7 Hz, 1H), 5.51 (dd, J = 15.6, 8.4 Hz, 1H),
3.70 (d, J = 17.0 Hz, 1H), 3.42 (d, J = 17.0 Hz, 1H), 3.16 (td, J = 8.6,
2.7 Hz, 1H), 2.96 (q, J = 8.2 Hz, 1H), 2.59 (q, J = 8.9 Hz, 1H), 2.04−
1.95 (m, 1H), 1.91−1.83 (m, 1H), 1.82−1.74 (m, 1H), 1.69−1.56 (m,
2H), 1.34 (s, 3H), 1.34 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ
1
=
8.9 Hz, 1H), 2.15 (br s., 1H), 2.04−1.95 (m, 1H), 1.92−1.84 (m,
3
1
1
1
6
2
H), 1.83−1.75 (m, 1H), 1.70−1.61 (m, 1H), 1.40 (t, J = 7.1 Hz, 3H),
141.2, 133.2 (2C), 131.5 (2C), 128.2, 122.2, 122.1, 86.4, 83.7, 70.5,
.34 (s, 3H), 1.34 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ 166.0,
1
3
64.7, 52.4, 41.2, 31.8, 29.8, 29.7, 22.1; IR (CH Cl ) 3372, 2970, 2875,
2
2
−
1
41.2, 135.8, 132.8, 130.7, 129.0, 128.3, 128.1, 123.7, 86.0, 83.8, 70.6,
4.6, 61.2, 52.4, 41.2, 31.8, 29.8, 29.7, 22.1, 14.3; IR (CH Cl ) 3384,
971, 2941, 2430, 2196, 1721, 1367, 1293, 1225, 1105, 974, 754 cm ;
2816, 1654, 1485, 1460, 1359, 1330, 1151, 973, 823 cm ; MS (ESI)
m/e (%) 350.1 ([M + 2 + H] , 100), 348.1 ([M + H] , 100), 194.1
(10); HR-MS (ESI) calcd. for C H NOBr [M + H] 348.0963,
+
+
2
2
−1
+
18
23
+
MS (ESI) m/e (%) 342.2 ([M + H] , 100), 229.1 (10), 143.1 (5);
HRMS (ESI) calcd. for C H NO [M + H] 342.2069, found
found 348.0966.
+
21
28
3
(E)-4-(1-(3-(2-Bromophenyl)prop-2-yn-1-yl)pyrrolidin-2-yl)-2-
1
342.2065.
methylbut-3-en-2-ol (1o). (0.83 g, 2.39 mmol, 77%). A yellow oil: H
(
E)-Ethyl 4-(3-(2-(3-hydroxy-3-methylbut-1-en-1-yl)pyrrolidin-1-
NMR (400 MHz, CDCl ) δ 7.58 (d, J = 8.1 Hz, 1H), 7.46 (dd, J = 7.6,
3
yl)prop-1-yn-1- yl)benzoate (1j). (0.22 g, 0.65 mmol, 43%). A yellow
1.4 Hz, 1H), 7.25 (td, J = 7.6, 1.3 Hz, 1H), 7.18−7.12 (m, 1H), 5.89
(d, J = 15.6 Hz, 1H), 5.51 (dd, J = 15.6, 8.5 Hz, 1H), 3.76 (d, J = 17.2
Hz, 1H), 3.59 (d, J = 17.2 Hz, 1H), 3.18−3.10 (m, 2H), 2.77 (q, J =
8.8 Hz, 1H), 2.04−1.96 (m, 1H), 1.92−1.84 (m, 1H), 1.82−1.75 (m,
1
oil: H NMR (400 MHz, CDCl ) δ 7.98 (d, J = 8.1 Hz, 2H), 7.48 (d, J
8.2 Hz, 2H), 5.84 (d, J = 15.5 Hz, 1H), 5.52 (dd, J = 15.6, 8.4 Hz,
3
=
1
1
2
1
H), 4.38 (q, J = 7.1 Hz, 2H), 3.74 (d, J = 17.1 Hz, 1H), 3.47 (d, J =
7.1 Hz, 1H), 3.17 (td, J = 8.7, 2.7 Hz, 1H), 2.98 (q, J = 8.2 Hz, 1H),
.61 (q, J = 8.8 Hz, 1H), 2.05−1.96 (m, 1H), 1.92−1.84 (m, 1H),
1
3
1
1H), 1.69−1.62 (m, 1H), 1.34 (s, 3H), 1.34 (s, 3H); C{ H} NMR
(100 MHz, CDCl ) δ 141.3, 133.5, 132.3, 129.1, 128.1, 126.9, 125.4
3
.83−1.73 (m, 1H), 1.70−1.56 (m, 2H), 1.39 (t, J = 7.2 Hz, 3H), 1.34
(2C), 89.9, 83.4, 70.6, 64.0, 52.0, 40.9, 31.8, 29.8, 29.7, 22.2; IR
(CH Cl ) 3370, 2970, 2942, 2359, 1930, 1803, 1469, 1360, 1153, 947,
1
(
s, 3H), 1.34 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ 166.1,
3
2
2
−
1
+
1
6
2
41.2, 131.6 (2C), 129.7, 129.4 (2C), 128.1, 127.9, 88.3, 84.2, 70.6,
4.7, 61.1, 52.5, 41.3, 31.8, 29.8, 29.7, 22.1, 14.3; IR (CH Cl ) 3396,
964, 2194, 1719, 1629, 1365, 1307, 1274, 1106, 767, 740 cm ; MS
ESI) m/e (%) 342.2 ([M + H] , 100); HRMS (ESI) calcd. for
754 cm ; MS (ESI) m/e (%) 350.1 ([M + 2 + H] , 95), 348.1 ([M +
H] , 100), 341.1 (5), 145.0 (10); HRMS (ESI) calcd. for C H NOBr
[M + H] 348.0963, found 348.0955.
+
2
2
18 23
−
1
+
+
(
(E)-2-Methyl-4-(1-(3-(2-nitrophenyl)prop-2-yn-1-yl)pyrrolidin-2-
+
1
C H NO [M + H] 342.2069, found 342.2068.
1
yl)but-3-en-2-ol (1p). (0.37 g, 1.19 mmol, 79%). A yellow oil: H
2
28
3
G
DOI: 10.1021/acs.joc.5b02025
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
NMR (400 MHz, CDCl ) δ 8.01 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 7.6
= 1:1) to give of 7a (0.06 g, 0.22 mmol, 85%) as a yellow oil: H NMR
3
Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 5.88 (d, J =
(600 MHz, CDCl ) δ 7.40−7.37 (m, 2H), 7.34−7.28 (m, 3H), 5.01
3
1
1
5.5 Hz, 1H), 5.50 (dd, J = 15.5, 8.4 Hz, 1H), 3.78 (d, J = 17.4 Hz,
H), 3.59 (d, J = 17.4 Hz, 1H), 3.17−3.05 (m, 2H), 2.72 (q, J = 8.8
(dt, J = 9.6, 1.3 Hz, 1H), 4.04 (d, J = 16.1 Hz, 1H), 3.82 (dd, J = 16.1,
3.0 Hz, 1H), 3.47−3.42 (m, 1H), 3.35 (q, J = 5.3 Hz, 1H), 3.22−3.15
(m, 1H), 2.67 (dt, J = 10.0, 8.1 Hz, 1H), 2.12−2.05 (m, 1H), 2.00−
Hz, 1H), 2.07−1.98 (m, 1H), 1.92−1.84 (m, 1H), 1.84−1.77 (m, 1H),
13
1
1
.70−1.60 (m, 2H), 1.35 (s, 3H), 1.34 (s, 3H); C{ H} NMR (100
1.92 (m, 1H), 1.91−1.83 (m, 1H), 1.64 (d, J = 1.3 Hz, 3H), 1.63−1.59
(m, 1H), 1.58 (d, J = 1.3 Hz, 3H); 13C{ H} NMR (150 MHz, CDCl
1
)
MHz, CDCl ) δ 150.0, 141.4, 134.9, 132.6, 128.4, 128.0, 124.5, 118.6,
3
3
9
3
4.0, 80.1, 70.6, 64.2, 52.1, 41.1, 31.8, 29.8, 29.7, 22.2; IR (CH Cl )
δ 151.5 (d, J = 239.7 Hz), 132.5, 132.0 (d, J = 29.6 Hz), 128.4, 127.7
(2C), 127.0 (d, J = 6.1 Hz, 2C), 125.0, 122.1 (d, J = 21.3 Hz), 73.9,
2
2
−
1
383, 2967, 2876, 2419, 1545, 1525, 1351, 1143, 980, 741 cm ; MS
+
(
ESI) m/e (%) 315.2 ([M + H] , 100), 229.1 (10), 143.1 (5); HRMS
55.4 (d, J = 5.4 Hz), 54.2, 45.5 (d, J = 3.3 Hz), 29.8, 25.5, 24.5, 18.1;
+
19
(
ESI) calcd. for C H N O [M + H] 315.1709, found 315.1700.
F NMR (376 MHz, CDCl
3
) δ −103.5; IR (CH Cl ) 3404, 2908,
2 2
18
23
2
3
−1
(
E)-Ethyl 2-(3-(2-(3-hydroxy-3-methylbut-1-en-1-yl)pyrrolidin-1-
2847, 2541, 2358, 1702, 1600, 1443, 1375, 1272, 1051, 924 cm ; MS
(ESI) m/e (%) 272.2 ([M + H] , 100), 268.2 (10), 221.2 (10); HRMS
(ESI) calcd. for C H FN [M + H] 272.1815, found 272.1823.
