Investigations concerning the organolanthanide and group 3 metallocene-catalyzed cyclization-functionalization of nitrogen-containing dienes

Article abstract of DOI:10.1016/j.tet.2005.01.048

Organolanthanide catalyzed cyclization-silylation of nitrogen-containing polyunsaturated systems allows access to core structures commonly found in naturally occurring alkaloids. Nitrogen-containing dienes with various substitution patterns were investigated. The method was most successful for substrates with terminal alkenes. Cyclization upon pendant 1,1-disubstituted olefins was not realized under various conditions. Interestingly, sterically hindered sulfonamides, which were previously believed to render the catalyst inactive, were actually compatible with the catalyst, thus affording the cyclized products after prolonged reaction times. Variations using fused ring systems were also investigated.

Full text of DOI:10.1016/j.tet.2005.01.048

Tetrahedron 61 (2005) 2631–2643
Investigations concerning the organolanthanide and group 3
metallocene-catalyzed cyclization–functionalization of
nitrogen-containing dienes
*
Gary A. Molander and Jan Antoinette C. Romero
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
PA 19104-6323, USA
Received 3 November 2004; revised 14 January 2005; accepted 14 January 2005
Abstract—Organolanthanide catalyzed cyclization–silylation of nitrogen-containing polyunsaturated systems allows access to core
structures commonly found in naturally occurring alkaloids. Nitrogen-containing dienes with various substitution patterns were investigated.
The method was most successful for substrates with terminal alkenes. Cyclization upon pendant 1,1-disubstituted olefins was not realized
under various conditions. Interestingly, sterically hindered sulfonamides, which were previously believed to render the catalyst inactive,
were actually compatible with the catalyst, thus affording the cyclized products after prolonged reaction times. Variations using fused ring
systems were also investigated.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
NMR. The high diastereoselectivity associated with this
process was thought to result from the avoidance of
interactions between the catalyst and the piperidine ring
during the intramolecular insertion of the more hindered
vinyl group of the diene.2d
Carbon–carbon bond-forming reactions remain of great
importance to synthetic organic chemists. To this end,
organolanthanide metallocenes have demonstrated their
synthetic utility in the diastereoselective construction of
carbocycles from relatively simple acyclic polyunsaturated
precursors.1 Our research utilizing these catalysts has been
focused on the selective cyclization–functionalization of
dienes,2 enynes,3 and dienynes.4 During the course of our
studies, the process was found to be tolerant of tertiary
amines, thus providing opportunities for the incorporation
of nitrogen atoms within the unsaturated substrate. Success-
ful cyclization–silylations were realized with nitrogen-
containing dienes2c,d and enynes.3b Extension of this
method to nitrogen-containing heteroaromatic dienes was
effected, demonstrating ‘aryl-directed’ regioselectivity.2f
Furthermore, oxidation5 of the resultant organosilane
affords the corresponding amino alcohol, a structural
motif commonly found in naturally occurring alkaloids.
As a testament to the synthetic utility of the cyclization–
silylation–oxidation sequence, diene (1) was efficiently
cyclized and transformed to (G)-epilupinine (Scheme 1).
Remarkably, none of the trans isomers could be observed by
Scheme 1. The synthesis of (G)-epilupinine.
Owing to our successes in constructing relatively complex
nitrogen heterocycles selectively from simple polyunsatu-
rated systems, we sought to investigate the scope of the
organolanthanide-catalyzed cyclization of nitrogen-contain-
ing dienes. The requisite dienes could be easily assembled
from commercially available starting materials permitting
Keywords: Organolanthanide-catalyzed; Lanthanide; Organolutetium;
Catalysis; Nitrogen heterocycle; Cyclization–silylation reaction.
* Corresponding author. Tel.: C1 215 573 8604; fax: C1 215 573 7165;
e-mail: gmolandr@sas.upenn.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.048

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G. A. Molander, J. A. C. Romero / Tetrahedron 61 (2005) 2631–2643
(1)
Extension of this method to nitrogen-containing dienes with
various substitution patterns was investigated. Secondary
acyclic allylamine derivatives were synthesized by reduc-
tive amination with the corresponding aryl aldehyde (5 and
6) or N-alkylation procedures (7).6 Tertiary amines (8–10)
were assembled by alkylation with the corresponding allyl
bromide (Scheme 3).
Scheme 2. Variations of nitrogen-containing dienes.
various substitution patterns on the diene to be investigated
(Scheme 2). Given the increased steric demands of the
cyclization precursors, the potential for the lanthanide to
chelate to the initial organometallic intermediate is of
greater concern. High diastereoselectivity in the cyclization
event was anticipated based on previous studies within our
laboratories. Successful application of our protocol would
allow ready access to a variety of heterocyclic systems that
are widespread in nature.
Generally, the catalytic reactions of these more substituted
diallylamine derivatives were run at higher temperatures
and for longer reaction times in comparison to the
cyclization–functionalization of 1,6-heptadiene (Table 1).
Under the optimized reaction conditions, substrates contain-
ing monosubstitution at the allylic position (8) provided a
complete reaction within one hour (entry 1, Table 1).
Although this is a positive result, a less sterically hindered
catalyst is preferred to expand the scope of this method to
highly substituted olefins. Unfortunately, attempts at
employing [CpT2MSLu(m-Me)]2, a catalyst that provides a
more open coordination sphere, resulted in a complex
mixture of products (entry 2, Table 1). The progress of the
reaction could be complicated by Lewis acid–Lewis base
interactions between the lanthanide catalyst and the amine
moiety.
2. Results and discussion
2.1. Cyclization–functionalization of aminodienes
At the outset of our studies, diallylmethylamine was
surveyed for reactivity with Cp*2YMe$THF (2) and
Cp*2LuMe$THF (3) under a variety of conditions. Investi-
gations commenced with a screening of catalysts, silanes,
and solvents to determine the optimal reaction conditions to
effect the desired cyclization (Eq. 1). Methylphenylsilane
was found to be the required terminator in the reaction to
allow the second olefin insertion to occur. Employing
phenylsilane resulted in the premature trapping of the
initially generated organometallic intermediate, thus
affording uncyclized products. Catalyst 2 was effective at
providing the desired piperidine 4 in 71% yield after 12 h.
However, by simply changing the metal from yttrium to
lutetium, the same reaction was completed in 1 h with an
increase in yield (83%).
Increasing the steric bulk surrounding nitrogen required
fine-tuning of the catalyst to achieve the desired cyclization.
