Allysilane-imine cyclizations
by Jun Li
A thesis submitted in partial fulfillment of the requirement for the degree of Master of Science in
Chemistry
Montana State University
© Copyright by Jun Li (2001)
Abstract:
Allylsilane chemistry has been widely used in organic synthesis. The intramolecular nucleophilic
addition of allylsilane to imine allows the construction of many ring systems in a convenient pathway.
After the preparation of appropriate allylsilane-imine substrates, various conditions were applied to
furnish the formation of pyrrolidine derivatives. It was found triftuoroacetyl triflate could effect such
cyclization to form N-trifluoroacetyl-pyrrolidine with reasonable diastereoselectivity. F-19 NMR was
applied to determine the ratio of two possible diastereomers conveniently. The structures were
determined with H-1 NMR NOE measurements and confirmed by X-ray crystallography. ALLYSILANE-IMINE CYCLIZATIONS
by
Jun Li
A thesis submitted in partial fulfillment
o f the requirement for the degree
of
Master o f Science
in
Chemistry
MONTANA STATE UNIVERSITY
Bozeman, Montana
August 2001
11
APPROVAL
O f a thesis submitted by
Jun Li
This thesis has been read by each member o f the thesis committee and had been
found to be satisfactory regarding content, English usage, format, citations, bibliographic
style, and consistency, and is ready for submission to the College o f Graduate Studies.
Approved for the College o f Graduate Studies
e
Bruce McLeod
(Signature)
/ C . 'Z /- 1 9 /'
(Date)
iii
STATEMENT OF PERMISSION TO USE
In presenting this thesis in partial fulfillment o f the requirements for a master’s
degree at Montana State University, I agree that the Library shall make it available to
borrowers under rules o f the Library.
I f I have indicated my intension to copyright this thesis by including a copyright
notice page, copying is allowable only for scholarly purposes, consistent with “fair use”
as prescribed in the U.S. Copyright Law. Requests for permission for extended quotation
from or reproduction o f this thesis in whole or in parts may be granted only by the
copyright holder.
Signature
Date
L
iv
ACKNOWLEDGEMENT
This thesis was completed under the guidance of Prof. Tom Livinghouse. I would
like to thank him for his suggestion and patience. I would also thank all the members of
the Livinghouse Group, especially Dr. Donough O'Mahony, Dr. David Duncan and
David Belanger, for their help during the course of my work. I would thank Prof. Paul
Grieco and Prof. Edwin Abbott for being on my committee and their suggestion on the
thesis.
More thanks go to Dr. Joe Sears for his help on gas chromatography and mass
spectra, Dr. Scott Busse for his assistance on NM R spectroscopy, and Mr. Ray Larsen for
helping me confirm the final structure with X-ray crystallography.
TABLE OF CONTENTS
1. INTRODUCTION....................................................................................................... ]
2. RESULTS AND DISCUSSION................................................................................ 5
3. EXPERIMENTS......................................................................................................... 22
4. REFERENCES............................................................................................................ 39
APPENDIX A: REPRESENTATIVE SPECTRA
.40
vj
LIST OF TABLES
Table
- L ArllylsiIane-Imine Cyclizatjo
Page
n
s
;
....................................... 13
vii
LIST OF FIGURES
Figure
Page
I . Determination of ratio of diastereomers using F -19 N M R ............................. 18
-- 2.- X-ray crystallography structure of cz'j’-7V-Tosyl-2-(4-chIorophenyl)-ltrifluoroacetyl-3-vinylpyrrolidine............................................................... . .21
viii
LIST OF SCHEMES
Scheme
Page
I . AllylsiIane P-effect................................................................................................. I
-
2". ■ Allylsilane cyclzations........................................................................................... 2
3. Allylsilane addition to im in es................................................................. !............2
4. Intramolecular allylsilane addition to im in e s..................................................... 3
5. Intramolecular allylsilane addition to im in e s..................................................... 3
6. Bis(allylsilane) cyclization and monoallylsilane cyclization..............................4
7. Preparation o f allylsilane-imine............................................................................. 5
8.
Preparation o f allylsilane-imine................
5
9. Preparation o f allylsilane-imine............................■............................................... 6
10. Allylsilane-imine cyclization: initial investigation.............................................7
I I . Carbocation stability com parison......................................................................... 8
12. Preparation o f fluorinated alkene.......................................................................... 8
13. Catalyzed coupling..........................................
9
14. Catalyzed coupling.................................................................................................. 9
15. Activation of im ine................................................................................................ 10
16. Tosyliminium ion....................................................................................................10
17. Activation of im in e .......................
11
18. Activation o f imine with TFA T .............................'............................................ 12
19. Cyclization with TFAT
12
ix
20. Cyclization of aliphatic imines with TFAT....................................................... 14
21. Cyclization of aromatic imines with T F A T ..........................,......................... 14
22. Cyclization of electron-rich aromatic imines with T F A T .................
15
23. Intermediate in allylsilane-imine cyclization............................................. ,...15
-24-. Cyclization of ketone-derived im in e ......................................... ■..................... 16
25. Transition s ta te s..................................................................................................17
26. NOE experim ents-."
................\ ............................................................19
27. Conversion to N-tosylpyrrolidine..............................................................
19
ABSTRACT
Allylsilane chemistry has been widely used in organic synthesis. The
intramolecular nucleophilic addition of allylsilane to imine allows the construction of
many ring systems in a convenient pathway. After the preparation of appropriate
allylsilane-imine substrates, various conditions were applied to furnish the formation of
pyrrolidine derivatives. It was found triftuoroacetyl triflate could effect such cyclization
to form N -trifluoroacetyl-pyrrolidine with reasonable diastereoselectivity. F -19 NMR
was applied to determine the ratio of two possible diastereomers conveniently. The
structures were determined with H-I NMR NOE measurements and confirmed by X-ray
crystallography.
]
CHAPTER ]
INTRODUCTION
AIlyIsilanes have proven to be amonp the most versatile o f the silicon-containing
carbon nucleophiles. The inter- or intramolecular addition of an allylsilane to carbon
electrophiles has been widely used in organic synthesis, often with high level of
stereocontrol J A large majority of allylsilane chemistry is based on [3-effect, the ability
of silicon atom to stabilize the carbocation next to a C-Si bond. These systems tend to
lose silyl group and form a double bond, thus give much higher regioselectivity than
losing a proton in the analog without silyl group. (Scheme I)
"V,
vL:
SiMe3
E
,SiMe3
uL
I
Scheme I
The most commonly used substrates o f allylsilane addition include aldehydes and
ketones, acetals, a, (3-unsaturated ketones. The intramolecular addition reactions have
been widely used in construction o f various ring systems. 2I (Scheme 2)
O
Scheme 2
!mines are also seen as substrates of allylsilane addition although not as widely
used as the others. Compared to that of aldehydes, the reaction of imines with allylsilanes
is sluggish even in the presence o f Lewis acids. However, some examples have been
reported.^ (Scheme 3)
CsF, THF
20- 94%
13
R1
'hX
R2
H
15
14
Scheme 3
It was reported that iminium salts, generated either from primary or secondary
amine, are more reactive to the addition of
a lly lsila n e .4
An intramolecular version gave
rise to the adduct from simple phenylacetaldehyde. (Scheme 4)
Br,,
CF1CO1H
HCHO
NH
-S iM e1
Bn
-----------------------------►
S iM e5
H: 0-THF (3:1)
18
17
Bn
CF3CO2H
CeH3CH2CHO
NH5
-S iM e5
HN^
S iM e3
H2O -TH F(H l)
SS0C
19
21
20
Scheme 4
]t was also reported that these reactions could be used in the construction of more
complex ring system such as isoquinoline derivatives.5 (Scheme 5)
SiMfc3
R 2CHO
M e ,S iC K Z nl;
M eO H 1 reflux
48-88%
23
22
24
Scheme 5
This project is directly related to what was done earlier in these laboratories. An
intramolecular addition of allylbis(silane) was developed earlier, showing that the
pyrrolidine ring can be constructed stereoselectively.6 (Scheme 6) In most cases, these
cyclizations showed interesting stereochemistry, with aromatic imines favoring cis-
4
pyrrolidines and aliphatic imines favoring vans- pyrrolidines. The goal of this project
was to explore the appropriate conditions for similar cyclizations of the analogous
allylsilane-imines and their stereochemistry .
M e3S '
\
R
N'
H
R
30
29
Scheme 6
CHAPTER 2
RESULTS AND DISCUSSION
The synthetic route to the allylsilane-imine precyclization substrates 31 is similar
to the methods developed earlier in our laboratory and in the literature. f' ' These imines
can be conveniently prepared from amine 32 and a variety of aldehydes. (Scheme 7).
while amine 32 can be prepared as shown below.