+
yl)prop-1-yn-1- yl)benzoate (1q). (0.31 g, 1.81 mmol, 60%). A
yellow oil: H NMR (400 MHz, CDCl ) δ 7.90 (dd, J = 7.8, 1.1 Hz,
1
+
3
18 23
1
(
8
(
H), 7.55 (dd, J = 7.8, 0.9 Hz, 1H), 7.44 (td, J = 7.5, 1.4 Hz, 1H), 7.34
td, J = 7.7, 1.3 Hz, 1H), 5.89 (d, J = 15.6 Hz, 1H), 5.53 (dd, J = 15.5,
.4 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.77 (d, J = 17.1 Hz, 1H), 3.57
d, J = 17.2 Hz, 1H), 3.17 (td, J = 8.6, 2.8 Hz, 1H), 3.09 (q, J = 8.2 Hz,
(1S*,7aR*,Z)-2-(Fluoro(m-tolyl)methylene)-1-(2-methylprop-1-
en-1-yl)hexahydro-1H-pyrrolizine (7b). The crude residue obtained
from the reaction of 1b (73 mg, 0.26 mmol) with Ph
0.52 mmol) in CH Cl (26 mL) was purified by flash column
chromatography to give 7b (53 mg, 0.18 mmol, 71%) as a yellow oil:
CBF (0.17 g,
3 4
2
2
1
1
1
1
6
2
H), 2.71 (q, J = 8.9 Hz, 1H), 2.05−1.95 (m, 1H), 1.92−1.83 (m,
1
H), 1.83−1.76 (m, 1H), 1.71−1.63 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H),
H NMR (400 MHz, CDCl ) δ 7.24−7.18 (m, 3H), 7.13−7.07 (m,
3
.34 (s, 3H), 1.34 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ 166.3,
41.4, 134.4, 132.4, 131.4, 130.0, 128.1, 127.6, 123.7, 90.4, 83.4, 70.6,
4.5, 61.1, 52.3, 41.3, 31.8, 29.8, 29.6, 22.2, 14.3; IR (CH Cl ) 3404,
1
1H), 5.04 (d, J = 9.7 Hz, 1H), 3.95 (d, J = 15.6 Hz, 1H), 3.77 (dd, J =
16.1, 2.9 Hz, 1H), 3.47−3.37 (m, 1H), 3.30−3.21 (m, 1H), 3.13−3.00
(m, 1H), 2.69−2.56 (m, 1H), 2.33 (s, 3H), 2.09−2.00 (m, 1H), 1.99−
1.89 (m, 1H), 1.86−1.78 (m, 1H), 1.66 (d, J = 1.1 Hz, 3H), 1.63−1.56
3
2
2
969, 2427, 2195, 1966, 1720, 1460, 1365, 1276, 1080, 974, 756, 740
−1
+
13
1
cm ; MS (ESI) m/e (%) 342.2 ([M + H] , 100); HRMS (ESI) calcd.
for C H NO [M + H] 342.2069, found 342.2065.
(m, 4H); C{ H} NMR (100 MHz, CDCl ) δ 151.2 (d, J = 238.2
3
+
Hz), 137.3, 132.2 (d, J = 29.5 Hz), 131.8, 129.0, 127.6, 127.6 (d, J =
5.6 Hz), 125.7, 123.9 (d, J = 6.2 Hz), 122.8 (d, J = 21.5 Hz), 73.8, 55.5
(d, J = 5.2 Hz), 54.0, 45.6 (d, J = 3.2 Hz), 29.8, 25.5, 24.5, 21.4, 18.1;
21
28
3
(
E)-2-Methyl-4-(1-(3-(thiophen-3-yl)prop-2-yn-1-yl)pyrrolidin-2-
1
yl)but-3-en-2-ol (1r). (1.02 g, 3.72 mmol, 80%). A brown oil: H
NMR (400 MHz, CDCl ) δ 7.42−7.39 (m, 1H), 7.25 (dd, J = 5.0, 3.1
Hz, 1H), 7.10 (dd, J = 4.9, 0.9 Hz, 1H), 5.83 (d, J = 15.5 Hz, 1H), 5.51
19
F NMR (376 MHz, CDCl ) δ −104.7; IR (CH Cl ) 3754, 2967,
3
3
2
2
−1
2375, 1686, 1376, 1123, 1050, 927 cm ; MS (ESI) m/e (%), 286.2
([M + H] , 100), 282.2 (5), 221.2 (5); HRMS (ESI) calcd. for
C H FN [M + H] 286.1971, found 286.1963.
+
(
dd, J = 15.6, 8.4 Hz, 1H), 3.69 (d, J = 17.2 Hz, 1H), 3.42 (d, J = 17.0
Hz, 1H) 3.14 (td, J = 8.8, 2.6 Hz, 1H), 2.96 (q, J = 8.2 Hz, 1H), 2.60
q, J = 8.9 Hz, 1H), 2.02−1.94 (m, 1H), 1.91−1.82 (m, 1H), 1.80−
.73 (m, 1H), 1.68−1.61 (m, 1H), 1.55 (br s., 1H), 1.34 (s, 3H), 1.33
+
1
9
25
(
(1S*,7aR*,Z)-2-(Fluoro(p-tolyl)methylene)-1-(2-methylprop-1-en-
1-yl)hexahydro-1H-pyrrolizine (7c). The crude residue obtained from
the reaction of 1c (0.0737 g, 0.26 mmol) with Ph CBF (0.17 g, 0.52
mmol) in CH Cl (26 mL) was purified by flash column
chromatography to give 7c (37 mg, 0.13 mmol, 50%) as a yellow
1
(
s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ 141.1, 130.0, 128.3,
1
3
3
4
1
2
1
1
28.2, 125.1, 122.3, 84.6, 79.7, 70.5, 64.6, 52.4, 41.2, 31.8, 29.8, 29.7,
2
2
2.1; IR (CH Cl ) 3386, 2970, 2822, 2338, 2231, 1676, 1459, 1359,
2
2
−1
+
1
148, 974, 780 cm ; MS (ESI) m/e (%) 276.5 ([M + H] , 100),
21.4 (2); HRMS (ESI) calcd. for C H NOS [M + H] 276.1422,
oil: H NMR (400 MHz, CDCl
= 8.1 Hz, 2H), 5.02 (dt, J = 9.6, 1.4 Hz, 1H), 3.94 (dt, J = 16.3, 2.2 Hz,
H), 3.75 (dd, J = 16.1, 3.1 Hz, 1H), 3.45−3.36 (m, 1H), 3.28−3.19
m, 1H), 3.05 (ddd, J = 10.2, 8.0, 4.2 Hz, 1H), 2.62 (dt, J = 10.1, 8.0
Hz, 1H), 2.35 (s, 3H), 2.07−1.98 (m, 1H), 1.98−1.86 (m, 1H), 1.85−
3
) δ 7.28 (d, J = 8.2 Hz, 2H), 7.12 (d, J
+
16
22
1
(
found 276.1421.
(E)-3-Methyl-1-(1-(3-phenylprop-2-yn-1-yl)pyrrolidin-2-yl)pent-1-
en-3-ol (1s). (0.16 g, 0.55 mmol, 55%). Compound 1s was obtained as
a mixture of diastereomers. A yellow oil: H NMR (400 MHz, CDCl )
δ 7.46−7.40 (m, 2H + 2H′), 7.32−7.27 (m, 3H + 3H′), 5.75 (d, J =
1
1
13
1
1.77 (m, 1H), 1.65 (d, J = 1.1 Hz, 3H), 1.62−1.54 (m, 4H); C{ H}
NMR (100 MHz, CDCl ) δ 151.2 (d, J = 237.6 Hz), 138.1, 131.8,
3
3
5.7 Hz, 1H), 5.74 (d, J = 15.8 Hz, 1H′), 5.52 (dd, J = 15.6, 8.4 Hz,
H), 5.50 (dd, J = 15.7, 8.5 Hz, 1H′), 3.72 (d, J = 17.0 Hz, 1H), 3.72
129.5 (d, J = 30.1 Hz), 128.4 (2C), 126,7 (d, J = 6.1 Hz, 2C), 125.7,
122.3 (d, J = 21.7 Hz), 73.8, 55.5 (d, J = 5.2 Hz), 54.0, 45.7 (d, J = 3.7
1
Hz), 29.8, 25.5, 24.5, 21.3, 18.1; 19F NMR (376 MHz, CDCl
) δ
−105.0; IR (CH Cl ) 2971, 2929, 2474, 1671, 1607, 1449, 1375, 1297,
2 2
(
1
d, J = 17.0 Hz, 1H′), 3.48 (d, J = 17.0 Hz, 1H), 3.47 (d, J = 16.9 Hz,
3
H′), 3.17−3.11 (m, 1H + 1H′), 3.06−2.98 (m, 1H + 1H′), 2.64 (q, J
−1
+
1
109, 823 cm ; MS (ESI) m/e (%) 286.2 ([M + H] , 100), 276.1 (5);
=
8.8 Hz, 1H), 2.64 (q, J = 8.8 Hz, 1H′), 2.04−1.94 (m, 1H + 1H′),
+
HRMS (ESI) calcd. for C H FN [M + H] 286.1971, found
1
1
1
3
1
5
2
.91−1.82 (m, 1H + 1H′), 1.82−1.74 (m, 1H + 1H′), 1.69−1.61 (m,
H + 1H′), 1.61−1.54 (m, 2H + 2H′), 1.53−1.39 (br s., 1H + 1H′),
.30 (s, 3H), 1.28 (s, 3H′), 0.90 (t, J = 7.4 Hz, 3H), 0.89 (t, J = 7.5 Hz,
19 25
2
86.1972.