Aminodiene 9 failed to cyclize under the reaction conditions
established for substrate 8 (entry 3, Table 1). Pleasingly,
geminal substitution at the allylic position could be tolerated
by employing a less hindered metallocene to accommodate
theincreasedstericdemandsofthesubstrate(entry 4,Table1).
The cyclization of diene 9 was successfully realized by
utilizing [CpT2MSLu(m-Me)]2, a precatalyst that has a more
open coordination sphere because of the smaller ligands
surrounding the metal center. Although catalysts based upon
Scheme 3. Synthesis of acyclic diallylamine substrates.

G. A. Molander, J. A. C. Romero / Tetrahedron 61 (2005) 2631–2643
Table 1. Cyclization–silylation of aminodienes 8–10
2633
Entry
Substrate
Catalyst
Temperature
Time
Results
Products
11
Complete reaction,
mixture of four diastereomersa
8
9
1
2
Cp*2LuMe$THF
rt
rt
1 h
1 h
major
[CpT2MSLu(m-Me)]2
Incomplete reactionb
—
12
3
4
5
Cp*2LuMe$THF
[CpT2MSLu(m-Me)]2
[CpT2MSLu(m-Me)]2
100 8C
100 8C
50 8C
1.5 h
12 h
84% Uncyclized product
13
14
77% Cyclized product
10
O24 h
30% Uncyclized product
a Upon oxidation of the crude silane, the resultant alcohol was obtained in 89:11 ds, 39% yield.
b Very low conversion after 24 h (!10%) with uncyclized material as the only product as determined by H NMR spectroscopy.
1
the CpTMS ligand were ineffective at cyclizing diene 8, we
postulate that geminal substitution a to nitrogen suppresses
Lewis base chelation with the more accessible lanthanide.
Thus, by sterically shielding the nitrogen, intramolecular
olefin insertion is preferred and the desired piperidine 13
can be readily accessed.
catalyst be based upon a more open ligand framework
(e.g., CpTMS, Me2SiCpTMS, Me2SiCpt-Bu). Presumably, in
the cyclization event, intramolecular olefin coordination
precedes olefin insertion. Such an intermediate has been
observed by Casey and coworkers and has been used to
explain the high diastereoselectivity associated with cycli-
zation reactions.7 Thus, more ‘open’ catalysts are necessary
to accommodate more substituted alkenes. Unfortunately,
by providing a more accessible metal atom, the Lewis basic
nitrogen atom competes effectively with the carbon–carbon
Pendant 1,1-disubstituted olefins (10) were not effective in
the cyclization event under a variety of conditions (entry 5,
Table 1). The steric demand of the olefin requires that the
Figure 1. Proposed pathways for the reaction of 10 with [CpT2MSLu(m-Me)]2.

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G. A. Molander, J. A. C. Romero / Tetrahedron 61 (2005) 2631–2643
Scheme 4. Synthesis and catalytic reaction of 15.
double bond for coordination with the Lewis acidic
lanthanide. As such, formation of a five-membered chelate
via binding between the nitrogen and the lutetium atoms of
the hydrometalated olefin intermediate interferes with
intramolecular olefin insertion, thus affording uncyclized
silanes (Fig. 1).3b
temperature.11 The desired volatile dienes 22 and 23 were
isolated after column chromatography and careful distilla-
tion in 32 and 50% yields, respectively, over two steps
(Scheme 5).
Over a range of reaction conditions, dienes 22 and 23 failed
to afford the desired fused bicycle, providing instead silanes
24 and 25, respectively (Eq. 2). Interestingly, the initial
olefin insertion occurs under milder reaction conditions than
previously employed for the cyclization of acyclic sub-
strates. Perhaps unfavorable interactions with the pyrroli-
dine or piperidine hamper intramolecular coordination of
the lanthanide and the nitrogen atoms, thereby facilitating
premature termination of the organometallic intermediate.
In efforts to favor cyclization onto 1,1-disubstituted olefins,
several methods were employed. Investigations commenced
with applying steric variations to inhibit the intramolecular
coordination. Successful cyclization of substrates contain-
ing geminal substitution a to nitrogen encouraged us to
investigate the use of tert-butyl protecting groups as
opposed to benzyl. Presumably, intramolecular chelation
is disfavored in the presence of the steric hindrance
surrounding nitrogen. Diallylamine derivative 15 was
assembled by sequential alkylation of tert-butylamine with
the appropriate electrophiles. Unfortunately, all attempts at
cyclization failed to afford the desired cyclized product
(Scheme 4).
(2)
Another structural variation incorporated the diallylamine
motif onto a ring. Dienes based upon the pyrrolidine and
piperidine systems have similarities with the polyunsatu-
rated precursor of epilupinine, which was known to undergo
facile cyclization. Commercially available 2-pyrrolidine-
methanol and 2-piperdinemethanol were converted to the
BOC protected amino alcohols 16 and 17 in 94 and 86%
yields, respectively, by treatment with di-tert-butyl dicar-
bonate in the presence of triethylamine.8 Parikh–Doering
oxidation (SO3$pyr, DMSO) of the alcohols afforded
aldehydes 18 and 19 efficiently after 2 h at 0 8C.9 Wittig
olefination using 2 equiv of both freshly prepared potassium
tert-butoxide and methyltriphenylphosphonium bromide
provided the corresponding alkenes in excellent yields.10
The amines were deprotected by exposure to trifluoroacetic
acid in CH2Cl2 and the crude trifluoroacetic acid amine salts
were allylated using 3-bromo-2-methylpropene in the
presence of excess potassium carbonate in MeCN at room
Based on the above results, the basicity of the nitrogen
would have to be attenuated by inductive methods.
Unfortunately, conventional electron-withdrawing nitrogen
protecting groups (e.g., amide, carbamate, sulfonamide) are
not compatible with the highly Lewis acidic lanthanide
metal center because of the presence of the Lewis basic
oxygens. Previous studies directed at enhancing the rate of
the termination step demonstrated that perfluorinated silanes
were compatible with the lanthanide metallocenes.12 In an
attempt to reduce the basicity of the nitrogen, fluorine atoms
were incorporated onto the benzyl protecting group. To test
the compatibility of incorporating a fluorine atom on the
substrate, p-fluorobenzyldiallylamine (26) was assembled
in 93% yield by reductive amination of diallylamine and
p-fluorobenzaldehyde. Gratifyingly, p-fluorobenzyldiallyl-
amine was cyclized using catalyst 3, albeit in low yield and
under harsher reaction conditions (Eq. 3).
(3)
To induce a greater electron withdrawing effect, penta-
fluorobenzyldiallylamine substrates were investigated.