Me2Si
34
35
Scheme 7
The commercially available chloromethyltrimethylsilane 36 was converted to the
corresponding iodide 35 by treatment with sodium iodide and tetrabutylammonium
iodide in water. * Alkylation of the THP-proteeted 3-butyn-l-ol 37 9 with iodomethyltrimethylsilane 35 gave alkylated product 38. (Scheme 8)
^
Me3Si'
Nal / Ii-Bu4N'*!"
^CI
36
H2O173%
Me,SI
1
35
72% (2 steps)
Scheme 8
33
6
After acidic deprotection. 6-(trimethy]si]y])-4-hexyn-1-ol 33 was partially reduced
to cis -alkenol 39 by P-2 nickel-catalyzed hydrogenation in high yield. A subsequent
Mitsunobu reaction (modified from the literature. Initial temperature at —40OC)
converted alcohol into A'-substituted phthalimide 40. which generated unprotected amine
32 upon hydrazinolysis.6 (Scheme 9)
P h ,P , DEA D
phthalim ide, THF
-3 O11C to rt. n I Oh. 98%
E tO H . reflux
RCHO
M S 4 A .T H 1
or MgSO4. CHnCu
Scheme 9
The desired allylsilane-imines 31 for cyclizations were prepared from amine 32
and aldehyde under 4A molecular sieves (THF. dichloromethane. or hexane) or
anhydrous
magnesium
sulfate
(dichloromethane)
conditions.
Condensations with
molecular sieves were slower but gave cleaner products than those with magnesium
sulfate. For imines that tend to form enamine, magnesium sulfate must be used to avoid
tautomerization during prolonged reaction period. In most cases, condensations were
complete within 12 hours, whereas sterically hindered aldehydes need much longer time
to form imines.
Various methods were then explored to effect cyclization. The first attempt made
was to use Lewis acid, following the existing model o f bis(allylsilane)-imine substrates. 6
AllylsiJane-imine 4] (made from isobutyraldehyde) was treated with T1CI4 at -78°C. The
temperature was then allowed to rise gradually to room temperature and stay at room
temperature for 2 hours. The reaction mixture was then quenched with saturated aqueous
sodium bicarbonate and worked up. After tosylaled, cyclized product 43 was detected.
However, the yield was only 6%. (Scheme 10)
Scheme 10
Considering that pyrrolidine 42 with an isopropyl side-chain had a small
molecular weight and might be volatile, which could cause loss in handling and workup,
another allylsilane-imine ( 31, R=Ph) was made and tested for cyclization again (-78°C,
then O0C for 12 hours). However, it didn't give good yield either.
Other Lewis acids (BF3 EtaO, TiF4, EtzAlCl, ZrCE) as well as Bronsted acids
(CF3CO2H, CF3SO3H) were tried in attempts to activate the imine moiety. They didn’t
give the cyclized product. The same conditions used for the allylbis(silane)-imine
cyclization were not suitable in the new system. Presumably, the allylbis(silane) can
8
stabilize the cationic intermediate 47 much better and it is more effectively nucleophilic
than the allylsilane (Scheme 11).
Scheme 11
To accomplish the proposed cyclization, we must increase the reactivity o f the
allylsilane-imine substrate, either the allylsilane moiety or the imine moiety. Fluorine was
known to be able to stabilize its adjacent carbocation.111 If a Huorinated allylsilane-imine
substrate 48 was made, fluorine atom might help increase the reactivity of allylsilane
moiety thus promote the cyclization. A route toward the desired Huoroallylsilane-imine
substrate was explored. (Scheme 12)
Scheme 12
9
Following the preparation of phosphonamide 50 then ylide salt 51. a Wittig-type
reaction was carried out. 1.1-Chlorofluoroalkene 5b was termed with no stereoselectivity
between two possible isomers.11 Unfortunately, catalyzed coupling reaction between
chloroalkene 56 and trimethylsilylmethyl zinc reagent (generated from Grignard reagent
and zinc chloride) could not be accomplished under various conditions. Neither Pd-based
catalysts
(Pd(PPhs)^CF.
Pd(dppb)2CF.
P d ^ p p t^C F ).
nor
N i-based
catalysts
(Ni(PP)IsFCF , Ni(dppfFCF) could furnish the coupling. (Scheme 13)
cal "Ni" m "Pd"
no reaction
Mc3SiCH2ZnCI
C
56
Scheme 13
A structural analogue 57 with no other functionality was also made and tested. It
didn’t give coupling product, either. (Scheme 14) The adjacent fluorine atom could make
the C-Cl bond more electron-deficient thus difficult for palladium insersion. which is
crucial to the whole catalytic process. The exact reason remains unclear.
CFCI2
Q"NMe2
Me2N
NMe2
cat. "Ni" or "Pd"
n-CyH I5CHO
cZn-Cu, THF
C
IOh
H-C7K16
55 %
------------------- ►
no reaction
M esSiC H 2MgCl
or M esSiCH 2ZnCl
51
Scheme 14
Besides activating the allylsilane moiety, the reactivity of the imine moiety also
affects the desired cyclization. Several Lewis had been tested and failed to give
satisfactory results. In order to increase the reactivity o f iminium ion, another pathway to
10
the desired the pyrrolidine product was explored. It has been known that A^acyliminium
ions are much more reactive than the corresponding imines. Allylsilane was added to the
A'-acyliminium ion intermediate 59 generated from the aminal 58.12:1 By converting iminc
61 into an A’-acyliminium ion 62, pyrrolidine 63 was formed by cyclization, although
o n ly
aromatic imines were explored. ,2h (Scheme 15)
M e 2S il
HCO2H.
or SnCl4.
or El2AlCl
69-81%
Scheme 15
Tosyliminium ions react in a similar manner. It was used in the contraction of a
tricyclic system. (Scheme 16)
Scheme 16
]]
Similar lo a lileralure procedure. I2h dimelhylpyrocarhonate and Lewis acid were
used consequently to convert an allylsilane-imine substrate 41 to iminium ion. cyclized
product 68 was isolated as a single isomer. But an effort following the known procedure6
toward a single-step conversion by using trifluoroacetic anhydride didn't generate the
cyclized product. (Scheme 17)
41
41
Scheme 17
Trifluoroacetyl
Inflate
69
(TFAT)
was
claimed
an
extremely
reactive
electrophile.1'1 It can be made in the lab by condensation of triflic acid and trifluoroacetic
acid with P2Cfs. Because o f its high reactivity with electron-rich substrate, it was expected
to form trifluoroacetyliminium ion with allylsilane-imine substrate 29, therefore promote
the cyclization by activating the imine moiety. Since inflate is an excellent leaving group,
it was possible to generate A^acyliminium ion 70 without further activation by Lewis
acid, thus give rise to the cyclized product 30 in a single step. (Scheme 18)
ex C F 3C O 2H
TFAl
C F 2S O 3H
PnO.
72',.
70
Scheme 18
To that end. treatment of an allylsilane-imine 29a with TFAT at -78°C, followed
by gradual warming to room temperature, gave the pyrrolidine derivative 30a in 54%
yield in a single step (Scheme 19). With optimized conditions (-40°C), the yield was
increased to 72%. The product was determined to be diastereomeric mixture of 4.6:1.
with
frow -isom er
as
the
major
product
(see
below).
The
lability
of
trifluoromethylacetamide to basic hydrolysis makes it a favorable amine-protecting
group. Unprotected pyrrolidine for further conversion can be generated upon basic
hydrolysis.
4.6:1
29a
71
Scheme 19
After optimizing the experiment conditions, more imines were subjected to
cyclizations. Most cyclizations were carried out at -40°C for 2-6 hours. For less reactive
13
substrates, longer reaction time was needed. The scope of this reaction has been
evaluated with a variety of substrates. The results are collected in Table I .
M e3S
TFAT(1.2-1.5eq
\ _
A
CH2Cl:
>
30
29
Table I Allylsilane-Imine Cyclizations
entry
R
Temp (0C)
Time (h)
Yield (%)
Ratio
a
/-Pr
-40
2.5
72
1:4.6
b
z-Bu
-40
3.5
55
1:1.8
C
Z7-C7H15
-40
5
56
1:1.4
d
Ph
-40
2.5
84
1:6.2
e
p-CIPh
-30
14
85
1:9.2
f
p-MeOPh
-20
19
40
1:2.3
g
o-MeOPh
-30
14
61
1:1.5
Both aliphatic and aromatic imines undergo cyclization under these conditions.