(
1S*,7aR*,Z)-2-([1,1′-Biphenyl]-4-ylfluoromethylene)-1-(2-meth-
13
1
ylprop-1-en-1-yl)hexahydro-1H-pyrrolizine (7d). The crude residue
obtained from the reaction of 1d (90 mg, 0.26 mmol) with Ph CBF
4
H′); C{ H} NMR (100 MHz, CDCl ) δ 140.0, 139.9, 131.7 (2C),
3
29.2, 129.1, 128.2 (2C), 127.9, 123.3, 84.9, 84.7, 73.0, 72.9, 64.6, 52.3,
2.2, 41.1, 35.2, 35.2, 31.9, 27.5, 27.3, 22.1, 8.4, 8.3; IR (CH Cl ) 3406,
3
(
0.17 g, 0.52 mmol) in CH Cl (26 mL) was purified by flash column
2 2
2
2
−
1
chromatography to give 7d (36 mg, 0.10 mmol, 40%) as a yellow oil:
967, 2329, 2231, 1598, 1460, 1367, 1151, 976, 756, 692 cm ; MS
1
+
H NMR (400 MHz, CDCl ) δ 7.60 (d, J = 7.2 Hz, 2H), 7.56 (d, J =
3
(
ESI) m/e (%) 284.7 ([M + H] , 100), 268.4 (4); HRMS (ESI) calcd.
+
8.2 Hz, 2H), 7.48−7.43 (m, 4H), 7.39−7.34 (m, 1H), 5.06 (d, J = 9.6
Hz, 1H), 4.05 (d, J = 16.2 Hz, 1H), 3.83 (dd, J = 16.2, 2.9 Hz, 1H),
for C H NO [M + H] 284.2014, found 284.2013.
19
26
General Experimental Procedure for Ph CBF -Promoted
3
4
3
.53−3.45 (m, 1H), 3.41−3.32 (m, 1H), 3.23−3.13 (m, 1H), 2.67 (dt,
Carbofluorination of (E)-2-Methyl-4-(1-(3-phenyprop-2-yn-1-
yl)pyrrolidin-2-yl)but-3-en-2-ol (1a). Synthesis of (1S*,7aR*,Z)-2-
J = 10.0, 8.1 Hz, 1H), 2.15−2.05 (m, 1H), 2.02−1.92 (m, 1H), 1.91−
1
3
1
(
Fluoro(phenyl)methylene)-1-(2-methylprop-1-en-1- yl)hexahydro-
1.83 (m, 1H), 1.69 (d, J = 0.7 Hz, 3H), 1.67−1.60 (m, 4H); C{ H}
1
H-pyrrolizine (7a). To a solution of Ph CBF (0.17 g, 0.52 mmol)
NMR (100 MHz, CDCl ) δ 151.2 (d, J = 238.8 Hz), 141.1, 140.4,
3
4
3
in CH Cl (26 mL) was added 1a (70 mg, 0.26 mmol) at room
132.5, 131.0 (d, J = 29.6 Hz), 128.8 (2C), 127.6, 127.3 (d, J = 6.1 Hz,
2C), 127.0 (2C), 126.4 (2C), 125.2, 122.5 (d, J = 22.1 Hz), 73.8, 55.4
2
2
temperature under nitrogen. The mixture was stirred for 25 min until
a was disappeared as monitored by TLC. The reaction mixture was
1
9
1
(d, J = 5.5 Hz), 54.1, 45.6 (d, J = 3.4 Hz), 29.9, 25.5, 24.5, 18.2; F
quenched with saturated NaHCO (10 mL). The resulting mixture
NMR (376 MHz, CDCl ) δ −98.3; IR (CH Cl ) 2923, 2345, 2654,
3
3
2
2
−1
was extracted with DCM (3 × 30 mL). The organic phase was dried
over MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (EtOAc/hexanes
1447, 1379, 1265, 1077, 845, 734, 699 cm ; MS (ESI) m/e (%) 348.2
+
([M + H] , 100), 328.3 (5); HRMS (ESI) calcd. for C H FN [M +
2
4
27
+
H] 348.2128, found 348.2129.
H
DOI: 10.1021/acs.joc.5b02025
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
1S*,7aR*,Z*)-2-(Fluoro(3-methoxyphenyl)methylene)-1-(2-
= 29.3 Hz), 133.0, 130.0, 129.3, 128.9 (2C), 126.6 (d, J = 6.5 Hz, 2C),
124.5, 73.8, 61.1, 55.6 (d, J = 5.5 Hz), 54.1, 45.6 (d, J = 2.9 Hz), 29.8,
methylprop-1-en-1-yl)hexahydro-1H-pyrrolizine (7f). The crude
residue obtained from the reaction of 1f (78 mg, 0.26 mmol) with
Ph CBF (0.17 g, 0.52 mmol) in CH Cl (26 mL) was purified by flash
25.5, 24.4, 28.2, 14.3; 19F NMR (376 MHz, CDCl ) δ −105.4; IR
3
−1
3
4
2
2
(CH Cl ) 2936, 2475, 1719, 1366, 1277, 1106, 1080, 773, 739 cm ;
MS (ESI) m/e (%) 344.2 ([M + H] , 100); HRMS (ESI) calcd. for
2
2
+
column chromatography to give 7f (41 mg, 0.14 mmol, 52%) as a
yellow oil: H NMR (400 MHz, CDCl ) δ 7.26 (t, J = 7.9 Hz, 1H),
1
+
3
C H FNO [M + H] 344.2026, found 344.2031.
21 27
2
7
1
3
.02−6.94 (m, 2H), 6.89 (dd, J = 8.3, 2.4 Hz, 1H), 5.13 (d, J = 9.4 Hz,
H), 4.23 (d, J = 16.1 Hz, 1H), 3.89 (dd, J = 15.9, 2.7 Hz, 1H), 3.80 (s,
H), 3.68−3.63 (m, 1H), 3.55−3.44 (m, 2H), 2.75 (dt, J = 10.8, 8.1
(1S*,7aR*,Z)-2-(Fluoro(3-nitrophenyl)methylene)-1-(2-methyl-
prop-1-en-1-yl)hexahydro-1H-pyrrolizine (7k). The crude residue
obtained from the reaction of 1k (82 mg, 0.26 mmol) with Ph CBF
3
4
Hz, 1H), 2.25−2.16 (m, 1H), 2.03−1.92 (m, 2H), 1.71−1.61 (m, 7H);
(0.17 g, 0.52 mmol) in CH Cl (26 mL) was purified by flash column
2 2
1
3
1
C{ H} NMR (100 MHz, CDCl ) δ 159.3, 152.3 (d, J = 243.4 Hz),
chromatography to give 7k (41 mg, 0.13 mmol, 50%) as a yellow oil:
3
1
133.8, 132.6 (d, J = 28.7 Hz), 129.0, 124.1, 119.5 (d, J = 6.0 Hz), 119.1
H NMR (400 MHz, CDCl ) δ 8.27 (t, J = 1.8 Hz, 1H), 8.14 (ddd, J =
3
(
6
(
2
d, J = 17.9 Hz), 114.6, 112.8 (d, J = 6.0 Hz), 73.3, 55.3, 54.5 (d, J =
.3 Hz), 54.4, 45.1 (d, J = 3.4 Hz), 30.4, 25.5, 24.5, 18.2; F NMR
8.3, 2.2, 1.0 Hz, 1H), 7.73 (dt, J = 7.9, 1.2 Hz, 1H), 7.50 (t, J = 8.1 Hz,
1H), 4.97−4.90 (m, 1H), 4.01 (dt, J = 16.7, 2.4 Hz, 1H), 3.84 (dd, J =
16.9, 3.4 Hz, 1H), 3.52−3.45 (m, 1H), 3.33−3.26 (m, 1H), 3.10 (ddd,
J = 10.1, 8.0, 4.0 Hz, 1H), 2.62 (dt, J = 10.0, 8.0 Hz, 1H), 2.14−2.05
(m, 1H), 2.03−1.94 (m, 1H), 1.92−1.83 (m, 1H), 1.73−1.65 (m, 4H),
19
376 MHz, CDCl ) δ −98.6; IR (CH Cl ) 3050, 2929, 2966, 2415,
3
2
2
348, 2305, 1680, 1600, 1581, 1453, 1433, 1290, 1228, 1044, 736
−1
+
cm ; MS (APCI) m/e (%) 302.2 ([M + H] , 100); HRMS (APCI):
calcd. for C H FNO [M + H] 302.1920, found 302.1912.