Scheme 5. Synthesis of cyclic dienes 22 and 23.

G. A. Molander, J. A. C. Romero / Tetrahedron 61 (2005) 2631–2643
2635
sufficient steric shielding of the oxygens from coordinating
to the lanthanide metal center. After an extended period of
time, diallylmesitylsulfonamide 32, assembled from the
reaction of diallylamine and mesitylsulfonyl chloride, did
indeed cyclize, despite previous beliefs that polar nitrogen
protecting groups would deactivate group 3 metallocenes
(Scheme 7). Upon oxidation of the purified silane, primary
alcohol 34 was isolated in 63% yield. The structure of 34
was confirmed by X-ray structure determination. Unfortu-
nately, attempts at extending this method to 1,1-disubsti-
tuted olefins were unsuccessful.
Despite our best efforts to reduce the ability of nitrogen to
chelate to the catalyst, cyclization onto 1,1-disubstituted
alkenes was not realized. Therefore, we sought to take
advantage of the electron-donating ability of nitrogen to
enhance olefin reactivity. The exciting possibility exists to
utilize enamine moieties in the cyclization reaction. We
reasoned that the enamine moiety would provide added
electron density to allow the Lewis acid-driven reaction
with the pendant organometallic. Marks and co-workers
have shown that enamines can be generated in the
intramolecular hydroamination of N-allyl-4-pentyn-1-
amine.13 This newly formed pyrrolidine can be envisioned
to undergo a C–C bond-forming cyclization reaction. To test
this hypothesis, enamine 35 was synthesized by the
alkylation of 2,3,3-trimethylindoline.14 Geminal substi-
tution at the benzylic position was necessary to avoid
isomerization of the exocyclic double bond to give the
aromatic indole. Unfortunately, subjecting the substrate to
the catalytic conditions did not provide the desired tricyclic
compound. However, it is surprising that hydrosilylation of
the isolated olefin was possible in the presence of the
enamine moiety (Eq. 4).
Scheme 6. Synthesis of 29 and 30.
Substrates were easily synthesized by reductive amination
of allylamine and pentafluorobenzaldehyde and subsequent
alkylation with the appropriate allyl bromide (Scheme 6).
To our delight, the catalytic reaction of 29 with 5 mol%
[CpT2MSY(m-Me)]2, a catalyst with smaller ligands and a
larger metal, successfully afforded the desired cyclized
product (Table 2). Utilizing
a catalyst that had
both smaller ligands and a larger metal center provided
two handles for tuning the catalyst. Unfortunately, varia-
tions in both the handles did not provide positive results.
Reactions with pendant 1,1-disubstituted olefins remained
elusive.
The failures encountered above led us to reevaluate the
protecting group on nitrogen. Mesityl sulfonamides are
electron-withdrawing and highly sterically encumbered. As
such, the ortho methyl groups were expected to provide
Table 2. Catalytic reactions with 29 and 30
Substrate
Catalyst
Temperature
Time
Results
29
30
30
[CpT2MSY(m-Me)]2
[CpT2MSLu(m-Me)]2
[CpT2MSY(m-Me)]2
50 8C
0–100 8C
50 8C
8 h
4–12 h
12 h
97% cyclized, 3% uncyclized
NR
NR
Scheme 7. Reaction of N-sulfonamide 32.

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G. A. Molander, J. A. C. Romero / Tetrahedron 61 (2005) 2631–2643
Scheme 8. Synthesis of diene 40.
(4)
(7)
The final substrates investigated were those that would
demonstrate aryl-directed regioselectivity.2f,15 The sub-
strates were constructed starting with known aldehyde 44.
Aldehyde 44 was synthesized by directed aryl substitution
of 1,2,3,4-tetrahydroquinoline.16 Subsequent N-alkylation
and Wittig olefination provided the desired dienes 47 and 48
in moderate yields (Scheme 9).
Other nitrogen heterocyclic scaffolds were investigated.
Diallylamines based upon isoquinoline systems provided
interesting results. Substrate 40, bearing vinyl substitution
at the 3-position, was synthesized in the same fashion as
substrates 22 and 23 (Scheme 8).
Isoquinoline 41 with the vinyl moiety at the pseudobenzylic
position was synthesized from known 3,4-dihydroisoquino-
line (Eq. 5). The imine was treated with allyl bromide to
generate the N-allyl iminium ion in situ, which was reacted
with vinylmagnesium bromide to provide the desired diene.
(5)
Isoquinoline 40 underwent efficient cyclization, and after
oxidation of the C–Si bond and esterification, the resulting
acetate was obtained in 52% yield over three steps in a 5:4
diastereomeric ratio (Eq. 6). Surprisingly, 41 failed to
undergo cyclization under a variety of conditions (Eq. 7). It
is possible that the vinyl moiety adopts a pseudo-axial
orientation to minimize steric interactions with the aryl ring.
This perturbation forces the initially generated organo-
metallic to proceed through a transition state that is less
chair-like during the insertion step, thus slowing the
reaction and providing an opportunity for premature
silylation.
Scheme 9. Synthesis of dienes 47 and 48.
(6)
Scheme 10. Catalytic reaction of 47 and 48.

G. A. Molander, J. A. C. Romero / Tetrahedron 61 (2005) 2631–2643
2637
Upon subjection to the catalytic reaction conditions
(5 mol% [CpT2MSLu(m-Me)]2, PhMeSiH2, C6D6) the diene
systems failed to react. The lack of reactivity could be
explained by the formation of a 5-membered chelate with
the adjacent nitrogen, resulting in deactivation of the
organolanthanide (Scheme 10).
4.1.1. N-Methylpiperidine-3-methylphenylsilylmethane
(4) (representative procedure for the cyclization–silyla-
tion of an aminodiene with organolanthanide catalysts).
In a sealed tube initially prepared in the glovebox,
Cp*2LuMe$THF (10 mg, 5.0 mol%) was dissolved in
cyclohexane (1.0 mL). To this solution was added diallyl-
methylamine (42 mg, 0.37 mmol) and methylphenylsilane
(55 mg, 0.45 mmol). The reaction was stirred at room
temperature for 1 h. GC analysis of the crude reaction
mixture indicated that the reaction was complete. The clear,
colorless solution was diluted with diethyl ether and filtered
through a small plug of silica to remove the catalyst. The
resulting solution was concentrated by rotary evaporation.