Aliphic imines 29a and 29b formed ?/-<ms--predominant pyrrolidines. (Scheme 20)
14
M e1S
M e3S.,
I 4:1
TFAT
CH1Cl3. -4()°C. 5h. 56%
30c
29c
Scheme 20
It is interesting to observe the change o f stereochemistry when aromatic imines
were used for cychzation. When the side chain was changed to aromatic groups, the
cvclization reaction formed pyrrolidines as expected, but with 2,3-cis predominant
products, usually with higher selectivity. (Scheme 21)
Scheme 21
15
When aromatic imines with electron-donating group were used, the yields were
apparently lower than others. Presumably, an electron-donating group stabilizes the
cationic intermediate and lowers its reactivity. (Scheme 22)
Scheme 22
In all cases, especially in 29f and 29g when imines had electron-donating groups,
a considerable amount o f byproduct 71 was detected, varying from 1% to 30%.14 It was
possibly generated from aqueous quenching of trifluoroactyliminium ion intermediate 70.
When imine had electron-donating groups that help stabilize the carbocation. the highest
amount of byproduct 71 was obtained. It could be seen as evidence that the cyclizations
occur via a cationic pathway. (Scheme 23)
Me3Si1
\
Me3S ii
TFAT
%
-D T f
H
F3C.
JiMe3
70
71
Scheme 23
16
There was one ketone tested for the cyclizaiton. Ethyl veluvinate was condensed
with the precursor amine. The formed imine was subjected to the routine cyclization
conditions. The product was formed in good yield and with reasonable diastereoselectivity. The final stereochemistry has not been assigned yet. (Scheme 24)
32
73
Scheme 24
The reaction cyclization is 5-exo-trig for allylsilane moiety, while 5-endo-trig for
imine moiety. Its transition state may be an envelop-shaped 5-member ring. (Scheme 25)
To avoid higher steric hindrance, two groups prefer to stay at two faces (76). In the cases
of aromatic !mines, the aromatic substituent can stabilize the adjacent carbocation.
Rotation around the C-N bond transforms tram orientation to cis. Moreover, LUMO of
the imine moiety is delocalized through trifluoroactyl group and aromatic substituent. To
reach the maximum overlapping with HOMO o f allylsilane moiety, aromatic group
prefers to be at the same face with allylsilane group (78).
17
Scheme 25
There was difficulty in the determination of exact ratio of two possible pyrrolidine
stereoisomers. 1H-NMR and GC are among the easiest methods used to determine the
ratio o f a pair o f stereoisomers. In this case, the complicated signals o f amide compounds
hindered the direct reading of ratio from 1H-NMR spectra. Their similar chromatographic
property made it difficult to isolate enough pure sample for GC calibration. Quantitative
13C-NMR were also tried but failed to give accurate integration due to the insufficient
signal intensities.
19F-NMR was finally chosen to determine the ratio of two stereoisomers. In most
cases, however, four peaks representing two AMrifluoroactylpyrrolidine isomers, and two
close peaks representing byproduct were observed. Analytically pure samples were
isolated with preparative gas chromatography. When two isomers were too close to
separate, a partial separated sample was subjected to 19F-NMR measurement. The change
in relative intensity o f signals was used to assign the peaks in the original 19F-NMR
spectrum.
IS
Z
fl
[?
t,
:
-S
-S
r
■?
-S
■7
7"
-T
W
-T
e ra - ltfti- -
•7
-T
I
-°
y
-T
-T
-T
-T
Ii
Figure I. Determination of ratio of diastereomers using F-19 NMR
-T
19
The stereochemistry at the 2- and 3-position of the pyrrolidine was determined to
be n ans in the cases o f aliphatic side-chains, and cis- in the cases o f aromatic side-chains
by NOE experiments. (Scheme 26) The results are similar to those from bis(allylsilane)imine cyclizations.
2.1-6,2%-
77F /
%
R 1=CF3CO. Ts
I80
81
Scheme 26
In computer modeling experiment. 2-0 and 3-0 are closer in allylsilane-imine in
cis- than in irons- orientation. In addition, coupling constant is consistent with
structurally related compounds formed from allylbis(silane)-imines.6
NOE experiments showed similar results. In products o f cis- orientation,
significant NOE was observed between C2-H and 03-El. To confirm the structural
assignment, one product was converted to the corresponding AMosylpyrrolidine (Scheme
27). The result of NOE experiment o f AMosylpyrrolidine was consistent with that o f Ntrifluoroacetylpyrrolidine.
Scheme 27
20
A single crystal'of the resulting JV-tosylpyrrolidine (grown in ethyl ether/hexane)
was subjected to X-ray crystallography. The elucidated structure supported the
proceeding stereochemistry assignment.
21
Figure 2. X-ray crystallography structure of c/j-A^-Tosyl-2(4-chlorophenyl)-1-trifluoroacetyl-3-vinylpyrrolidine
22
CHAPTER 3
EXPERIMENTS
General Experimental Details: 1H N M R , 13C NM R and 19F NMR spectra were measured
at 300 MHz, 75 MHz, and 282.2 MHz respectively, with a Bruker AC-300 spectrometer.
1H NM R NOE experiments were performed at 250MHz, with a Bruker AC-250
spectrometer. 1H NMR, data were reported in 5 value in ppm relative to residual proton
signals in CDCI3 or CgDe- 1H NMR coupling constants are reported in Hz and refer to
real or apparent multiplicities indicated as follows: s ( singlet); d (doublet); t (triplet); q
(quartet); m (multiplet); br (broad); dd (doublet o f doublet); dt ( doublet o f triplet); dq (
doublet o f quartet); etc. Infrared spectra were recorded on a Bruker IFS 25 IR. Electronic
impact mass spectra (70 eV) were obtained with a Hewlett Packard 5970 series GCmasspec. High resolution mass spectra were recorded on a VG Instrument 70E-HF
spectrometer. Melting points were obtained using a Mel-Temp II apparatus equipped with
a Fluke 5 1 digital thermometer and are uncorrected.
Tetrahydrofuran, diethyl ether were distilled from sodium/benzophenone.
Dichloromethane, toluene and dimethylformamide were distilled from CaHz.
Unless otherwise noted, all reactions were carried out under an atmosphere of
argon in flamed or oven-dried vessel with magnetic stir bar and stir plate. Unless
otherwise stated, reagents were used without purification.
23
Iodomethyltrimethylsilane (35)
This procedure was slightly modified in separation from the literature procedure. A
mixture o f chloromethyltrimethylsilane (13.2 g, 107.5 mmol), sodium iodide (32.2 g, 215
mmol), tetrabutylammonium iodide (7.9 g, 21.5 mmol), and water (18 mL) was heated to
reflux for 4 hours. After cooled to room temperature, the mixture was partitioned
between water and pentane. The mixture settled into two phases with a thick interface o f
gray suspension. After filtration through a pad celite (washed with pentane), a clear twophase solution was obtained. The organic phase was separated and washed with water
(2x20 mL), then dried over magnesium sulfate. After filtration, pentane was evaporated
under reduced pressure while the flask containing the product was cooled with an ice
bath. The concentrated clear or lightly colored liquid was distilled (136 0C, 745 mmHg)
to afford the product as a clear liquid (16.726g, 73%). The resulting iodide was used
immediately. The compound shows pink color, a sign o f decomposition, within 24 hours
at 0 0C.
2-But-3 -ynyloxy-tetrahydro-pyran (37)
To a mixture o f 3—butyn-l-ol (2.9 mL, 38 mmol), dihydropyran (3.8 ml., 42 mmol) in
CHzCL (2 mL) cooled at 0# was added p-toluenesulfonic acid (10 mg; 20 mg) in one
portion. Stirring was continued at that temperature for 30 minutes, followed by at room
temperature for 16 hours. The solution was transferred to a separatory funnel, washed
with saturated NaHCOg (15 mL). The organic layer was separated and the aqueous phase
was extracted with CHzCL (20 mL). The combined CHzCL solution was dried over
24
NazSC^. After filtration and evaporation, the residue was distilled ( water aspirator, ~ 20
mmHg, 113-117 O C ) to afford 2-but-3-ynyloxy-tetrahydro-pyran ( THP-protected 3b u ty n -l-o l) ( 4.78 g, 82 % ) 1H NMR (300 MHz, CDCl3) 8 4.63 ( t, 1H, CH(OR)2), 3.84.0 (m, 2H, OCH2), 3.4-3.6 ( m, 2H, OCH2), 2.5 (m, 2H, C=CCH2), 2.0 (t, 1H, C=CH),
1.3-1.8 (m, 6H, (CH2)3)
6-(Trimethylsilyl)-4-hexyn-1-ol (33)
To a stirred solution o f THP-protected 3-butyn-l-ol (30.84 g, 0.20 mol) in THF (200 mL)
at -4 0 0C (bath) and under argon was added dropwise butyllithium ( 81.4 mL, 2.457 M in
hexane, 0.20 mol), followed by stirring a t-3 0 0C (bath) and 0 0C (bath) each for 15 min.