+
13
1
1.59 (d, J = 1.2 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 148.8
19
25
3
(
1S*,7aR*,Z)-2-(Fluoro(3-(trifluoromethyl)phenyl)methylene)-1-
(d, J = 237.8 Hz), 147.9, 134.3, 133.6 (d, J = 31.1 Hz), 132.2 (d, J =
6.1 Hz), 128.8, 126.6 (d, J = 19.5 Hz), 124.1, 122.9, 122.2 (d, J = 7.0
Hz), 74.2, 55.7 (d, J = 5.4 Hz), 53.9, 45.5 (d, J = 2.8 Hz), 29.6, 25.5,
24.4, 18.2; 19F NMR (376 MHz, CDCl ) δ −106.4; IR (CH Cl )
(
2-methylprop-1-en-1-yl)hexahydro-1H-pyrrolizine (7h). The crude
residue obtained from the reaction of 1h (88 mg, 0.26 mmol) with
Ph CBF (0.17 g, 0.52 mmol) in CH Cl (26 mL) was purified by flash
3
4
2
2
3
2
2
−1
column chromatography to give 7h (49 mg, 0.14 mmol, 55%) as a
yellow oil: H NMR (400 MHz, CDCl ) δ 7.65 (s,1H), 7.59 (d, J = 7.8
Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 4.95 (dt, J
2920, 2610, 2224, 1738, 1531, 1090, 923 cm ; MS (ESI) m/e (%)
1
+
3
317.2 ([M + H] , 100); HRMS (ESI) calcd. for C H FN O [M +
18 22
2
2
+
H] 317.1665, found 317.1666.
=
9.4, 1.4 Hz, 1H), 4.00 (dt, J = 16.6, 2.2 Hz, 1H), 3.81 (dd, J = 16.6,
(1S*,7aR*,Z)-2-(Fluoro(4-nitrophenyl)methylene)-1-(2-methyl-
3
=
.2 Hz, 1H), 3.49−3.38 (m, 1H), 3.28 (q, J = 5.5 Hz, 1H), 3.09 (ddd, J
prop-1-en-1-yl)hexahydro-1H-pyrrolizine (7l). The crude residue
10.1, 8.0, 4.0 Hz, 1H), 2.62 (dt, J = 10.0, 8.0 Hz, 1H), 2.12−2.03 (m,
obtained from the reaction of 1l (82 mg, 0.26 mmol) with Ph
(0.17 g, 0.52 mmol) in CH Cl (26 mL) was purified by flash column
chromatography to give 7l (48 mg, 0.15 mmol, 58%) as a yellow oil:
3 4
CBF
1
1
H), 2.02−1.92 (m, 1H), 1.90−1.82 (m, 1H), 1.71−1.60 (m, 4H),
2
2
.58 (d, J = 0.9 Hz, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ 149.6
1
3
1
(
1
=
d, J = 237.3 Hz), 133.3, 132.9 (d, J = 30.6 Hz), 130.2 (q, J = 32.3 Hz),
29.7 (d, J = 6.1 Hz), 128.3, 125.6 (d, J = 21.0 Hz), 124.8, 124.8 (q, J
3.7 Hz), 124.0 (q, J = 272.4 Hz), 123.9 (qd, J = 7.7, 3.9 Hz), 74.1,
H NMR (400 MHz, CDCl ) δ 8.19 (d, J = 8.8 Hz, 2H), 7.56 (d, J =
3
9.0 Hz, 2H), 5.01−4.92 (m, 1H), 4.03 (dt, J = 16.9, 2.4 Hz, 1H), 3.86
(dd, J = 16.9, 3.2 Hz, 1H), 3.53−3.46 (m, 1H), 3.36−3.28 (m, 1H),
3.11 (ddd, J = 10.2, 8.0, 4.1, 1H), 2.63 (dt, J = 10.1, 8.1 Hz, 1H),
2.17−2.07 (m, 1H), 2.04−1.95 (m, 1H), 1.94−1.85 (m, 1H), 1.76 (d, J
5
5.7 (d, J = 5.3 Hz), 53.9, 45.5 (d, J = 3.2 Hz), 29.6, 25.3, 24.4, 18.0;
1
9
F NMR (376 MHz, CDCl ) δ −63.6, −105.8; IR (CH Cl ) 2154,
3
2
2
−1
+
13
1
1
2
3
642, 1265, 723 cm . MS (EI) m/e (%) 339.2 (M , 100), 270.1 (18),
56.0 (16), 201.1 (13); HRMS (ESI) calcd. for C H NF [M ]
39.1610, found 339.1611.
Ethyl 3-((Z)-Fluoro((1S*,7aR*)-1-(2-methylprop-1-en-1-yl)-
= 1.2 Hz, 3H), 1.71−1.64 (m, 1H), 1.62 (d, J = 1.1 Hz, 3H); C{ H}
NMR (100 MHz, CDCl ) δ 149.1 (d, J = 237.3 Hz), 147.0, 138.1 (d, J
+
19
21
4
3
= 29.8 Hz), 133.3, 128.9 (d, J = 20.7 Hz), 127.3 (d, J = 6.7 Hz, 2C),
124.4, 122.9 (2C), 74.1, 56.0 (d, J = 5.3 Hz), 53.9, 45.9 (d, J = 2.7 Hz),
tetrahydro-1H-pyrrolizin- 2(3H)-ylidene)methyl)benzoate (7i). The
crude residue obtained from the reaction of 1i (89 mg, 0.26 mmol)
with Ph CBF (0.17 g, 0.52 mmol) in CH Cl (26 mL) was purified by
flash column chromatography to give 7i (46 mg, 0.14 mmol, 52%) as a
yellow oil: H NMR (400 MHz, CDCl ) δ 8.05 (t, J = 1.8 Hz, 1H),
29.7 (d, J = 5.7 Hz), 25.5, 24.3, 18.2; 19F NMR (376 MHz, CDCl ) δ
3
−106.9; IR (CH Cl ) 2928, 2853, 2527, 2246, 1734, 1521, 1346, 1091,
2
2
−1
+
950, 855 cm ; MS (ESI) m/e (%) 317.2 ([M + H] , 100), 297.2 (20);
HRMS (ESI) calcd. for C H FN O [M + H] 317.1665, found
3
4
2
2
+
18
22
2
2
1
317.1668.
3
7
1
.96 (dt, J = 7.8, 1.2 Hz, 1H), 7.58−7.52 (m, 1H), 7.38 (t, J = 7.8 Hz,
(1S*,7aR*,Z)-2-((4-Chlorophenyl)fluoromethylene)-1-(2-methyl-
H), 4.90 (dt, J = 9.5, 1.2 Hz, 1H), 4.39 (q, J = 7.0 Hz, 2H), 3.98 (dt, J
prop-1-en-1-yl)hexahydro-1H-pyrrolizine (7m). The crude residue
=
1
(
16.4, 2.3 Hz, 1H), 3.79 (dd, J = 16.7, 3.3 Hz, 1H), 3.51−3.41 (m,
H), 3.29−3.19 (m, 1H), 3.08 (ddd, J = 10.1, 8.0, 4.0 Hz, 1H), 2.63
dt, J = 10.0, 8.1 Hz, 1H), 2.10−2.01 (m, 1H), 1.99−1.92 (m, 1H),
obtained from the reaction of 1m (79 mg, 0.26 mmol) with Ph
(0.17 g, 0.52 mmol) in CH Cl (26 mL) was purified by flash column
chromatography to give 7m (48 mg, 0.16 mmol, 60%) as a yellow oil:
3 4
CBF
2
2
1
1
.87−1.82 (m, 1H), 1.69−1.61 (m, 4H), 1.53 (d, J = 1.0 Hz, 3H), 1.40
H NMR (400 MHz, CDCl ) δ 7.31 (d, J = 8.8 Hz, 2H), 7.28 (d, J =
3
t, J = 7.2 Hz, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ 166.1, 150.2
1
(
(
8.8 Hz, 2H), 4.95 (d, J = 9.6 Hz, 1H), 3.94 (dt, J = 16.4, 2.0 Hz, 1H),
3.76 (dd, J = 16.3, 3.1 Hz, 1H), 3.43−3.34 (m, 1H), 3.28−3.19 (m,
1H), 3.06 (ddd, J = 10.2, 8.0, 4.0 Hz, 1H), 2.60 (dt, J = 10.0, 8.0 Hz,
1H), 2.10−2.00 (m, 1H), 1.99−1.89 (m, 1H), 1.87−1.79 (m, 1H),
3
d, J = 238.7 Hz), 133.0, 132.4 (d, J = 30.2 Hz), 131.1 (d, J = 5.7 Hz),
130.1, 129.3, 128.2 (d, J = 6.1 Hz), 127.7, 124.6, 124.1 (d, J = 21.0
Hz), 73.7, 61.0, 55.3 (d, J = 5.2 Hz), 53.9, 45.3 (d, J = 3.2 Hz), 29.6,
5.4, 24.3, 18.1, 14.3; 19F NMR (376 MHz, CDCl ) δ −104.5; IR
13
1
2
1.66 (d, J = 0.8 Hz, 3H), 1.64−1.57 (m, 4H); C{ H} NMR (100
MHz, CDCl ) δ 150.0 (d, J = 237.5 Hz), 134.0, 132.4, 130.7 (d, J = 30
3
−1
(
CH Cl ) 2930, 2430, 1637, 1309, 1106, 739 cm ; MS (ESI) m/e
3
2
2
+
(
%) 344.2 ([M + H] , 100), 279.2 (10); HRMS (ESI) calcd. for
0.4 Hz), 128.2 (d, J = 6.1 Hz, 2C), 127.8 (2C), 125.1, 124.2 (d, J =
+
C H FNO [M + H] 344.2026, found 344.2026.