The crude product was purified by flash chromatography to
provide a mixture of diastereomers of the title compound as
a clear, colorless oil in 83% yield; Rf 0.25 (10:90 MeOH/
CH2Cl2); 1H NMR (500 MHz, CDCl3) d 7.53–7.51 (m, 2H),
7.35–7.32 (m, 2H), 6.95 (t, JZ7.0 Hz, 1H), 4.44–4.41 (m,
1H), 2.78–2.71 (m, 2H), 2.20 (app. d, JZ3.0 Hz, 3H), 1.80–
1.75 (m, 3H), 1.60–1.48 (m, 3H), 0.85–0.70 (m, 3H), 0.34
(app. dd, JZ1.9, 3.8 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 136.6, 134.2, 129.2, 127.8, 65.1, 64.9, 55.9, 46.6, 39.6,
33.4, 33.2, 33.0, 25.7, 19.3, 19.3, K5.0, K5.1; IR (neat)
3023, 2928, 1442 cmK1; LRMS (CI) m/z 232 (100), 218
(73); Anal. Calcd for C14H23NSi: C, 72.04; H, 9.93; Found:
C, 71.95; H, 9.90.
3. Conclusions
The group 3 metallocene-catalyzed cyclization–silylation of
various nitrogen-containing dienes was investigated. The
process was limited to monosubstituted olefins. Cyclization
onto 1,1-disubstituted olefins was not achieved under a
variety of conditions. Studies directed at reducing the
basicity of the nitrogen atom revealed that mesityl
sulfonamides are compatible with an organolutetium
catalyst and that a successful cyclization can be realized.
In the case of fused cyclic systems, intramolecular insertion
is sensitive to substitution upon the ring. Additionally,
enamines do not react with the lanthanide catalysts, while
allowing the hydrosilylation of pendant alkenes. Finally,
aryl-directive effects were not effective in promoting the
cyclization of non-heteroaromatic containing dienes.
4. Experimental
4.1.2. N-Allyl-N-benzylmethallylamine (8). N-Benzyl-
methallylamine was synthesized by a published pro-
4.1. Materials and methods
cedure.18
To
N-benzylmethallylamine
(0.808 g,
5.01 mmol) in 10.0 mL of MeCN was added K2CO3
(1.38 g, 10.0 mmol) in one portion. The suspension was
stirred for 0.5 h before adding allyl bromide (0.786 g,
6.50 mmol). The suspension was stirred overnight at room
temperature. The solvent was removed in vacuo, and the
crude residue was dissolved in 5 mL of Et2O and washed
with 2 mL of H2O. The organic layer was separated, dried
with MgSO4, and filtered. The resulting clear solution was
reduced in vacuo. The diene was purified by flash
chromatography to provide the title compound as a clear,
colorless oil in 88% yield; Rf 0.25 (10:90 MeOH/CH2Cl2);
1H NMR (500 MHz, CDCl3) d 7.34 (t, JZ7.1 Hz, 2H), 7.28
(t, JZ7.4 Hz, 2H), 7.20–7.22 (m, 1H), 5.78–5.92 (m, 2H),
5.05–5.19 (m, 4H), 3.62 (d, JZ14.1 Hz, 1H), 3.54 (d, JZ
14.1 Hz, 1H), 3.34–3.40 (m, 1H), 3.06 (ddd, JZ27.7, 14.4,
8.3–Hz, 2H), 1.13 (d, JZ3.6 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 140.8, 140.3, 137.3, 128.5, 128.1, 116.4, 115.3,
All catalytic experiments were performed in a nitrogen-
filled glovebox or in a sealed reaction vessel initially
prepared in the glovebox. The organolanthanide complexes
were prepared according to literature procedures.17 Et2O
and THF were distilled from sodium/benzophenone ketyl
immediately before use. Cyclohexane and d6-benzene were
distilled from sodium/benzophenone ketyl and stored in a
glovebox. Triethylamine and dichloromethane were dis-
tilled from CaH2 prior to use. Acetonitrile and N-methyl-
˚
pyrrolidinone (NMP) were dried and stored over 4 A
molecular sieves. Phenylsilane, phenylmethylsilane, and
toluene were distilled from sodium metal, sparged with
argon, freeze-pump-thaw-degassed, and transferred into and
stored in a glovebox. Potassium carbonate was dried and
stored in a drying oven. Potassium hydride was purchased as
a 35% dispersion in mineral oil. The white solid was
isolated after several washings with dry hexanes using
Schlenk techniques. All products synthesized were found to
be O95% pure by capillary GC analysis unless otherwise
indicated. All substrates for catalytic reactions were
vacuum-transferred from CaH2 into a Schlenk flask and
freeze-pump-thaw degassed prior to exposure to the
catalyst. Analytical thin-layer chromatography (TLC) was
performed on silica gel (60F–254) plates (0.25 mm)
precoated with a fluorescent indicator. Flash chromatog-
raphy was performed on silica gel (particle size 0.040–
0.063 mm). Yields refer to chromatographically and
spectroscopically pure compounds unless otherwise noted.
1H, 13C, and 19F, spectra were recorded on a 500 MHz
spectrometer. Chemical shifts are reported as d values
relative to internal tetramethylsilane (d 0.00), chloroform
56.1, 53.5, 52.6, 15.2; IR (neat) 3052, 2931, 1243 cmK1
;
LRMS (CI) m/z 201 (100), 104 (87); Anal. Calcd for
C14H19N: C, 83.53; H, 9.51; Found: C, 83.65; H, 9.33.
4.1.3. N-Allyl-N-benzyl-a,a-dimethylallylamine (9).
N-Benzyl-a,a-dimethylallylamine was synthesized by a
published procedure.6 To N-benzyl-a,a-dimethylallylamine
(0.527 g, 3.01 mmol) in 6.00 mL of MeCN was added
K2CO3 (0.829 g, 6.00 mmol) in one portion. The suspension
was stirred for 0.5 h before adding allyl bromide (0.527 g,
0.393 mL, 3.90 mmol). The suspension was stirred over-
night at room temperature. The solvent was removed in
vacuo, and the crude residue was dissolved in 5 mL of Et2O
and washed with 2 mL of H2O. The organic layer was
separated, dried with MgSO4, and filtered. The resulting
solution was reduced in vacuo. The diene was purified by
1
(d 7.26), or benzene (d 7.16) for H and either chloroform
(d 77.0) or benzene (d 128.0) for 13C.