Iodomethyltrimethylsilane (42.85 g, 0.20 mol) was added in one portion. The reaction
flask was then cover with aluminum foil and heated with stirring at 55 0C for 36 hours.
The reaction mixture was allowed to cool down to room temperature, then diluted with
500 mL o f pentane. The resulting mixture was washed with water (3x300 mL), dried over
MgS O4, and concentrated in vacuo. Crude product was obtained as a yellowish oil which
could be used without further purification ( GC > 98 %). (It could be purified with
Kugelrohr distillation to give a colorless oil in 70% yield).
To the solution o f the crude from the previous step in methanol (3 0 0 mL) was
added 2 drops o f 98% sulfuric acid. The mixture was stirred at room temperature for 12
hours. The mixture was transferred to a 2 L separatory funnel. 300 mL o f ethyl ether and
300 mL pentane were added. The resulting mixture was washed with half-saturated
NaHCO3 ( 400 mL), water ( 400 mL), and brine (4 0 0 mL), then dried over MgSO^ After
25
filtration and evaporation o f the solvent, fractional distillation ( 61-65°C, 2 rrunHg)
afforded the pure product as a clear liquid. ( 22.28g, 0.143 mol, 71.3% for 2 steps) 1H
NM R (300 MHz, CDCl3) 8 3.63 (t, 2H, J=6.2, OCH2), 3.37 (s, 1H, OH), 2.40 (m, 2H,
CH2C=), 1.41 (t, J=2.6,2H , CH2Si), 0 (s, 9H, Si(CH3)3); 13C NMR (75 MHz, CDCl3, 1H
decoupled) 8 129.1,122.5, 62.5, 30.6, 18.7, -1.8;
(Z)-5-(Trimethylsilyl)-3-penten-1-ol (39)
To a stirred solution o f nickel acetate hydrate (1.05 g, 4.2 mmol, 25% mol) in absolute
ethanol ( 30 mL), under an atmosphere o f argon, was added a solution o f NaBHt in
ethanol ( 4.2 mL, 4.2 mol, 1.0 M, 25% mol). The mixture turned black immediately upon
addition. The flask was purged with hydrogen and ethylenediamine ( 0.56 mL, 8.4 mmol,
50% mol) was introduced. After 5 min, a solution o f 6-(trimethylsilyl)-4-hexyn-1-ol
(2.64g, 16.9 m m o l) in absolute ethanol ( 4 mL) was added. The reaction mixture was
stirred vigorously under hydrogen atmosphere for 5 hours (TLC). Significant absorption
o f hydrogen was observed. The reaction mixture was concentrated under reduced
pressure and the residual was triturated with dichloromethane. Filtration through a short
column o f Florisil (CH2Cl2 as elutant), followed by evaporation o f the solvents under
reduced pressure gave the product which was pure enough ( GC > 96% ) for further
transformation ( 2.53g, 16.0 mmol, 94% ). 1H N M R (300 MHz, CDCl3) 8 5.48-5.66 (m,
1H, CH=C), 5.16-5.33 (m, 1H, C=CH), 3.62 (q, 2H, OCH2, J=6.4), 2.38 (q, 2H, J=7.2,
CH2C=), 1.50 (d, J=8.5, 2H, CH2Si), 0 (s, 9H, Si(CH3)3); 13C NMR (75 MHz, CDCl3, 1H
decoupled) 8 129.1, 122.5, 62.5, 30.6, 18.7, -1.8;
26
7V-(Z)-(5-Trimethylsilylpent-3-enyl)phthalimide (40)
The preparation o f phthalimide is modified from the literature. The reduction o f the initial
temperature (bath) to -4 0 0C greatly improved the yield. Presumably, the reaction o f
triphenylphosphine with diethyl diazocarboxylate is highly exothermic, which may cause
certain side effect in Mitsunobu reaction. To a stirred mixture o f (Z)-S -(trimethylsilyl)-3 penten-l-ol ( 6.62 g, 41.8 mmol), triphenylphosphine (12.06 g, 46.0 mmol, L I),
phthalimide ( 9.23 g, 62.7 mmol), and THF (1 6 0 m l) at -40 0C ( solids partially soluble)
was added dropwise diethyl azodicarboxylate (7.25 mL, 46.0 mmol) over 30 min. The
reaction mixture was allowed to warm to O0C over 5 hours. The reaction mixture was
then kept stirring at room temperature for 12 hours. Solvent was removed under reduced
pressure. After most triphenylphosphine oxide was removed by recrystalization ( ethyl
acetate / hexane), the residue was subject to a short column o f silica gel to remove the
rest o f triphenylphosphine oxide ( 10% ethyl acetate / hexane). Chromatography again on
silica gel afforded the pure product as a colorless viscous oil ( 11.79 g, 41.0 mmol, 98%).
1H NMR (300 MHz, CDCl3) d 7.72-7.82 (m, 2H, ArH), 7.58-7.68 (m, 2H, ArH), 5.355.55 (m, 1H, CH=C), 5.150-5.30 (m, 1H, C=CH), 3.65 (t, J=7.4,2H , NCH2), 2.32 (q, 2H,
J=7.2, CH2C=), 1.40 (d, 2H, J=8.7, CH2Si), -0.08 (s, 9H, Si(CH3)3); 13C NM R (75 MHz,
CDCl3, 1H decoupled) 8 168.8,134.2,132.6,129.2,123.5,122.8, 38.1,26.7,19.0, -1.5;
27
(Z)-S-TrimethyIsily-3-penten-1 -amine (32)
To a 100 mL, single-necked, round-bottom flask containing a solution o f phthalimide
(4.22g, 14.7mmol) in degassed absolute ethanol (4 5 mL) was added hydrazine
monohydrate (1.5 mL, 30 mmol) dropwise over 2 min via a syringe. The flask was then
fitted with a condenser and the mixture was heated to reflux for 2.5 hours, during with a
white solid precipitated. Upon cooling to room temperature, the solids was collected by
filtration and washed thoroughly with hexane. The solvents were evaporated under
reduce pressure and the residual was triturated with hexane. Filtration o f the supernatant
liquid followed by solvent removal in vacuo gave a cloudy liquid which was subject to
Kugelrohr distillation (55 0C, 1.1 mmHg) to furnish the pure product (1.66g, 72%). 1H
NM R (300 MHz, CDCl3) 5 5.43-5.56 (m, 1H, CH=C), 5.16-5.29 (m, 1H, C=CH), 2.642.77 (t, 2H, NCH2), 2.07-2.21 (q, 2H, CH2C=), 1.68 (s, br, 2H, NH2), 1.48 (d, 2H,
CH2Si), 0 (s, 9H, Si(CH3)3); 13C NM R (75 MHz, CDCl3, 1H decoupled) d 128.0,124.7,
42.4, 31.7, 19.0, -1.5; IR (film): 3338 (br), 2955, 1671, 1248, 856
(S)-Ethyl-(0-/ez7-butyldiphenylsilyl)lactate
To a 25 mL, single-necked, round-bottom flask containing a solution o f f-butylchlorodiphenylsilane (2 .6 mL, 10 mmol) and imidazole (1.63 g, 24 mmol) in DMF (5 mL)
was added (S)-ethyl lactate (1.36 mL, 12 mmol) dropwise over a 30 m in via a 5.0 mL
addition funnel. During the course for the addition, mild exotherms and precipitation o f a
clear oil were observed. The reaction mixture was stirred at room temperature for 5 hours
and let settle overnight into two layers. The bottom layer was removed with a separatory
28
funnel and extracted with hexane (3X 5 mL). The combined product layer and extracts
were washed with water ( 2X5 mL) the , dried over M gS04, filtered and concentrated.