21.2 Hz), 73.9, 55.6 (d, J = 5.1 Hz), 53.9, 45.6 (d, J = 3.4 Hz), 29.7,
21
27
2
25.5, 24.4, 18.1; 19F NMR (376 MHz, CDCl
) δ −105.3; IR (CH
Cl )
2
Ethyl 4-((Z)-Fluoro((1S*,7aR*)-1-(2-methylprop-1-en-1-yl)-
3
2
−1
tetrahydro-1H-pyrrolizin- 2(3H)-ylidene)methyl)benzoate (7j). The
crude residue obtained from the reaction of 1j (89 mg, 0.26 mmol)
with Ph CBF (0.17 g, 0.52 mmol) in CH Cl (26 mL) was purified by
2922, 2197, 1974, 1655, 1382, 1091, 739 cm ; MS (ESI) m/e (%)
+
+
308.1 ([M + 2 + H] , 25), 306.1 ([M + H] , 100), 302.1 (5); HRMS
+
3
4
2
2
(ESI) calcd. for C H ClFN [M + H] 306.1425, found 306.1418.
18 22
flash column chromatography to give 7j (43 mg, 0.12 mmol, 48%) as a
(1S*,7aR*,Z)-2-((4-Bromophenyl)fluoromethylene)-1-(2-methyl-
1
yellow oil: H NMR (400 MHz, CDCl ) δ 7.98 (d, J = 8.4 Hz, 2H),
prop-1-en-1-yl)hexahydro-1H-pyrrolizine (7n). The crude residue
3
7
2
3
.45 (d, J = 8.4 Hz, 2H), 4.98 (d, J = 9.6 Hz, 1H), 4.39 (q, J = 7.1 Hz,
H), 3.98 (d, J = 16.6 Hz, 1H), 3.81 (dd, J = 16.6, 3.0 Hz, 1H), 3.51−
.42 (m, 1H), 3.27 (q, J = 5.3 Hz, 1H), 3.14−3.02 (m, 1H), 2.67−2.56
obtained from the reaction of 1n (91 mg, 0.26 mmol) with Ph
(0.17 g, 0.52 mmol) in CH Cl (26 mL) was purified by flash column
chromatography to give 7n (60 mg, 0.17 mmol, 66%) as a yellow oil:
3 4
CBF
2
2
1
(
1
m, 1H), 2.10−2.02 (m, 1H), 2.00−1.89 (m, 1H), 1.89−1.79 (m, 1H),
H NMR (400 MHz, CDCl ) δ 7.44 (d, J = 8.5 Hz, 2H), 7.25 (d, J =
3
13
1
.71 (s, 3H), 1.67−1.56 (m, 4H), 1.40 (t, J = 7.1 Hz, 3H); C{ H}
8.6 Hz, 2H), 4.96 (d, J = 9.6 Hz, 1H), 3.94 (dt, J = 16.4, 2.2 Hz, 1H),
3.76 (dd, J = 16.4, 3.1 Hz, 1H), 3.43−3.33 (m, 1H), 3.30−3.21 (m,
NMR (100 MHz, CDCl ) δ 166.1, 150.5 (d, J = 239.0 Hz), 136.0 (d, J
3
I
DOI: 10.1021/acs.joc.5b02025
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
1
1
1
H), 3.08 (ddd, J = 10.3, 8.1, 4.1 Hz, 1H), 2.60 (dt, J = 9.9, 8.2 Hz,
H), 2.10−2.01 (m, 1H), 1.99−1.89 (m, 1H), 1.88−1.79 (m, 1H),
1.59 (d, J = 1.3 Hz, 3H), 1.53 (d, J = 1.3 Hz, 3H); 13C{ H} NMR (150
MHz, CDCl ) δ 199.9, 137.1, 135.1, 133.1, 128.5 (2C), 128.5 (2C),
124.2, 71.7, 58.3, 54.9, 54.6, 48.6, 29.9, 25.7, 25.2, 18.2; IR (CH Cl )
2923, 2854, 1676, 1596, 1443, 1375, 1241, 1221, 1097, 998, 834 cm ;
MS (ESI) m/e (%) 270.2 ([M + H] , 100), 268.2 (5); HRMS (ESI)
calcd. for C H NO [M + H] 270.1858, found 270.1862.
((1S*,2S*,7aR*)-1-(2-Methylprop-1-en-1-yl)hexahydro-1H-pyrro-
lizin-2-yl)(m-tolyl)methanone (8b). The solution of 1b (74 mg, 0.26
mmol) in CH Cl (2.6 mL) was added NHTf (0.15 g, 0.52 mmol).
2 2 2
The crude mixture was purified by flash column chromatography to
give 8b (27 mg, 0.09 mmol, 36%) as a yellow oil: H NMR (400 MHz,
CDCl ) δ 7.75−7.70 (m, 2H), 7.38−7.30 (m, 2H), 5.03−4.96 (m,
3
13
1
.66 (d, J = 0.7 Hz, 3H), 1.64−1.5 (m, 4H); C{ H} NMR (100
2
2
−
1
MHz, CDCl ) δ 150.1 (d, J = 237.8 Hz), 132.4, 131.1 (d, J = 30.3 Hz),
3
+
130.8 (2C), 128.4 (d, J = 6.1 Hz, 2C), 125.1, 124.2 (d, J = 21.2 Hz),
122.3, 73.8, 55.6 (d, J = 5.1 Hz), 54.0, 45.6 (d, J = 3.2 Hz), 29.7, 25.5,
2
4.4, 18.1; 19F NMR (376 MHz, CDCl ) δ −105.6; IR (CH Cl )
2
1
3
+
18
24
3
2
2
967, 2929, 2538, 1912, 1686, 1676, 1487, 1446, 1395, 1287, 1160,
−
1
+
091, 1010, 828 cm ; MS (ESI) m/e (%) 352.1 ([M + 2 + H] , 100),
+
50.1 ([M + H] , 100), 311.2 (5); HRMS (ESI) calcd. for
+
1
C H BrFN [M + H] 350.0920, found 350.0913.
18
22
(
1S*,7aR*,Z)-2-(Fluoro(thiophen-3-yl)methylene)-1-(2-methyl-
3
prop-1-en-1-yl)hexahydro-1H-pyrrolizine (7r). The crude residue
obtained from the reaction of 1r (83 mg, 0.30 mmol) with Ph CBF4
1H), 3.96 (td, J = 10.0, 7.6 Hz, 1H), 3.55 (dd, J = 10.2, 7.6 Hz, 1H),
3.46−3.41 (m, 1H), 3.08−3.00 (m, 2H), 2.86 (t, J = 10.1 Hz, 1H),
2.78−2.72 (m, 1H), 2.40 (s, 3H), 2.04−1.91 (m, 2H), 1.89−1.81 (m,
1H), 1.71−1.65 (m, 1H), 1.60 (d, J = 1.0 Hz, 3H), 1.54 (d, J = 1.0 Hz,
3
(0.20 g, 0.60 mmol) in CH Cl (30 mL) was purified by flash column
2 2
chromatography to give 7r (11 mg, 0.04 mmol, 14%) as a brown oil:
1
13
1
H NMR (400 MHz, CDCl ) δ 7.32−7.31 (m, 1H), 7.27−7.24 (m,
3H); C{ H} NMR (100 MHz, CDCl
133,9, 129,1, 128.4, 125.7, 124.3, 71.6, 58.3, 54.8, 54.7, 48.5, 30.0, 25.8,
25.2, 21.3, 18.2; IR (CH Cl ) 3406, 2969, 2924, 2536, 2484, 2377,
3
) δ 200.1, 138.3, 137.2, 135.0,
3
1
H), 7.14 (d, J = 5.1, 1.1 Hz, 1H), 5.14 (d, J = 9.2 Hz, 1H), 3.91 (dt, J
=
1
(
16.2, 2.3 Hz, 1H), 3.74 (dd, J = 16.0, 3.1 Hz, 1H), 3.41−3.37 (m,
H), 3.30−3.25 (m, 1H), 3.03 (ddd, J = 10.3, 8.0, 4.3 Hz, 1H), 2.59
dt, J = 10.2, 7.8 Hz, 1H), 2.11−2.03 (m, 1H), 1.97−1.88 (m, 1H),
2
2
−
1
2347, 1677, 1445, 1376, 1260, 1182, 1162, 1023, 999, 731, 683 cm ;
MS (ESI) m/e (%) 284.2 ([M + H] , 100); HRMS (ESI) calcd. for
+
+
C H NO [M + H] 284.2014, found 284.2012.
1
1
=
.85−1.77 (m, 1H), 1.72 (d, J = 1.1 Hz, 3H), 1.67 (d, J = 1.0 Hz, 3H),
19 26
13
1
(
(1S*,2S*,7aR*)-1-(2-Methylprop-1-en-1-yl)hexahydro-1H-pyrro-
lizin-2-yl)(p-tolyl)methanone (8c). The solution of 1c (74 mg, 0.26
mmol) in CH Cl (2.6 mL) was added NHTf (0.15 g, 0.52 mmol).