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G. A. Molander, J. A. C. Romero / Tetrahedron 61 (2005) 2631–2643
flash chromatography to provide the title compound as a
clear, colorless oil in 92% yield; Rf 0.25 (10:90 MeOH/
CH2Cl2); 1H NMR (500 MHz, CDCl3) d 7.35 (d, JZ7.4 Hz,
2H), 7.25 (m, 2H), 7.17 (t, JZ7.3 Hz, 1H), 5.99 (dd, JZ
10.8, 17.6 Hz, 1H), 5.70–5.84 (m, 1H), 5.07 (d, JZ17.6 Hz,
1H), 5.01 (dd, JZ0.8, 10.8 Hz, 1H), 4.96 (dd, JZ1.6,
17.2 Hz, 1H), 4.87 (dd, JZ1.3, 10.1 Hz, 1H), 4.68 (s, 2H),
3.20 (d, JZ6.4 Hz, 2H), 4.19 (s, 6H); 13C NMR (125 MHz,
CDCl3) d 147.4, 142.7, 138.7, 128.1, 127.9, 126.2, 115.0,
111.7, 59.6, 53.0, 52.9, 24.5; IR (neat) 3051, 2963,
1435 cmK1; LRMS (CI) m/z 215 (100), 200 (67), 104
(83); Anal. Calcd for C15H21N: C, 83.67; H, 9.83; Found: C,
83.80; H, 9.70.
1.23–1.32 (m, 1H), 0.99–1.02 (m, 2H), 0.82–0.94 (m, 1H),
0.25–0.27 (m, 3H).
4.1.6. 3-(N-Allyl-N-a,a-dimethylallyl)amino-3-methyl-
phenylsilylpropane (12). The title compound was prepared
according to the general procedure for the preparation of 4
using 5 mol% of Cp*2LuMe$THF at 100 8C in a sealed
tube. The reaction was complete after 1.5 h as indicated by
1H NMR analysis. Workup and purification by flash
chromatography gave the title compound in 84% yield; Rf
0.25 (10:90 MeOH/CH2Cl2); 1H NMR (500 MHz, CDCl3) d
7.39–7.41 (m, 2H), 7.29–7.34 (m, 5H), 7.23–7.27 (m, 2H),
7.09–7.13 (m, 1H), 4.93–5.99 (m, 1H), 4.97–5.04 (m, 2H),
4.20–4.23 (m, 1H), 3.64 (s, 2H), 2.52 (dd, JZ6.1, 7.4 Hz,
2H), 1.25–1.28 (m, 2H), 0.99 (s, 6H), 0.61–0.64 (m, 2H),
1.17–1.19 (m, 3H); 13C NMR (125 MHz, CDCl3) d 147.6,
143.5, 136.7, 134.3, 129.2, 127.9, 127.8, 127.8, 126.1,
111.4, 59.6, 54.9, 54.5, 25.4, 24.2, 10.9, K5.8; IR (neat)
3032, 2967, 2119, 1461 cmK1; LRMS (CI) m/z 337 (42),
336 (100), 240 (73); Anal. Calcd for C22H31NSi: C, 78.27;
H, 9.26; Found: C, 78.14; H, 9.21.
4.1.4. 1-(N-Allyl-N-benzylamino)-2-methyl-2-propene
(10). N-Benzylallylamine was synthesized by a published
procedure. To N-benzylallylamine (1.87 g, 10.0 mmol) in
20.0 mL of MeCN was added K2CO3 (2.76 g, 20.0 mmol)
in one portion. The suspension stirred for 0.5 h before
adding 3-bromo-2-methyl-1-propene (1.74 g, 1.30 mL,
12.9 mmol). The suspension was stirred overnight at room
temperature. The solvent was removed in vacuo, and the
crude residue was dissolved in 10 mL of Et2O and washed
with 5 mL of H2O. The organic layer was separated, dried
with MgSO4, filtered, and reduced in vacuo. The diene was
purified by flash chromatography to provide the title
compound as a clear, colorless oil in 93% yield; Rf 0.25
(10:90 MeOH/CH2Cl2); 1H NMR (500 MHz, CDCl3) d
7.32–7.34 (m, 2H), 7.27–7.30 (m, 2H), 7.12–7.22 (m, 1H),
5.78–5.92 (m, 1H), 5.18 (dd, JZ1.6, 17.2 Hz, 1H), 5.11 (dd,
JZ1.3, 10.2 Hz, 1H), 4.92–4.93 (m, 1H), 4.83–4.84 (m,
1H), 3.51 (d, JZ4.5 Hz, 2H), 2.98–3.01 (m, 2H), 2.91–2.96
(m, 2H), 1.73–1.75 (m, 3H); 13C NMR (125 MHz, CDCl3) d
144.0, 139.2, 136.1, 128.7, 128.1, 126.7, 116.8, 112.5, 60.5,
37.7, 56.3, 20.7; IR (neat) 3042, 2946, 1454 cmK1; LRMS
(CI) m/z 201 (100), 160 (63), 104 (87); Anal. Calcd for
C14H19N: C, 83.53; H, 9.51; Found: C, 83.06; H, 9.06.
4.1.7. N-Benzylpiperidine-2,2-dimethyl-3-methylphenyl-
silylmethane (13). The title compound was prepared
according to the general procedure for the preparation of 4
using 5 mol% of [CpT2MSLuMe]2 at 100 8C in a sealed tube.
1
The reaction was complete after 12 h as indicated by H
NMR analysis. Workup and purification by flash chroma-
tography gave the title compound as a mixture of
diastereomers in 84% yield; Rf 0.25 (10:90 MeOH/
CH2Cl2); 1H NMR (500 MHz, CDCl3) d 7.54–7.56 (m,
2H), 7.27–7.36 (m, 6H), 7.23–7.27 (m, 1H), 7.13–7.20 (m,
1H), 4.40–4.43 (m, 1H), 3.82–3.89 (m, 1H), 3.08–3.13 (m,
1H), 2.39–2.48 (m, 1H), 2.24–2.32 (m, 1H), 1.50–1.72 (m,
2H), 1.32–1.48 (m, 4H), 1.18–1.31 (m, 2H), 1.03–1.17 (m,
1H), 0.93 (s, 3H), 0.58–0.71 (m, 1H), 0.35–0.37 (m, 3H);
13C NMR (125 MHz, CDCl3) d 142.0, 137.0, 134.3, 134.3,
129.2, 128.2, 128.0, 128.0, 127.9, 126.3, 57.9, 54.3, 54.2,
47.0, 47.0, 42.7, 42.6, 31.6, 29.1, 28.9, 26.9, 25.5, 25.4,
25.3, 22.6, 16.2, 16.1, K4.6, K5.5; IR (neat) 3047, 2954,
2119, 1435 cmK1; LRMS (CI) m/z 337 (100), 218 (73);
Anal. Calcd for C22H31NSi: C, 78.27; H, 9.26; Found: C,
78.43; H, 9.06.