The residual was eluted through a plug o f silica gel and concentrated in vacuo to furnish
the protected ester (3.27 g, 92% ) as a colorless viscous oil. 1H NM R (300 MHz, CDCI3)
S 7.6-7:8 (m, 4H, ArH), 73-7.5 (m, 6H, ArH), 4.25 (q, 1H, J=6.8, OCH), 4.0 (q, 2H,
J=7.1, OCH2), 1.35 (d, 3H, 3=6.7, CHCH3), 1.13 (t, 3H, J=7.1, OCH2CTf3), 1.08 (s, 9H,
SiC(CH3)3); 13C NMR (75 MHz, CDCl3, 1H decoupled) S 204.1,136.1,133.7,133.4,
130.4, 128.2, 74.9, 27.3, 19.6, 18.8;
(5)-Ethyl-(0-tert-butyldiphenylsilyl)lactaldehyde
A 50 mL, single-necked, round-bottom flask containing a solution o f (5)-ethyl-(O fbutyldiphenylsilyl)lactate ( 3.25g, 9.12 mmol) in toluene (1 8 mL) was cooled to -78 0C
and diisobutylaluminum hydride (1 0 mL, 10 mmol, I .OM in toluene) was added
dropwise over 20 min via a 10 mL addition funnel. The reaction mixture was stirred for 2
hours and was carefully poured into half-saturated brine (5 0 mL). The biphasic mixture
was extracted with ether ( 3X20 mL). The combined organic phase was washed with
brine (4 0 mL), dried over MgSCL, filtered and concentrated. The residual was eluted
through a thin pad o f silica gel (hexane as elutant) to provide the aldehyde. ( 2.30 g,
81%). 1H N M R (300 MHz, CDCl3) S 9.6 (s, 1H, CHO), 7.6-7.S (m, 4H, ArH), 73-7.5
(m, 6H, ArH), 4.1 (q, 1H, J=6.8, OCH), 1.2 (d, 3H, J=6.7, CHCTf3), 1.13 (t, 3H, J=7.1,
OCH2CTf3), 1.08 (s, 9H, SiC(CH3)3);
29
Ethyl O-t-butylsimethylsilylactate
1H N M R (300 MHz, CDCl3) 5 4.29 (q, 1H, J=6.7, CHOTBS), 4.08-4.22 (m, 2H, OCH2),
1.38 (d, 3H, J=6.7, CHgCHOTBS), 1.26 (t, 3H, J=7.1, OCH2CH3), 0.89 (s, 9H,
SiC(CH3)3), 0.07 (d, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3, 1H decoupled) <5
174.5, 68.8, 61.1, 26.1, 21.7, 18.7, 14.6, -4.6, -4.9; IR (film) 2951, 2856, 1760, 1480,
1375, 1265, 1144, 1060, 830, 785;
O-Z-Butylsimethylsilylactaldehyde
1H N M R (300 MHz, CDCl3) § 9.58 (1H, N=CH), 4.06 (q, 1H, J=6.8, CHOTBS), 1.23 (d,
J=6.8, CH3), 0.89 (s, 9H, SiC(CH3)3), 0.07 (d, 6H, Si(CH3)2); 13C N M R (75 MHz,
CDCl3, 1H decoupled) § 204.5, 26.1,18.9, 18.5, -4.4(d); IR (film) 2391, 1741,1473,
1375, 1255,1134, 1098, 1007, 837, 778
General procedure for the generation o f allylsilane-imine: To a 10 mL single-necked
round-bottom flask containing a solution o f amine (I mmol) in THF ( 3 mL) was added
activated 4 A molecular sieves followed by fleshly distilled isobutyraldehyde. The
mixture was stirred at room temperature for appropriate time (mostly 12 hours) before
diluted with diethyl ether ( 3 mL) and filtered through a plug o f Celite. Evaporation o f
solvents and excessive aldehyde in vacuo afforded imine as colorless oil which was used
immediately for further transformation without any purification.
Isobutylidene-(Z)-(5-trimethylsilylpent-3 -enyl)amine (29a)
30
1H NM R (300 MHz, CDCl3) S 7.5 (1H, N=CH), 5.26-5.82 (m, 1H, CH=C), 5.0-5.2 (m,
1H, C=CH), 3.1-3.4 (m, 2H, NCH2), 2.0-2.4 (m, .2H, CH2C=), 1.3-1.5 (m, 2H,
=CCH2Si), 1.0 (dd, 6H, J=6.8), -0.05 (s, 9H, Si(CH3)3); 13C NMR (75 MHz, CDCl3, 1H
decoupled) S 170.2, 127.5, 124.6, 61.5, 34.4, 29.1,19.8, 19.0, -1.4;
Benzylidene-(Z)-(5-trimethylsilylpent-3-enyl)amine (29d)
1H NM R (300 MHz, CDCl3) d 8.3 (s, 1H, N=CH), 7.7 (m, 2H, ArH), 7.3 (m, 3H, ArH),
5.5 (m, 1H, CH=C), 5.3 (m, 1H, C=CH), 3.6 (m, 2H, NCH2), 2.4(q, J=I2 , CH2C=), 1.5
(d, J=8.5, 2H, CH2Si), 0(s, 9H, Si(CH3)3); 13C NM R (75 MHz, CDCl3, 1H decoupled) S
161.41, 136.72, 130.87, 128.95, 128.47, 127,68, 124.62, 62.03, 29.19, 19.05, -1.38; IR
(film) 3007, 2952, 2834, 1646, 1580, 1450, 1310, 1247,1149, 1052, 857, 753, 693
4-Chlorobenzylidene-(Z)-(5 -trimethylsilylpent-3 -enyl)amine (29e)
1H NM R (300 MHz, CDCl3) S 8.2 (s, 1H, N=CH), 7.6 (m, 2H, ArH), 7.4 (m, 2H, ArH),
5.5 (m, 1H, CH=C), 5.3 (m, 1H, C=CH), 3.6 (m, 2H, NCH2), 2.4(q, J=I2 , CH2C=), 1.5
(d, J=8.5, 2H, CH2Si), 0(s, 9H, Si(CH3)3); 13C NM R (75 MHz, CDCl3, 1H decoupled) S
160.0, 129.7, 129.2, 127.8, 124.5, 62.0, 29.1, 19.1, -1.4;
4-Methoxybenzylidene-(Z)-(5-trimethylsilylpent-3-enyl)amine (29f)
1H NM R (300 MHz, CDCl3) S 8.18 (s, 1H, N=CH), 7.61-7.69 (m, 2H, ArH), 6.86-6.94
(m, 2H, ArH), 5.39-5.53 (m, 1H, CH=C), 5.22-5.35 (m, 1H, CH=C), 3.81 (s, 3H,
31
ArOCH3), 3.19-3.61 (t, 2H, J=7.3, NCH2), 2.31-2.42 (q, 2H, JK7.2, NCH2CZZ2), 1.48 (d,
2H, J=8.6, CH2Si), -1.56 (s, 9H, Si(CH3)3); 13C NMR (75 MHz, CDCl3, 1H decoupled) 5
162.1,131.4, 131.1,128.9,126.1,116.1,115.7, 63.3, 57. 1, 30.7, 20.4, 0;
2-Methoxybenzylidene-(Z)-(5-trimethylsilylpent-3-enyl)amine (29g)
1H NM R (300 MHz, CDCl3) 5 8.68 (s, 1H, N=CH), 7.88-7.95 (m, 1H, ArH), 7.30-7.39
(m, 1H, ArH), 6.85-7.00 (m, 2H, ArH), 5.40-5.53 (m, 1H, CH=C), 5.24-5.35 (m, 1H,
CH=C), 3.85 (s, 1H, OCH3), 3.57-3.65 3.6 (td, 2H, J=7.4, 1.0, NCH2), 2.32-2.43 (q,
J=7.1, CH2C=), 1.46-1.53 (d, J=8.4, 2H, CH2Si), -0.01 (s, 9H, Si(CH3)3); 13C NMR (75
MHz, CDCl3, 1H decoupled) 8 159.1, 157.4, 132.1, 127.7, 127.5, 125.2, 124.8,121.2,
111.4, 62.3,55.9, 29.4,19.4,-1.4; IR (film) 3006, 2953,2836, 1638, 1600,1488,1465,
1248, 1159, 1029, 856, 754;
2-Z-Butyldimethylsiloxyethylidene-(Z)-(5-trimethylsilylpent-3-enyl)amine
1H NM R (300 MHz, CDCl3) 8 7.49 (d, 1H, J=5.0, N=CH), 5.26- 5.82 (m, 1H, CH=C),
5.50-5.25 (m, 1H, C=CH), 4.28-4.31 (dq, 1H, J=6.5, 5.4, CHOTBS), 3.33-3.38 (t, 2H,
J=7.2, NCH2), 2.22-2.29 (ddd, J=6.9, 7.1, 2H, CH2C=), 1.45 (d, 2H, J=8.6, =CCH2Si),
1.24 (d, 3H, J=6.5, CH3CHOTBS), 0.87 (s, 9H, SiC(CH3)3), 0.04 (d, 6H, Si(CH3)2),
-0.03 (s, 9H, Si(CH3)3); 13C N M R (75 MHz, CDCl3, 1H decoupled) 8 168.2 , 127,6, 124.5,
71.0, 61.1, 28.9, 26.2, 22.2, 19.1,18.6, -1.4, -4.2; IR (film) 2951, 2856, 1676, 1473,
. 1362, 1252, 1148, 1091,1005, 836, 777;
32
General procedure for allysilane-imine cyclizations: To a solution o f allysilane-imine in
dichloromethane (0.1-0.16M) a t-78 0C was added 1.2-1.5 equivalent o f TFAT over two
minutes. The mixed solution was kept at the -7 8 0G for ten minutes, then at the setting
temperature ( ranging from - 40°C to -20 0C). After an appropriate reaction time, the
reaction was quenched with saturated aqueous NaHCOs solution. The mixture was stirred
at 0 0C for I hour. The organic phase was separated. The aqueous phase was extracted
with dichloromethane for three times. The combined dichloromethane solution was dried
over MgSOzt. After filtration o f M gS04 followed by evaporation o f dichloromethane, the
residue was subjected to flash chromatography on silica gel and gave the cyclized
product o f A-trifluoromethyIated pyrrolidine. An analytical sample o f pure isomer was
isolated by preparative gas chromatography.