The crude mixture was purified by flash column chromatography to
give 8c (27 mg, 0.09 mmol, 36%) as a yellow oil: H NMR (400 MHz,
.66−1.60 (m, 1H); C{ H} NMR (100 MHz, CDCl ) δ 148.2 (d, J
3
234.2 Hz), 133.8 (d, J = 33.6 Hz), 132.0, 126.2 (d, J = 1.4 Hz), 126.0
(
d, J = 5.3 Hz), 124.9, 122.9 (d, J = 6.7 Hz), 122.1 (d, J = 21.1 Hz),
2
2
2
7
1
2
4.1, 55.2 (d, J = 4.7 Hz), 53.8, 45.7 (d, J = 3.7 Hz), 30.1, 25.6, 24.4,
1
8.3; 19F NMR (376 MHz, CDCl ) δ −104.7; IR (CH Cl ) 3712,
3
2
2
−
1
CDCl ) δ 7.83 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 5.00−4.96
925, 2435, 1673, 1446, 1376, 1246, 1188, 1090, 838, 789 cm ; MS
3
+
(m, 1H), 3.89 (td, J = 9.9, 7.6 Hz, 1H), 3.47 (dd, J = 10.0, 7.6 Hz, 1H),
3.35−3.30 (m, 1H), 3.03 (q, J = 9.7 Hz, 1H), 2.99−2.93 (m, 1H), 2.82
(
ESI) m/e (%), 278.5 ([M + H] , 100); HRMS (ESI) calcd. for
+
C H NFS [M + H] 278.1379, found 278.1378.
16
21
(
t, J = 9.9 Hz, 1H), 2.73−2.67 (m, 1H), 2.40 (s, 3H), 1.98−1.86 (m,
(
1S*,7aR*,Z)-2-(Fluoro(phenyl)methylene)-1-(2-methylbut-1-en-
2
3
1
5
2
1
H), 1.84−1.76 (m, 1H), 1.68−1.61 (m, 1H), 1.60 (d, J = 1.0 Hz,
1
-yl)hexahydro-1H-pyrrolizine (7s). The crude residue obtained from
H), 1.55 (d, J = 1.1 Hz, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ
1
the reaction of 1s (85 mg, 0.30 mmol) with Ph CBF (0.20 g, 0.60
mmol) in CH Cl2 (30 mL) was purified by flash column
chromatography to give 7s (52 mg, 0.18 mmol, 60%) as a mixture
of E and Z isomers: H NMR (400 MHz, CDCl ) δ 7.44−7.36 (m, 2H
+
3
3
4
99.9, 143.8, 134.9, 134.4, 129.1 (2C), 128.6 (2C), 125.0, 71.8, 58.7,
5.0 (2C), 48.5, 30.1, 25.8, 25.3, 21.6, 18.2; IR (CH Cl ) 2964, 2927,
690, 2357, 1982, 1674, 1597, 1578, 1448, 1377, 1250, 1185, 1069,
002, 704 cm ; MS (ESI) m/e (%) 284.2 ([M + H] , 100), 270.2
2
2
2
1
3
−1
+
2H′), 7.34−7.26 (m, 3H + 3H′), 5.03 (d, J = 9.5 Hz, 1H′), 5.00−
+
(
15); HRMS (ESI) calcd. for C H NO [M + H] 284.2014,
4
1
3
1
.94 (m, 1H), 4.02−3.92 (m, 1H + 1H′), 3.78 (dd, J = 16.2, 3.1 Hz,
H), 3.76 (dd, J = 16.1, 3.2 Hz, 1H′), 3.48−3.42 (m, 1H + 1H′),
.29−3.22 (m, 1H + 1H′), 3.12−3.05 (m, 1H + 1H′), 2.63 (dt, J =
0.0, 8.0 Hz, 1H + 1H′), 2.21−1.97 (m, 2H + 2H′), 1.97−1.90 (m, 1H
19 26
2
84.2006.
(
(1S*,2S*,7aR*)-1-(2-Methylprop-1-en-1-yl)hexahydro-1H-pyrro-
lizin-2-yl) (naphthalen-1-yl)methanone (8e). The solution of 1e (83
mg, 0.26 mmol) in CH Cl (2.6 mL) was added NHTf (0.15 g, 0.52
mmol). The crude mixture was purified by flash column chromatog-
raphy to give 8e (17 mg, 0.05 mmol, 20%) as a yellow oil: H NMR
400 MHz, CDCl ) δ 8.42 (dd, J = 8.4, 0.9 Hz, 1H), 7.96 (d, J = 8.2
+
1H′), 1.89−1.80 (m, 2H + 2H′), 1.66−1.59 (m, 4H), 1.59−1.54 (m,
2
2
2
13
1
4
H′), 0.99 (t, J = 7.6 Hz, 3H′), 0.97 (t, J = 7.5 Hz, 3H); C{ H}
1
NMR (100 MHz, CDCl ) δ 151.1 (d, J = 238.3 Hz), 151.1 (d, J =
3
(
2
1
38.1 Hz), 137.4, 137.3, 132.3 (d, J = 29.6 Hz), 132.3 (d, J = 30.0 Hz),
28.2, 128.2, 127.7 (2C), 127.7 (2C), 127.0 (d, J = 5.9 Hz, 2C), 127.0
3
Hz, 1H), 7.88−7.85 (m, 1H), 7.76 (dd, J = 7.2, 1.0 Hz, 1H), 7.58−
.46 (m, 3H), 4.97−4.92 (m, 1H), 3.94 (td, J = 10.0, 7.5 Hz, 1H), 3.53
dd, J = 10.1, 7.5 Hz, 1H), 3.38−3.33 (m, 1H), 3.11−2.97 (m, 3H),
7
(
(
5
d, J = 5.8 Hz, 2C), 125.3, 124.0, 123.3 (d, J = 21.6 Hz), 73.9, 73.8,
5.5 (d, J = 5.2 Hz), 55.4 (d, J = 5.6 Hz), 54.1, 54.0, 45.4 (d, J = 3.6
Hz), 45.3 (d, J = 3.8 Hz), 32.2, 29.9, 29.8, 24.9, 24.5, 24.4, 22.4, 16.3,
2
.78 (dt, J = 10.5, 6.4 Hz, 1H), 2.03−1.81 (m, 3H), 1.69−1.64 (m,
13
1
2.4; 1 F NMR (376 MHz, CDCl ) δ −104.5, −104.6; IR (CH Cl )
9
1H), 1.52 (s, 6H); C{ H} NMR (100 MHz, CDCl ) δ 204.5, 137.0,
3
1
3
3
2
2
−1
134.7, 133.8, 132.3, 130.0, 128.3, 127.7, 127.4, 126.4, 125.6, 124.5,
124.5, 124.3, 71.7, 58.9, 58.4, 55.1, 49.3, 30.0, 25.7, 25.3, 18.2; IR
(CH Cl ) 3367, 3049, 2970, 2925, 2437, 2359, 1681, 1506, 1445,
376, 1266, 1244, 1179, 1111, 1043, 804 cm ; MS (ESI) m/e (%)
20.2 ([M + H] , 100), 311.2 (5); HRMS (ESI) calcd. for C H NO
357, 2966, 1684, 1446, 1272, 1051, 766, 696 cm ; MS (ESI) m/e
+
(
%), 286.6 ([M + H] , 100); HRMS (ESI) calcd. for C H NF [M +
19 25
+
2
2
H] 286.1971, found 286.1973.
−1
1
3
General Experimental for the NHTf -Promoted Cycloisome-
2
+
rization of (E)-2-Methyl-4-(1-(3-phenylprop-2-yn-1-yl)-
22 26
+
pyrrolidin-2-yl)but-3-en-2-ol (1a). Synthesis of ((1S*,2S*,7aR*)-
[M + H] 320.2014, found 320.2013.
1
-(2-Methylprop-1-en-1-yl)hexahydro-1H-pyrrolizin-2-yl)(phenyl)-
(3-Methoxyphenyl)((1S*,2S*,7aR*)-1-(2-methylprop-1-en-1-yl)-
hexahydro-1H-pyrrolizin-2-yl)methanone (8f). The solution of 1f
(78 mg, 0.26 mmol) in CH Cl (2.6 mL) was added NHTf (0.15 g,
2 2 2
0.52 mmol). The crude mixture was purified by flash column
chromatography to give 8f (23 mg, 0.08 mmol, 30%) as a yellow oil:
H NMR (400 MHz, CDCl ) δ 7.50 (d, J = 7.6 Hz, 1H), 7.46−7.45
methanone (8a). A solution of 1a (0.0700 g, 0.26 mmol) in CH Cl
2
2
(2.6 mL) was added NHTf (0.15 g, 0.52 mmol). The mixture was
2
stirred for 1 min until all 1a was disappeared as monitored by TLC.
The reaction mixture was quenched with saturated NaHCO (10 mL).