4.1.5. trans-N-Benzylpiperidine-2-methyl-3-methylphe-
nylsilylmethane (11). The title compound was prepared
according to the general procedure for the preparation of 21
using 5 mol% of Cp*2LuMe$THF at room temperature in a
glovebox. The reaction was complete after 1 h as indicated
by GC analysis. Workup and purification by flash
chromatography gave the title compound as a mixture of
diastereomers in 84% yield; Rf 0.25 (10:90 MeOH/CH2Cl2);
1H NMR (500 MHz, CDCl3) d 7.53–7.60 (m, 2H), 7.20–
7.35 (m, 8H), 4.38–4.41 (m, 1H), 3.79–3.85 (m, 1H), 3.30–
3.34 (m, 1H), 2.59–2.66 (m, 1H), 2.24–2.29 (m, 1H), 2.09–
2.15 (m, 1H), 1.76–1.83 (m, 1H), 1.48–1.63 (m, 2H), 1.34–
1.48 (m, 1H), 1.19–1.32 (m, 1H), 1.08–1.15 (m, 4H), 0.78–
0.90 (m, 1H), 0.31–0.34 (m, 3H); 13C NMR (125–MHz,
CDCl3) d 140.0, 134.3, 129.1, 128.9, 128.1, 127.8, 126.6,
61.7, 61.7, 58.6, 50.3, 50.2, 38.1, 38.0, 30.6, 23.7, 23.6,
18.4, 18.2, 15.0, –4.7, –5.1; IR (neat) 3048, 2928, 2116,
1442 cmK1; LRMS (CI) m/z 322 (100), 218 (73); Anal.
Calcd for C21H29NSi: C, 77.96; H, 9.03; Found: C, 77.43; H,
4.1.8. 1-(N-Allyl-N-tert-butylamino)-2-methyl-2-propene
(16). N-(tert-Butylamino)-2-methyl-2-propene was synthe-
sized by a published procedure.6 To N-(tert-butylamino)-2-
methyl-2-propene (0.382 g, 3.00 mmol) in 6.00 mL of
MeCN was added K2CO3 (0.829 g, 6.00 mmol) in one
portion. The suspension was stirred for 0.5 h before adding
3-bromo-2-methyl-1-propene
(0.526 g,
0.393 mL,
3.90 mmol). The suspension was stirred overnight at room
temperature. The solvent was removed in vacuo, and the
crude residue was dissolved in 5 mL of Et2O and washed
with 3 mL of H2O. The organic layer was separated, dried
with MgSO4, filtered, and reduced in vacuo. The diene was
purified by flash chromatography to provide the title
compound as a clear, colorless oil in 82% yield; Rf 0.25
(10:90 MeOH/CH2Cl2); 1H NMR (500 MHz, CDCl3) d
5.84–5.92 (m, 1H), 5.01–5.07 (m, 1H), 4.92–4.95 (m, 2H),
4.75 (dd, JZ1.2, 2.5 Hz, 1H), 3.15 (d, JZ6.2 Hz, 1H), 3.00
(s, 3H), 1.70 (s, 3H), 1.07 (s, 9H); 13C NMR (125 MHz,
CDCl3) d 146.3, 139.5, 114.3, 110.8, 55.3, 54.8, 52.4, 27.5,
1
8.95. Minor diastereomer: H NMR (500 MHz, CDCl3) d
7.44–7.47 (m, 2H), 7.28–7.34 (m, 7H), 7.22–7.26 (m, 1H),
4.30–4.32 (m, 1H), 3.61–3.66 (m, 1H), 3.41–3.44 (m, 1H),
2.78–2.82 (m, 1H), 2.29–2.35 (m, 1H), 2.19–2.27 (m, 1H),
1.70–1.85 (m, 1H), 1.51–1.62 (m, 4H), 1.38–1.45 (m, 1H),

G. A. Molander, J. A. C. Romero / Tetrahedron 61 (2005) 2631–2643
2639
20.5; IR (neat) 3052, 2921, 1435 cmK1; LRMS (CI) m/z 167
(100), 110 (89); Anal. Calcd for C11H21N: C, 78.97; H,
12.65; Found: C, 79.04; H, 12.57.
LRMS (CI) m/z 199 (36), 126 (54); Anal. Calcd for
C10H17NO3: C, 60.28; H, 8.60; Found: C, 60.15; H, 8.72.
4.1.12. N-(tert-Butylcarbonyl)-2-piperidinecarbaldehyde
(19). The title compound was synthesized from 17
according to the procedure for the preparation of 18. The
title compound was isolated as a mixture of rotamers in 97%
yield; Rf 0.22 (20:80 EtOAc/Hexane); 1H NMR (500 MHz,
CDCl3) d 9.59 (br s, 1H), 4.38–4.71 (m, 1H), 3.78–4.10 (br
m, 1H), 2.73–3.82 (br m, 1H), 2.11–2.21 (m, 1H), 1.57–
1.71(m, 3H), 1.30–1.71 (m, 10H), 1.26 (br s, 1H); 13C NMR
(125 MHz, CDCl3) d 201.3, 158.6, 80.3, 75.1, 65.3, 61.5,
60.6, 43.0, 41.9, 28.4, 28.3, 25.3, 24.7, 23.5, 20.9, 19.2; IR
(neat) 2983, 1694, 1681, 1210 cmK1; LRMS (CI) m/z 213
(43), 140 (83), 57 (100); Anal. Calcd for C11H19NO3: C,
61.95; H, 8.98; Found: C, 61.87; H, 8.89.
4.1.9. N-(tert-Butylcarbonyl)-2-pyrrolidinemethanol
(16). To a solution of 2-pyrrolidinemethanol (0.910 g,
9.00 mmol) in CH2Cl2 (45.0 mL) was added triethylamine
(3.31g, 4.60 mL, 32.7 mmol) via syringe followed by
di(tert-butyl)dicarbonate (2.36 g, 10.8 mmol) in one portion
The reaction stirred for 1 h after which the resulting yellow
solution was poured into 50 mL of water. The layers were
separated, and the organic layer was washed with 2!10 mL
of water. The organic layers were combined, dried with
MgSO4, filtered, and the solvent was removed in vacuo.