tram-2-Isopropyl-l-trifluoroacetyl-3-vinylpyrrolidine (30a, tram)
1H NM R (300 MHz, CDCl3) <5 5.8-6.0 (m, 1H, C=CH), 5.1-5.2 (m, 2H, C=CH2), 4.2 (t,
0.8H, J=6.7, C2-H), 3.3-3.9 (m, 2.2H, C5-H, C2-H), 2.1-2.9 (m, 1H, C3-H), 1.7-2.2 (m,
2H, C4-H); 13C NM R (7 5 MHz, CDCl3, 1H decoupled) 8 137.3,129.1,128.0,127.9,
125.9, 125.3,117.1, 116.5, 67.9, 52.7, 51.2, 47.9, 47.5, 31.1, 26.5; 19F-NMR ( 82.2MHz
CDCl3) <5-71.4, -72.9; IR (film): 2960,1693,1557,1455,1204,1146, 920, 854; HRM S:
235.1178 (calc 235.1184); NOE enhancement between C2-H and C3-H: 5.7%;
33
fra/M ^-Isobutyl-1-trifluoroacetyl-3 -vinylpyrrolidine (30b, tram)
1H NM R (300 MHz, CDCl3) <S 5.66-5.85 (m, 1H, C=CH), 5.02-5.24 (m, 2H, C=CH2),
4.14-4.40 (m, 1H, C2-H), 3.30-3.80 (m, 2H, C5-H), 2.68-2.90 (m, 1H, C3-H), 1.85-2.33
(m, 2H, C4-H), 1.20-1.65 (m, 3H, C2-CH2CH), 1.10-1.20 (m, 0.5H, CH(Cfl3)2), 0.75- .
1.14 (m, 5.5H, CH(Cfl3)2); 13C NMR (7 5 MHz, CDCl3, DEPT 135) S 135.2, 117.5, 59.8,
45.0, 44.9, 38.7, 28.7, 25.5, 22.8, 22.7; 19F-NMR ( 282.2MHz CDCl3) 8 -70.6, -72.7; IR
(film); 2958, 1692, 1592, 1447, 1245, 1200, 1141, 855; HRMS: 249.1343 (calc
249.1340); NOE enhancement between C2-H and C3-H: 6.2%;
Z/'a«j'-2-Heptyl-1-trifluoroacetyl-3-vinylpyrrolidine (30c, tram)
1H NM R (300 MHz, CDCl3) 8 5.60-5.85 (m, 1H, C=CH), 4.92-5.24 (m, 2H, C=CH2),
3.82-4.02 (m, 1H, C2-H), 3.82-4.02 (m, 1H, C5-H), 3.40-3.60 (m, 1H, C5-H), 2.55-2.80
(m, 1H, C3-H), 2.05-2.23 (m, 1H, C4-H), 1.41-1.90 (m, 3H, C4-H, C2-CH2), 1.10-1.41
(s, br, I OH, C2-CH2(Cfl2)5), 0.77-0.95 (m, 3H, CH3); 13C NM R (7 5 MHz, CDCl3, 1H
decoupled) 8 139.0,116.0, 64.1,46.2,45.7, 32.2,29.9,2 9 .6 ,2 6 .7 ,2 5 .7 , 23.0,14.5; 19FN M R (282.2MHz CDCl3) 5 -7 1 .0 , -72.7; IR (film); 2928, 2857, 1691,1452,1240, 1200,
1141, 919; HRM S: 291.1804 (calc 291.1810); NOE enhancement between C2-H and C3H: 2.1%;
cz'j^-Heptyl-1-trifluoroacetyl-3-vinylpyrrolidine (30c, cis)
1H N M R (300 MHz, CDCl3) 8 5.58-5.90 (m, 1H, C=CH), 5.00-5.28 (m, 2H, C=CH2),
4.18-4.35 (m, 0.8H, C2-H), 3.98-4.10 (m, 0.2H, C2-H), 3.45-3.85 (m, 2H, C5-H), 2.70-
34
2.92 (m, 1H, C3-H), 1.88-2.15 (m, 2H, C4-H), 1.11-1.62 (m, 12H, C2-(CH2)6), 0.77-0.95
(m, 3H, CH3); 13C NMR ( 75 MHz, CDCl3, 1H decoupled) <5 135.5, 117.9, 62.0, 45.5,
45.2, 32.2, 30.1, 30.0, 29.5, 29.2, 27.0, 23.0, 14.5; 19F-NMR (282.2MHz CDCl3) <5-70.8,
-72.7; IR (film); 2929, 2856, 1691, 1449, 1241, 1201, 1141, 919; HRMS: 291.1819 (calc
291.1810); NOE enhancement between C2-H and C3-H: 7.7%;
cz"5-2-Phenyl-1-trifluoroacetyl-3 -vinylpyrrolidine (3 Od3 cis)
1H N M R (300 MHz, CDCl3) S 7.18-7.36 (m, 3H, ArH), 6.94-7.08 (m, 2H, ArH), 5.155.28 (m, 1H, ArCHN), 4.88-5.14 (m, 3H, C=CH), 4.03-4.20 (m, 0.6H, NCH), 3.92-4.03
(m, 0.4H, NCH), 3.70-3.89 (m, 1H, NCH), 2.97-3.21 (m, 1H, C3-H), 1.81-2.20 (m, 2H,
C4-H); 13C NMR (75 MHz, CDCl3, 1H decoupled) S 138.7,137.6, 135.9, 135.8,128.7,
128.1, 128.0, 127.1, 126.9, 122.4,118.6, 118.3, 118.0, 117.8, 114.8, 65.9, 65.4, 49.7,
48.5, 47.1, 47.0, 46.9, 29.5, 26.2; 19F-NMR (282.2MHz CDCl3) <5-71.5, -73.1; IR (film):
2980,2903,1695,1448,1347,1240,1200,1139, 923, 756, 702; HRMS: 269.1028 (calc
269.1027); NOE enhancement between C2-H and C3-H: 9.4%
tram -2-Phenyl-1-trifluoroacetyl-3-vinylpyrrolidine (30d, tram)
1H NMR (300 MHz, CDCl3) S 6.7-7A (m, 6H, ArH), 5.75-5.92 (m, 1H, C=CH), 5.0-5.2
(m, 2.2H, C=CH2, C2-H), 4.8 (d, 0.8H, J=6.1, C2-H), 3.7-4.1 (m, 2H, C5-H), 2.7-2.9 (m,
1H, C33-H), 1.8-2.4 (m, 2H, C4-H) 13C NM R (7 5 MHz, CDCl3, 1H decoupled) <5137.3,
129.1, 128.0, 127.9, 125.9, 125.3, 117.1, 116.5, 67.9, 52.7, 51.2, 47.9, 47.5, 31.1, 26.5;
19F-NMR (282.2M H z CDCl3) <5-71.3,-72.8; IR (film): 2932,1692, 1448, 1239, 1195,
35
1140, 997, 754; HRMS: 269.1018 (calc 269.1027); NOE enhancement between C2-H
and C3-H: 2.5%
cN-2-(4-Chlorophenyl)-l-trifluoroacetyl-3-vinylpyrrolidine (30e, cis)
1H NM R (300 MHz, CDCl3) S 7.18-7.36 (m, 2H, ArH), 6.85-7.03 (m, 2H, ArH), 4.905.24 (m, 4H, ArCHN, CH=CH2), 3.90-4.18 (m, 1H, C5-H), 3.70-3.89 (m, 2H, C5-H),
2.97-3.22 (m, 1H, C3-H), 1.75-2.20 (m, 2H, C4-H); 13C NM R (75 MHz, CDCl3, 1H
decoupled) d 137.3, 136.3, 135.4,135.3,134.0, 133.8, 129.0,128.4, 128.2, 118.5, 118.3,
114.7, 65.4, 64.8, 49.5, 48.5, 47.0, 46.7, 29.5, 26.1; IR (film): 2936,1692, 1491, 1448,
1239, 1202, 1145, 1091; HRM S: 361.0906 (calc 361.0903); NOE enhancement between
C2-H and C3-H: 12%
cA-2-(4-Methoxyphenyl)-1-trifluoroacetyl-3-vinylpyrrolidine (3 Of, cis)
1H NM R (300 MHz, CDCl3) S 6.77-7.0 (m, 3H, ArH), 4.90-5.22 (m, 4H, C2-H,
CH=CH2), 3.88-4.15 (m, 1H, C5-H), 3.7-3.S (d, 3H, ArOCH3), 2.95-3.14 (m, 1H, NCH),
1.8-2.2 (m, 2H, C4-H); 13C N M R (75 MHz, CDCl3, 1H decoupled) S 136.0, 130.8,129.7,
128.2, 128.0, 117.9, 117 .7 ,114.1, 114.0, 65.5, 65.0, 55.6, 50.0, 48.4, 47.0, 29.5, 26.2;
19F-NMR ( 282.2MHz CDCl3) <5-71.6, -73.2; IR (film): 2958, 2838, 1694,1612,1586,
1612,1514,1450,1248,1199, 1143,1071, 831; HRM S: 299.1132 (calc. 299.1133); NOE