The resulting mixture was extracted with DCM (3 × 30 mL). The
organic phase was dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification of the residue by flash column
3
1
3
(m, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.10 (dd, J = 8.2, 2.6 Hz, 1H), 4.99
(d, J = 9.7 Hz, 1H), 3.90 (td, J = 9.9, 7.6 Hz, 1H), 3.85 (s, 3H), 3.50
(dd, J = 10.0, 7.8 Hz, 1H), 3.37−3.32 (m, 1H), 3.04 (q, J = 9.5 Hz,
1H), 3.00−2.95 (m, 1H), 2.83 (t, J = 10.0 Hz, 1H), 2.74−2.68 (m,
1H), 2.00−1.87 (m, 2H), 1.84−1.77 (m, 1H), 1.66−1.62 (m, 1H),
chromatography (EtOAc/hexanes = 2:1) gave 8a (31 mg, 0.10
1
mmol, 45%) as a yellow oil: H NMR (400 MHz, CDCl ) δ 7.93−7.91
3
(
(
m, 2H), 7.55 (tt, J = 7.4, 1.3 Hz, 1H), 7.46−7.43 (m, 2H), 5.01−4.98
m, 1H), 3.96 (td, J = 10.0, 7.6 Hz, 1H), 3.56 (dd, J = 10.2, 7.6 Hz,
1.61 (s, 3H), 1.56 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ 200.1,
1
3
1
H), 3.46−3.42 (m, 1H), 3.07−3.01 (m, 2H), 2.90 (t, J = 10.1 Hz,
159.8, 138.7, 134.6, 129.4, 124.8, 121.2, 119.7, 112.5, 71.7, 58.6, 55.4,
1H), 2.78−2.74 (m, 1H), 2.03−1.82 (m, 3H), 1.68−1.64 (m, 1H),
55.2, 55.0, 48.5, 30.1, 25.8, 25.2, 18.2; IR (CH Cl ) 2961, 2934, 2348,
2
2
J
DOI: 10.1021/acs.joc.5b02025
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
678, 1596, 1582, 1450, 1430, 1287, 1262, 1195, 1044, 825, 796, 739
mmol). The crude mixture was purified by flash column chromatog-
raphy to give 8r (18 mg, 0.065 mmol, 25%) as a brown oil: H NMR
−1
+
1
cm ; MS (ESI) m/e (%) 300.2 ([M + H] , 100); HRMS (ESI) calcd.
for C H NO [M + H] 300.1964, found 300.1972.
+
19
26
2
(400 MHz, CDCl ) δ 8.01 (dd, J = 2.8, 1.2 Hz, 1H), 7.53 (dd, J = 5.3,
3
(
4-Methoxyphenyl)((1S*,2S*,7aR*)-1-(2-methylprop-1-en-1-yl)-
1.3 Hz, 1H), 7.29 (dd, J = 5.2, 3.0 Hz, 1H), 5.02−5.00 (m, 1H), 3.71
hexahydro-1H-pyrrolizin-2-yl)methanone (8g). The solution of 1g
(
td, J = 9.9, 7.6 Hz, 1H), 3.49−3.42 (m, 1H), 3.36−3.29 (m, 1H),
(
78 mg, 0.26 mmol) in CH Cl (2.6 mL) was added NHTf (0.15 g,
2 2 2
3.02−2.93 (m, 2H), 2.89 (t, J = 9.9 Hz, 1H), 2.71 (dt, J = 10.2, 6.2 Hz,
1
1
0
.52 mmol). The crude mixture was purified by flash column
H), 1.99−1.87 (m, 2H), 1.87−1.76 (m, 1H), 1.65−1.60 (m, 4H),
chromatography to give 8g (18 mg, 0.04 mmol, 15%) as a yellow oil:
13 1
.52 (d, J = 1.1 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 194.4,
3
1
H NMR (400 MHz, CDCl ) δ 7.92 (d, J = 8.8 Hz, 2H), 6.92 (d, J =
3
142.8, 134.8, 132.6, 127.2, 126.1, 124.8, 71.8, 58.3, 56.9, 54.9, 48.7,
8
3
3
2
3
1
5
1
8
.9 Hz, 2H), 5.00 (d, J = 9.7 Hz, 1H), 3.94 (dt, J = 10.1, 7.5 Hz, 1H),
.87 (s, 3H), 3.58 (dd, J = 10.2, 7.4 Hz, 1H), 3.54−3.49 (m, 1H),
.13−3.07 (m, 1H), 3 03 (q, J = 9.7 Hz, 1H), 2.92 (t, J = 10.3 Hz, 1H),
.83−2.77 (m, 1H), 2.04−1.86 (m, 3H), 1.75−1.65 (m, 1H), 1.59 (s,
3
1
1
2
0.1, 25.8, 18.2; IR (CH Cl ) 3103, 2938, 1668, 1511, 1417, 1244,
2
2
−1
+
182, 1101, 834, 749 cm ; MS (ESI) m/e (%), 276.5 ([M + H] ,
+
00), 258.4 (3); HRMS (ESI) calcd. for C H NOS [M + H]
16
22
76.1422, found 276.1420.
H), 1.51 (s, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ 197.8, 163.7,
1
3
(
E)-2-(3-Methylbuta-1,3-dien-1-yl)-1-(3-phenylprop-2-yn-1-yl)-
35.5, 130.9 (2C), 130.1, 123.8, 113.7 (2C), 71.7, 58.2, 55.5, 54.8,
3.8, 48.7, 29.9, 25.7, 25.1, 18.2; IR (CH Cl ) 3841, 2939, 2358, 2030,
662, 1600, 1575, 1512, 1459, 1422, 1379, 1310, 1253, 1172, 1027,
pyrrolidine (9a). The crude mixture was purified by flash column
2
2
chromatography to give 9a (29 mg, 0.08 mmol, 32%) as a colorless oil:
1
H NMR (400 MHz, CDCl ) δ 7.47−7.41 (m, 2H), 7.33−7.29 (m,
−1
+
3
47 cm ; MS (ESI) m/e (%) 300.2 ([M + H] , 100); HRMS (ESI)
3
2
(
1
H), 6.34 (d, J = 15.6 Hz, 1H), 5.55 (dd, J = 15.5, 8.7 Hz, 1H), 4.98 (s,
H), 3.75 (d, J = 17.0 Hz, 1H), 3.51 (d, J = 17.0 Hz, 1H), 3.24−3.13
+
calcd. for C H NO [M + H] 300.1964, found 300.1956.
19
26
2
(
4-Chlorophenyl)((1S*,2S*,7aR*)-1-(2-methylprop-1-en-1-yl)-
m, 2H), 2.75−2.67 (m, 1H), 2.08−1.99 (m, 1H), 1.97−1.89 (m, 1H),
hexahydro-1H-pyrrolizin-2-yl)methanone (8m). The solution of 1m
13 1
.87 (s, 3H), 1.85−1.77 (m, 1H), 1.76−1.67 (m, 1H); C{ H} NMR
(
79 mg, 0.26 mmol) in CH Cl (2.6 mL) was added NHTf (0.15 g,
2 2 2
(
100 MHz, CDCl ) δ 141.6, 136.1, 131.7, 130.1, 128.3, 128.2, 123.0,
0
.52 mmol). The crude mixture was purified by flash column
3
1
16.5, 85.4, 84.0, 65.4, 52.0, 41.1, 31.8, 22.1, 18.6; IR (CH Cl ) 2980,
2 2
chromatography to give 8m (36 mg, 0.12 mmol, 45%) as a yellow oil:
−1
1
2540, 1440, 1001, 764, 740 cm ; MS (ESI) m/e (%) 252.2 ([M +
H] , 100), 199.0 (5), 190.0 (5), 176.1 (5); HRMS (ESI) calcd. for
C H N [M + H] 252.1752, found 252.1749.
H NMR (400 MHz, CDCl ) δ 7.86 (d, J = 8.6 Hz, 2H), 7.42 (d, J =
3
+
8
3
2
1
.5 Hz, 2H), 4.98 (d, J = 9.7 Hz, 1H), 3.86 (dt, J = 9.8, 7.6 Hz, 1H),
.46 (dd, J = 10.0, 7.7 Hz, 1H), 3.37−3.32 (m, 1H), 3.02−2.95 (m,
H), 2.86 (t, J = 9.9 Hz, 1H), 2.47−2.68 (m, 1H), 1.98−1.86 (m, 2H),
+
18 22
(
Z)-3-((1S*,7aR*)-1-(2-Methylprop-1-en-1-yl)tetrahydro-1H-pyr-
rolizin-2(3H)-ylidene)isobenzofuran-1(3H)-one (11). The crude
residue obtained from the reaction of 1q (89 mg, 0.26 mmol) with
Ph CBF (0.17 g, 0.52 mmol) in CH Cl (26 mL) was purified by flash
.85−1.78 (m, 1H), 1.65−1.60 (m, 1H), 1.60 (s, 3H), 1.52 (s, 3H);
1
3
1
C{ H} NMR (100 MHz, CDCl ) δ 199.2, 139.6, 135.6, 134.9, 129.9
3
3
4
2
2
(
1
2C),128.8 (2C), 124.6, 71.8, 58.3, 55.0 (2C), 48.8, 30.1, 25.8, 25.2,
8.2; IR (CH Cl ) 3390, 2930, 2196, 1662, 1589, 1382, 1909, 1010,
column chromatography to give 11 (31 mg, 0.10 mmol, 40%) as a
2 2
1
−1
+
yellow oil: H NMR (400 MHz, CDCl ) δ 7.94−7.87 (m, 1H), 7.68−
8
41, 740 cm ; MS (ESI) m/e (%)306.1 ([M + 2+ H] , 25), 304.1
3
+
+
7.60 (m, 1H), 7.53−7.44 (m, 2H), 5.25−5.16 (m, 1H), 4.09 (dd, J =
(
[M + H] , 100); HR-MS (ESI) calcd. for C H ClNO [M + H]
18 23
1
(
7.4, 2.1 Hz, 1H), 3.99 (d, J = 17.3 Hz, 1H), 3.69−3.61 (m, 1H), 3.40
3
04.1468, found 304.1460.