The crude orange oil was purified by flash column
chromatography to afford the title compound as a white
1
solid in 94% yield; Rf 0.33 (1:1 EtOAc/Hexane); H NMR
4.1.13. N-(tert-Butylcarbonyl)-2-vinylpyrrolidine (20).
To a suspension of freshly prepared potassium tert-butoxide
(2.22 g, 19.8 mmol) in 60 mL of diethyl ether was added
methyltriphenylphosphonium bromide (7.08 g, 19.8 mmol)
in two portions. The bright yellow mixture was heated at
reflux for 1 h. The yellow mixture was allowed to cool to
room temperature. A solution of 18 (1.99 g, 10.0 mmol) in
20 mL of Et2O was added via cannula to the mixture. The
yellow suspension was stirred overnight at room tempera-
ture. The reaction was quenched with 20 mL of water and
the layers were separated. The aqueous layer was extracted
with 2!20 mL of Et2O. The organic layers were combined,
dried with MgSO4, filtered, and the solvent was removed in
vacuo. The resulting solids were triturated with cold
petroleum ether (40–60) and the organic extracts were
reduced in vacuo. The crude residue was purified by flash
column chromatography to afford the title compound as a
mixture of rotamers in 89% yield; Rf 0.30 (30:70 EtOAc/
(500 MHz, CDCl3) d 4.70 (br s, 1H), 3.96 (br s, 1H), 3.60 (br
s, 2H), 3.39–3.52 (m, 1H), 3.23–3.39 (m, 1H), 1.94–2.12 (m,
1H), 1.68–1.94 (m, 2H), 1.57–1.68 (m, 1H), 1.47 (s, 9H);
13C NMR (125 MHz, CDCl3) d 157.0, 80.1, 67.4, 64.8, 55.3,
47.5, 28.6, 28.4, 24.0; IR (neat) 3268, 3054, 2963, 1694,
1442 cmK1; LRMS (CI) m/z 200 (23), 99 (74), 57 (100);
Anal. Calcd for C10H19NO3: C, 59.68; H, 6.96; Found: C,
59.65; H, 7.02.
4.1.10. N-(tert-Butylcarbonyl)-2-piperidinemethanol
(17). The title compound was synthesized from 2-piperi-
dinemethanol according to the procedure for the preparation
of 16. The title compound was isolated as a white solid in
88% yield; Rf 0.32 (1:1 EtOAc/Hexane); 1H NMR
(500 MHz, CDCl3) d 4.22–4.35 (m, 1H), 3.86–4.01 (m,
1H), 3.72–3.85 (m, 1H), 3.55–3.66 (m, 1H), 2.86 (br t, JZ
12.2, 1H), 2.42 (br s, 1H), 1.65–1.79 (m, 1H), 1.53–1.65 (m,
4H), 1.36–1.52 (m, 1H), 1.46 (s, 9H); 13C NMR (125 MHz,
CDCl3) d 156.2, 79.7, 61.5, 52.5, 39.9, 28.4, 25.2, 25.1,
19.5; IR (neat) 3204, 3016, 2926, 1694, 1472 cmK1; LRMS
(CI) m/z 214 (14), 128 (74), 57 (100); Anal. Calcd for
C11H21NO3: C, 61.37; H, 6.51; Found: C, 61.47; H, 6.56.
1
Hexane); H NMR (500 MHz, CDCl3) d 5.74 (br s, 1H),
5.05 (br s, 2H), 4.20–4.40 (br m, 1H), 3.40 (br s, 2H), 1.95–
2.10 (br s, 1H), 1.79–1.90 (m, 2H), 1.69–1.73 (m, 1H), 1.44
(br s, 9H); 13C NMR (125 MHz, CDCl3) d 154.6, 138.9,
138.5, 113.6, 78.9, 59.1, 46.4, 46.0, 31.9, 31.3, 28.4, 23.3,
22.6, 14.0; IR (neat) 3052, 2928, 1694, 1242 cmK1; LRMS
(CI) m/z 197 (43), 104 (72), 57 (100); Anal. Calcd for
C11H19NO2: C, 66.97; H, 9.71; Found: C, 67.06; H, 9.78.
4.1.11. N-(tert-Butylcarbonyl)-2-pyrrolidinecarbalde-
hyde (18). To a solution of 16 (0.910 g, 9.00 mmol) in
CH2Cl2 (45.0 mL) at 0 8C was added triethylamine via
syringe followed by SO3$pyr in DMSO via cannula. The
reaction was stirred at 0 8C for 1 h. The reaction mixture
was partitioned between 100 mL of 2:1 hexanes/diethyl
ether and 20 mL of saturated NaHCO3. The aqueous layer
was extracted with 2!20 mL of 2:1 hexanes/diethyl ether.
The organic layers were combined and washed with 20 mL
of 1 M NaH2PO4 and 20 mL of saturated NaCl. The organic
layer was dried over Na2SO4, filtered, and the solvent was
removed in vacuo. Flash column chromatography of the
crude material afforded the title compound as a mixture of
4.1.14. N-(tert-Butylcarbonyl)-2-vinylpiperidine (21).
The title compound was synthesized from 19 according to
the procedure for the preparation of 20. The title compound
was isolated as a clear, colorless oil in 76% yield; Rf 0.28
(30:70 EtOAc/Hexane); 1H NMR (500 MHz, CDCl3) d
5.72–5.76 (m, 1H), 5.17 (ddd, JZ1.4, 1.6, 10.7 Hz, 1H),
5.11 (dt, JZ1.5, 17.4 Hz, 1H), 4.78 (br s, 1H), 3.90–4.00
(m, 1H), 2.82–2.90 (m, 1H), 1.68–1.81 (m, 2H), 1.56–1.65
(m, 2H), 1.48 (s, 9H), 1.30–1.49 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 155.4, 136.9, 115.4, 79.2, 52.4, 39.7,
28.9, 28.4, 25.5, 19.4; IR (neat) 3061, 2936, 1694,
1230 cmK1; LRMS (CI) m/z 197 (63), 104 (87), 57 (100);
Anal. Calcd for C12H21NO2: C, 68.21; H, 10.02; Found: C,
68.15; H, 10.13.
1
rotamers in 98% yield; Rf 0.23 (20:80 EtOAc/Hexane); H
NMR (500 MHz, CDCl3) d 9.56 (s, 1H, minor rotamer),
9.46 (s, 1H, major rotamer), 4.20 (br s, 1H, minor rotamer),
4.03–4.06 (br s, 1H, major rotamer), 3.50–3.56 (m, 2H,
minor rotamer), 3.44–3.50 (m, 2H, major rotamer), 1.80–
2.05 (m, 8H), 1.48 (s, 9H, minor rotamer), 1.43 (s, 9H, major
rotamer); 13C NMR (125 MHz, CDCl3) d 200.6, 200.3,
153.9, 80.5, 80.1, 64.9, 64.8, 46.8, 46.6, 28.3, 28.2, 27.9,
4.1.15. N-(2-Methyl-2-propenyl)-2-vinylpyrrolidine (22).
To a solution of 20 (1.97 g, 10.0 mmol) in 100 mL of
CH2Cl2 was added 10 mL of trifluoroacetic acid via syringe.