enhancement between C2-H and C3-H: 8.2%
36
2-(2-Methoxyphenyl)-1-trifluoroacetyl-3-vinylpyrrolidine (3Og)
1H NM R (300 MHz, CDCl3) 8 1.1-1.3 (m, IR, ArH), 6.8-7.0 (m, 3H, ArH), 5.6-6.0 (m,
1H, C=CH), 4.8-5.4 (m, 3H, C=CH2, C2-H), 3.7-4.0 (m, 5H, CH3, C3-H, C5-H), 2.8-3.2
(m, 1H, C5-H), 1.8-2.3 (m, 2H, C 4-H );; 19F-NMR ( 282.2MHz CDCl3) 8 major: -71.9, 73.0; minor: -71.6, -72.8; 13C NMR (7 5 MHz, CDCl3, 1H decoupled) 8 138.2, 129.0,
126.9, 125.9, 120.9, 116.1, 111.3, 64.5, 55.8, 48.1, 47.0, 30.3,25.8; IR (film); 2922,
1694, 1492, 1454, 1237, 1195, 1142, 1108, 754; HRMS: major: 299.1132; minor:
299.1129 (calc 299.1133);
2-(2-Ethoxycarbonylethyl)-2-methyl-1-trifluoroacetyl-3 -vinylpyrrolidine (74)
1H NM R (300 MHz, CDCl3) 8 5.66-5.90 (m, 1H, C=CH), 4.96-5.34 (m, 2H, C=CH2),
4.14-4.40 (m, 1H, C2-H), 4.05-4.24 (q, 2H, J=7.1, OCH2CH3), 3.70-3.98 (m, 1H, C5-H),
3.36-3.58 (m, 1H, C5-H), 2.52-2.70 (m, 2H, CH2COO), 1.83-2.36 (m, 5H, C3-H, C4-H,
C2-CH2), 1.18-1.35 (m, 6H, C2-CH3, OCH2CH3); 13C NMR (7 5 MHz, CDCl3, 1H
.decoupled) <5 173.5,135.0,119.2,118.5, 69.1,61.0, 49.1,4 7 .3 ,3 0 .7 ,2 9 .3 ,2 8 .6 ,2 4 .5 ,
19.6,14.6; 19F-NMR ( 282.2MHz CDCl3) 5 -6 7 .5 , -68.4, -72.9, -73.1; IR (film); 2981,
1735, 1690, 1440, 1247, 1202, 1142, 1110; HRM S: major 307.1395, minor
307.1395(calc 307.1386);
H-((Z)-5-Trimethylsilyl-3-enyl)trifluoroacetamide (71)
1H NM R (300 MHz, CDCl3) 8 6.3(1H, s, br, NH), 5.6 (1H, m, C=CH), 5.2 (1H, m,
C=CH), 3.3 (2H, q, J=6.5, NCH2), 2.3 ( 2H, q, J=6.6, CH2CH=), 1.5(2H, d, J=8.6,
37
CH2Si), 0(9H, s, Si(CH3)3); 13C NMR ( 75 MHz, CDCl3, 1H decoupled) S 130.5, 122.2,
39.9, 26.7, 19.2, -1.4; 19F-NMR ( 282.2MHz CDCl3) S -76.41(1F, s), -76.46(3.7F, s); IR
(film): 3310, 3107, 3013, 2955, 1704, 1560, 1445, 1369, 1250, 1207, 1184, 956, 723,
701, 644; HRM S: 253.1122 (calc 253.1110);
General procedure for converting AMrifluoroacetylpyrrolidine to AMosylpyrrolidine: Ntrifluoroacetylpyrrolidine (Imol) was dissolved in 10 mL o f a solution OfK2CO3 (I.SM)
in MeOHZH2O (1:1). The mixture was stirred at room temperature for 48 hours. TLC
showed that starting material disappeared. The solution was diluted with water (1 0 mL)
then extracted with dichloromethane (4X10 mL). The combined dichloromethane
solution was dried over MgSOzt. After filtration and evaporation o f solvent under reduced
pressure, the residue was triturated with pentane. After filtration through a pad o f Celite
and evaporation o f pentane under reduced pressure, the crude pyrrolidine was treated
with tosyl chloride (1.5 mmol) and pyridine (3 mmol) in dichloromethane ( 2 mL) at 0
DC for I hour then at room temperature for 2 hours. Water ( 2 mL) was added to the
reaction vessel and the resulting mixture was stirred vigorously for I hour. The organic
phase was separated and the remaining aqueous phase was extracted with
dichloromethane (3x5 mL). The combined dichloromethane solution was dried over
MgSCL. After filtration and evaporation o f solvent under reduced pressure, the residue
was subjected to column chromatography (silica gel).
cz'5,-2-(4-Chlorophenyl)-1-tosyl-3-vihy!pyrrolidine (83)
38
1H NM R (300, MHz, C6D6) S 7.7-7.S (d, 2H, ArH), 7.1 (m, 2H, ArH), 6.S-6.9 (m, 4H,
ArH), 4.58-4.90 (m, 4H, C2-H, CH=CH2), 3.47-3.58 (m, 1H, C5-H), 3.17-3.32 (m, 1H,
C5-H), 2.37-2.43 (m , 1H, C3-H), 2.0 (s, 3H, ArCH3), 1.28-1.57 (m, 2H, C4-H); 13C
NM R ( 75 MHz, CDCl3, 1H decoupled) J 143.9, 138.4, 136.1, 135.4, 133.4, 130.0, 129.3,
128.5, 127.8, 117.5, 65.9, 49.1,48.4,29.6,21.9; IR (film): 2918, 2848, 1490,1348, 1161,
1090,1011, 922, 817, 665; HRM S: 361.0906 (calc 361.0903); m.p. 97.8-98.8°C; NOE
enhancement between C2-H and C3-H ( C6D6 ): 14.2%; A single crystal for X-ray
crystallography experiment was obtained from ethyl ether/hexane.
39
REFERENCES
1. Fleming, I.; Barbero, A. Walter, D. Chem. Rev., 1997, 97, 2063.
2. for example: (a) Kadota, I., Gevorgyan, V., Yamada, J. Synlett. 1991, 823; (b)
Majetich, G.; Song J.-S.; Leigh, A. J.; Condon, S. M. J. Org. Chem. 1993, 58, 1030.
3. (a) Laschat, S. D.; Kunz, H. J. Org. Chem. 1991, 56, 5883. (b) Kira, M.; Hino, T.;
Sakura, H. Chem Lett. 1991,277.
4. (a) Larsen, S. D.; Grieco, P. A.; Fobare, W. F. J Am. Chem. Soc. 1986, 108, 3512. (b)
Grieco, P. A.; Fobare, W. F. Tetrahedron Lett. 1986, 27, 5067. (c) Fuchigami, T.;
Ichikawa, S.; Kanna, A. Chem. Lett. 1989, 1987.
5. (a) synthesis o f isoquinoline skeleton: Heerding, D. A.; Hong, C. Y.; Kado, N.; Look
G. C.; Overman, L. E. J. Org. Chem. 1993, 58, 6947. (b) Polyolefin cyclization:Grieco, P. A.; Fobare, W. F. J. Chem. Soc., Chem. Commun. 1987, 185.
6. (a) Kercher, T. Doctoral Thesis, Montana State University, 1997. (b) Kercher, T.,
Livinghouse, T. J. Am. Chem. Soc., 1996, 118, 4200.
7. Hiemstra, H.; Sno, M. H. A. M.; Vijn, R. J.; Speckamp, W. N. J. Org. Chem. 1985, 50,
4041.