4-Bromophenyl)((1S*,2S*,7aR*)-1-(2-methylprop-1-en-1-yl)-
hexahydro-1H-pyrrolizin-2-yl)methanone (8n). The solution of 1n
dt, J = 7.2, 4.8 Hz, 1H), 3.07 (ddd, J = 10.3, 7.8, 4.1 Hz, 1H), 2.56 (dt,
(
J = 10.2, 7.9 Hz, 1H), 2.23−2.14 (m, 1H), 2.01−1.93 (m, 1H), 1.92−
13
1
(
91 mg, 0.26 mmol) in CH Cl (2.6 mL) was added NHTf (0.15 g,
1.84 (m, 4H), 1.80−1.73 (m, 4H); C{ H} NMR (100 MHz, CDCl )
3
2
2
2
0
.52 mmol). The crude mixture was purified by flash column
δ 166.9, 140.2, 138.0, 134.0, 133.0, 129.7, 128.8, 125.4, 125.3, 125.1,
chromatography to give 8n (34 mg, 0.10 mmol, 38%) as a yellow oil:
123.1, 74.3, 56.9, 53.5, 46.0, 30.1, 25.5, 24.4, 18.6; IR (CH Cl ) 2954,
2
2
1
H NMR (400 MHz, CDCl ) δ 7.79−7.76 (m, 2H), 7.60−7.57 (m,
2929, 2430, 2048, 1845, 1776, 1641, 1446, 1380, 1273, 1033, 764
3
−
1
+
2
9
9
1
H), 5.00−4.95 (m, 1H), 3.85 (tr, J = 9.8, 7.6 Hz, 1H), 3.46 (dd, J =
.7, 7.8 Hz, 1H), 3.38−3.32 (m, 1H), 3.02−2.95 (m, 2H), 2.86 (t, J =
.8 Hz, 1H), 2.74−2.68 (m, 1H), 1.98−1.75 (m, 3H), 1.67−1.57 (m,
H), 1.60 (d, J = 0.8 Hz, 3H), 1.52 (d, J = 0.8 Hz, 3H); 13C{ H} NMR
cm ; MS (ESI) m/e (%) 296.2 ([M + H] , 100); HR-MS (ESI) calcd.
+
for C H NO [M + H] 296.1651, found 296.1659.
19
22
2
(E)-4-(1-(3-Phenylprop-2-yn-1-yl)pyrrolidin-2-yl)but-3-en-2-ol
1
(12). (0.47 g, 1.86 mmol, 53%). Compound 12 was obtained as a
1
(
100 MHz, CDCl ) δ 199.2, 135.9, 135.1, 131.7 (2C), 130.0 (2C),
mixture of diastereomers. A yellow oil: H NMR (400 MHz, CDCl ) δ
3
3
1
28.4, 124.2, 71.6, 58.1, 54.9, 54.6, 48.8, 30.0, 25.7, 25.1, 18.2; IR
7.46−7.41 (m, 2H + 2H′), 7.32− Jonsnow57.27 (m, 3H + 3H′), 5.79
(dd, J = 6.2, 0.8 Hz, 1H′), 5.75 (dd, J = 6.2, 0.8 Hz, 1H), 5.55 (dd, J =
8.5, 1.0 Hz, 1H), 5.51 (dd, J = 8.5, 1.0 Hz, 1H′), 4.38−4.29 (m, 1H +
1H′), 3.74 (d, J = 5.0 Hz, 1H′), 3.70 (d, J = 5.0 Hz, 1H), 3.50 (d, J =
9.7 Hz, 1H), 3.46 (d, J = 9.7 Hz, 1H′), 3.18−3.11 (m, 1H + 1H′), 3.02
(
CH Cl ) 3404, 2922, 2547, 2359, 2345, 1959, 1676, 1585, 1400,
2
2
−
1
1
+
251, 1105, 1071, 1009, 840, 739 cm ; MS (ESI) m/e (%) 350.1 ([M
2+ H] , 100), 348.1 ([M + H] , 100); HRMS (ESI) calcd. for
+
+
+
C H BrNO [M + H] 348.0963, found 348.0958.
18
23
(
2-Bromophenyl)((1S*,2S*,7aR*)-1-(2-methylprop-1-en-1-yl)-
(
q, J = 8.2 Hz, 1H + 1H′), 2.64 (q, J = 8.9 Hz, 1H + 1H′), 2.04−1.93
m, 2H + 2H′), 1.92−1.83 (m, 1H + 1H′), 1.83−1.74 (m, 1H + 1H′),
hexahydro-1H-pyrrolizin-2-yl)methanone (8o). The solution of 1o
(
(
91 mg, 0.26 mmol) in CH Cl (2.6 mL) was added NHTf (0.15 g,
2 2 2
.52 mmol). The crude mixture was purified by flash column
1
.71−1.60 (m, 1H + 1H′), 1.30 (d, J = 2.8 Hz, 3H), 1.28 (d, J = 2.7
0
13 1
Hz, 3H′); C{ H} NMR (100 MHz, CDCl ) δ 137.3, 137.3, 131.7
3
chromatography to give 8o (29 mg, 0.08 mmol, 32%) as a yellow oil:
(2C), 131.3, 131.3, 128.2 (2C), 128.0, 123.3 84.9, 84.8, 84.8, 68.3,
1
H NMR (400 MHz, CDCl ) δ 7.58 (dd, J = 7.9, 1.0 Hz, 1H), 7.33
3
6
4.4, 64.3, 52.3, 52.3, 41.2, 41.1, 31.7, 31.7, 23.4, 23.3, 22.1; IR
(
(
(
1
3
2
5
1
td, J = 7.5, 1.0 Hz, 1H), 7.28−7.22 (m, 2H), 4.91−4.84 (m, 1H), 3.78
td, J = 10.0, 7.5 Hz, 1H), 3.50 (dd, J = 10.1, 7.4 Hz, 1H), 3.31−3.26
m, 1H), 3.04−2.96 (m, 2H), 2.91 (q, J = 9.8 Hz, 1H), 2.77−2.72 (m,
−1
(CH Cl ) 3050, 2855, 2450,1221, 990, 887 cm ; MS (ESI) m/e (%)
2 2
+
2
56.2 ([M + H] , 100), 238.4 (3), 144.1 (4), 115.1 (11); HRMS (ESI)
+
calcd. for C H NO [M + H] 256.1701, found 256.1700.
17
22
H), 2.00−1.79 (m, 3H), 1.65−1.60 (m, 1H), 1.59 (d, J = 1.0 Hz,
H), 1.57 (d, J = 1.0 Hz, 3H); 13C{ H} NMR (100 MHz, CDCl ) δ
1
3
04.3, 142.0, 134.8, 133.5, 131.5, 128.4, 127.1, 124.0, 119.0, 71.6, 58.8,
7.5, 55.0, 49.7, 29.8, 25.7, 25.1, 18.3; IR (CH Cl ) 2929, 2538, 2691,
ASSOCIATED CONTENT
Supporting Information
■
2
2
−1
*
S
431, 1380, 1053, 764, 740 cm ; MS (ESI) m/e (%) 350.1 ([M + 2+
+
+
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02025.
H] , 100), 348.1 ([M + H] , 100), 298.2 (5); HRMS (ESI) calcd. for
C H BrNO [M + H] 348.0963, found 348.0962.
+
18
23
(
(1S*,2S*,7aR*)-1-(2-Methylprop-1-en-1-yl)hexahydro-1H-pyrro-
NMR spectra for compounds 1a−s, 3−6, 7a−d, 7f, 7h−
n, 7r−s, 8a−c, 8e−g, 8m−o, 8r, 9a, 11, and 12. (PDF)
lizin-2-yl) (thiophen-3-yl)methanone (8r). The solution of 1r (72 mg,
0
.26 mmol) in CH Cl (2.6 mL) was added NHTf (0.15 g, 0.52
2
2
2
K
DOI: 10.1021/acs.joc.5b02025
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
19) (a) Kobayashi, S.; Murakami, M.; Mukaiyama, T. Chem. Lett.
AUTHOR INFORMATION
■
*
1
985, 953. (b) Hashimoto, Y.; Mukaiyama, T. Chem. Lett. 1986, 755.
c) Hashimoto, Y.; Sugumi, H.; Okauchi, T.; Mukaiyama, T. Chem.
Lett. 1987, 1691.
20) (a) Pearson, A. J. Acc. Chem. Res. 1980, 13, 463. (b) Yeh, M. C.
P.; Shieh, B. A.; Fu, H. W.; Tau, S. I.; Chuang, L. W. J. Am. Chem. Soc.
993, 115, 5941.
21) (a) Ichikawa, J.; Yokota, M.; Kudo, T.; Umezaki, S. Angew.
Corresponding Author
E-mail: cheyeh@ntnu.edu.tw.
(
(
Notes
The authors declare no competing financial interest.
1
(
ACKNOWLEDGMENTS
Chem., Int. Ed. 2008, 47, 4870. (b) Lartia, R.; Bertrand, H.; Teulade-
Fichou, M. P. Synlett 2006, 610.
■
This work has been supported by the Ministry of Science and
Technology (MOST 104-2113-M-003-003) and National
Taiwan Normal University.
(
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DOI: 10.1021/acs.joc.5b02025
J. Org. Chem. XXXX, XXX, XXX−XXX