8. Ambasht, S.; Chiu, S. K.; Peterson, P. E.; Queen, J. Synthesis, 1980, 318.
9. Miller, M., Hegedus, L. S., J. Org. Chem. 1993, 58, 6779.
10. (a) Johnson, W. S.; Chenera B., Tham F. S.; Kullnig. R. J. Am. Chem. Soc. 1993, 115,
493. (b) Johnson, W. S.; Fletcher, V. R.; Chenera B.; Bartlett, W. R.; Tham F. S.;
Kullnig, R. J. Am. Chem. Soc. 1993, 115, 497. (c) Johnson, W. S.; Buchanan. R. A.,
Bartlett, W. R.; Tham F. S.; Kullnig, R. J. Am. Chem. Soc. 1 993, 115, 504.
11. Hamme, M. J. V.; Burton, D., J. Organometallic Chem. 1979, 169, 123.
12. (a) Thaning, M.; Wistrand, L. G. J. Org. Chem. 1990, 5 5 , 1406. (b) Hiemstra, H.;
Fortgens, H. P.; Speckamp W. N. Tetrahedron Lett. 1985, 26, 3151.
13. Forbus, T. R., Jr.; Taylor, S. L.; Martin, J. C. J. Org. Chem. 1987, 52, 4156.
14. entry 6 had the highest amount o f byproduct, 30% based on trifluoroacetamide (19FNMR)
40
APPENDIX A
REPRESENTATIVE SPECTRA
41
(Z)-5-Trimethylsily-3 -penten-1 -amine 1H -N M R ................................................................ 42
(Z)-5-Trimethylsily-3-penten-l-amine 13C -N M R ........................................
43
Isobutylidene-(Z)-(5-trimethylsilylpent-3-enyl)amine 1H -N M R ...................................... 44
Isobutylidene-(Z)-(5-trimethylsilylpent-3-enyl)amine 13C -N M R .......................................45
4-Methoxybenzylidene-(Z)-(5-trimethylsilylpent-3-enyl)amine 1H -N M R ......................46
4-Methoxybenzylidene-(Z)-(5 -trimethylsilylpent-3 -enyl)amine 13C -N M R .......... ........... 47
czj,-2-(4-Chlorophenyl)-1-trifluoroacetyl-3 -vinylpyrrolidine 1H -N M R ..............................48
czj,-2-(4-Chlorophenyl)-1-trifluoroacetyl-3 -vinylpyrrolidine 13C -N M R ........................... 49
cz's-jV-Tosyl-2-(4-chlorophenyI)-1 -trifluoroacetyl-3-vinylpyrrolidine 1H -N M R ...............50
cz's-7V-Tosyl-2-(4-chlorophenyl)-1-trifluoroacetyl-3-vinylpyrrolidine 1H-NMR COSY ..51
cz's-jV-Tosyl-2-(4-chlorophenyl)-1-trifluoroacetyl-3 -vinylpyrrolidine 13C -N M R ............ 52
trazzs-2-Isopropyl-1-trifluoroacetyl-3-vinylpyrrolidine 1H -N M R .......................................53
tmzzs-2-Isopropyl-1-trifluoroacetyl-3 -vinylpyrrolidine 1H-NMR C O S Y ......................... 54
fnms-jV"-Tosyl-2-isopropyl-1-trifluoroacetyl-3-vinylpyrrolidine 1H -N M R ....................... 55
Zrazzs-jV"-Tosyl-2-isopropyI-1 -trifluoroacetyl-3 -vinylpyrrolidine 1H-NM R C O S Y .......... 56
cz's-2-Phenyl-1-trifluoroacetyl-3 -vinylpyrrolidine 1H -N M R ............................................... 57
czs-2-Phenyl-1-trifluoroacetyl-3 -vinylpyrrolidine 1H-NMR C O S Y ............................... ,..58
cz's-2-Phenyl-1-trifluoroacetyl-3 -vinylpyrrolidine 13C -N M R .............................................. 59
Zrazzs-2-Phenyl-1-trifluoroacetyl-3-vinylpyrrolidine 1H -N M R ............................................ 60
/razzs-2-Phenyl-1-trifluoroacetyl-3 -vinylpyrrolidine 1H-NMR C O S Y ............................... 61
Zrazzs-2-Phenyl-1-trifluoroacetyl-3 -vinylpyrrolidine 13C -N M R ........................................... 62
czs-2-(4-Methoxyphenyl)-1-trifluoroacetyl-3 -vinylpyrrolidine 1H -N M R ......................... 63
cz's-2-(4-Methoxyphenyl)-1-trifluoroacetyl-3-vinylpyrrolidine 1H-NM R COSY...............64
czs-2-(4-Methoxyphenyl)-1-trifluoroacetyl-3 -vinylpyrrolidine 13C -N M R ........................ 65
2-Phenyl-1-trifluoroacetyl-3-vinylpyrrolidine (crude) 19F-NMR .......................................66
cz's-2-Phenyl-1-trifluoroacetyl-3 -vinylpyrrolidine 19F -N M R ........................' ..................... 67
Zrazzs-2-Phenyl-1-trifluoroacetyl-3-vinylpyrrolidine 19F -N M R ........................................... 68
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I
I
zra/zs-.A/-tosyl-2-isopropyl-l-lriiluoroacetyi-3-vmyipyrruiiumc
1H-NMR
I
ppm
Z/-fl/M-//-tosyl-2-isopropyl-l-trifluoroacetyl-3-vinylpyrroIidine
1H-NMR COSY
1
6 8
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0
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3 8
2
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HHHO^mmmc n mmm
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m-2-phenyl-l-trifluoroacetyl-3-vinylpyrrolidine
1H-NMR
’ I *
10
7
r~~
H
<T
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VO
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Cl
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6
5
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C Sj
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ppm
c«-2-phenyl-l-trifluoroacetyl-3-vinylpyrrolidine
LDlOO^CMLDCTvVDLOLOOO^rCOOlOOO
co c M r"crv M io r^ r-o o o ^rcM co co O n -i
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P O C O C O C O C M C M C M C M C M C M C M f —I i H r H t H f H
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s r 'T <r <r
old
cm cm
I
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i—I
I
—I
I
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c/'j-2-phenyl-l-trifluoroacetyl-3-vinylpyrrolidine
13C-NMR
Ln
LO
I
I
~\
200
'
I
180
'
I
160
'
I
140
'
JLwswwvLetwtWwt
I
120
'
I
100
'-----------r
80
I
60
40
■
r
I
20
0
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I
ppm
I—I
ooc\ja\ir>mcrvo*r
r-coLocncocricoLn
O rH V D L D C T lO rH O O
CM CsJ CO I—I O I—) CO r
O r H r H C M O C N 1T r H
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C M r H O O V D r ^ iT
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co i/“) o
C T iO O cH O O C N rH C N U O
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t
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m r o m c N C N C N H O
O lD T i—I O O C T i C O
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CM Ch rHCD CM rH r H
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rc o i o t o t o 1T
1T 1T
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'H-NMRhen^1' 1 tri^u0r0acetyl3vinylpyrrolidine
I ..................I ....................I
1 0
9
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8
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7
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p p m
ppm :
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1 -
K R Phr o s lYl‘lrm,,or°acc,yl"3"vinylp>Trolidin=
014
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2-
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11
10
9
8
7
6
5
4
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2
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1
0
ppm
r - ' i - H o o r o v o r ' - r ^ i T )
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Os
to
200
180
160
140
120
100
I
I
I
60
I
80
40
20
I
ppm
xru)(')srr~coo<rmr-HmcN
r-^TrHcorooor^^rcNj
l<T»CT»crvOOCXDOOCvlrHrHrH
c o r - m^ r mo mr ^
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CO VD < r cm
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c/j-2-(4-methoxyphenyl)-l-trifluoroacetyl-3-vinylpyrrolidine
1H-NMR
/
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c n v D ^ r m m r D m v o o o
« - i c N M O o o r ~ u n < r m
O r H r H r H O O O O O
c/i-2-(4-methoxyphenyl)- l-trifluoroacetyl-3-vinylpyrrolidine
1H-NMR COSY
O-
2
-
JfQ
a
6
0
4
0*
-
4
6-
8-
9 -
10-
11
-
ppm
(— <r
m m r O C N C M C N r H n H M M
i f - 1 « —I r - l i —I t —i r - l r - l t —I t —I
m-2-(4-methoxyphenyl)-l-trifluoroacetyl-3-vinylpyrrolidine
1C-NMR
m ld
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r- r-
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2-phenyl-l-trifluoroacetyl-3-vinylpyrrolidine (.cirude)
19F-NMR
/
I
Cl
Cl
i m
... ..........
—67
I.........I.......... .... i —68
—69
—70
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m
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- 7 9 ppm
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H
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I
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r~ r~
m-2-phenyl-l-trifluoroacetyI-3-vinylpyn'olidine
19F-NMR
ON
I
I
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.
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-5 0
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ppm
r—<
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. BOZEMAN
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