The solution was stirred for 30 min at room temperature.
26.6, 24.6, 23.9; IR (neat) 3056, 2983, 1694, 1673 cmK1
;

2640
G. A. Molander, J. A. C. Romero / Tetrahedron 61 (2005) 2631–2643
The solvent was removed in vacuo, and the brown residue
was dissolved in tetrahydrofuran. To the resulting solution
was added K2CO3 (1.38 g, 10.0 mmol) in one portion. The
suspension was stirred for 0.5 h before adding 3-bromo-2-
methyl-1-propene (1.35 g, 1.01 mL, 10.0 mmol). The sus-
pension was heated to reflux and was stirred for 12 h. The
reaction was quenched with water and the layers were
separated. The aqueous layer was extracted with 2!10 mL
of Et2O. The organic layers were combined, dried with
MgSO4, and filtered. The solvent was removed by careful
distillation at ambient pressure. The crude residue was
purified by flash chromatography followed by Kugelrohr
distillation at 120 8C to provide the title compound as a
clear, colorless oil in 32% yield; Rf 0.22 (10:90 EtOAc/
Hexane); 1H NMR (500 MHz, CDCl3) d 5.70 (ddd, JZ8.1,
10.1, 17.2 Hz, 1H), 5.13 (ddd, JZ0.6, 1.9, 17.2 Hz, 1H),
5.06 (dd, JZ2.0, 10.1 Hz, 1H), 4.86 (t, JZ0.8 Hz, 1H), 4.77
(q, JZ1.3, 2.6 Hz, 1H), 3.32 (d, JZ13.0 Hz, 1H), 3.03 (dt,
JZ2.8, 9.2 Hz, 1H), 2.67 (dd, JZ8.1, 16.2 Hz, 1H), 4.49 (d,
JZ13.1 Hz, 1H), 2.01 (dd, JZ8.8, 17.8 Hz, 1H), 1.90–1.97
(m, 1H), 1.65–1.80 (m, 2H), 1.74 (d, JZ0.5 Hz, 3H), 1.56–
1.64 (m, 1H); 13C NMR (125 MHz, CDCl3) d 144.5, 141.3,
116.0, 111.5, 68.8, 61.0, 53.5, 31.6, 22.2, 21.0; IR (neat)
3057, 2926 cmK1; LRMS (CI) m/z 151 (79), 124 (100);
Anal. Calcd for C10H17N: C, 79.41; H, 11.33; Found: C,
79.35; H, 11.26.
chromatography gave the title compound in 92% yield; Rf
0.25 (10:90 MeOH/CH2Cl2); 1H NMR (500 MHz, CDCl3) d
7.49–7.52 (m, 2H), 7.32–7.39 (m, 3H), 4.82 (br s, 1H), 4.78
(br s, 1H), 4.32–4.35 (m, 1H), 3.18–3.25 (m, 1H), 2.72–2.78
(m, 1H), 2.48–2.53 (m, 1H), 2.11–2.17 (m, 1H), 1.90–1.96
(m, 1H),1.70 (s, 3H), 1.58–1.67 (m, 1H), 1.38–1.58 (m, 6H),
1.22–1.32 (m, 1H), 0.82–0.98 (m, 1H), 0.70–0.82 (m, 1H),
0.30–0.32 (m, 3H).
4.1.19. p-Fluorobenzyldiallylamine (26). (General pro-
cedure for the reductive amination of an aldehyde). To a
solution of p-fluorobenzaldehyde (0.621 g, 5.00 mmol) in
25.0 mL of methanol was added diallylamine (0.486 g,
0.617 mL, 5 mmol) via syringe. After stirring for one hour
at room temperature, the reaction was cooled to 0 8C and
NaBH4 (0.284 g, 7.50 mmol) was added in three portions to
the solution. The resulting suspension was warmed to room
temperature and stirred for an additional 8 h. The reaction
mixture was diluted with 10 mL of Et2O and washed with
2!5 mL of water. The organic layer was dried with
Na2SO4, filtered, and the solvent was removed in vacuo. The
crude residue was purified by flash column chromatography
to afford the title compound in 92% yield; Rf 0.27 (10:90
1
EtOAc/Hexane); H NMR (500 MHz, CDCl3) d 7.24–7.29
(m, 2H), 6.98 (t, JZ8.7 Hz, 2H), 5.82–5.90 (m, 2H), 5.12–
5.20 (m, 4H), 3.53 (s, 2H), 3.03–3.06 (m, 4H); 13C NMR
(125 MHz, CDCl3) d 162.3 (JC–FZ2 Hz), 135.2, 135.6,
130.7, 130.6, 117.8, 115.3 (JC–FZ0.2 Hz), 57.1, 56.8; 19F
NMR (470 MHz, CDCl3) d K116.8; IR (neat) 3047,
2920 cmK1; LRMS (CI) m/z 205 (57), 164 (100); Anal.
Calcd for C13H16FN: C, 76.06; H, 7.86; Found: C, 75.98; H,
7.78.
4.1.16. N-(2-Methyl-2-propenyl)-2-vinylpiperidine (23).
The title compound was synthesized from 21 according to
the procedure for the preparation of 22. The title compound
was isolated as a clear, colorless oil in 50% yield; Rf 0.28
(10:90 EtOAc/Hexane); 1H NMR (500 MHz, CDCl3) d 5.75
(ddd, JZ8.5, 10.2, 17.3 Hz, 1H), 5.10 (dd, JZ1.9, 17.3 Hz,
1H), 5.02 (dd, JZ1.9, 10.2 Hz, 1H), 4.83 (d, JZ0.6 Hz,
1H), 4.78 (q, JZ1.3 Hz, 1 H), 3.36 (d, JZ13.5 Hz, 1H),
2.83–2.87 (m, 1H), 2.51–2.56 (m, 1H), 2.39 (d, JZ13.5 Hz,
1H), 1.75 (dt, JZ2.8, 11.5 Hz, 1H), 1.70 (s, 3H), 1.60–1.69
(m, 1H), 1.56–1.60 (m, 2H), 1.39–1.51 (m, 2H), 1.24–1.33
(m, 1H); 13C NMR (125 MHz, CDCl3) d 144.2, 142.6,
115.2, 111.9, 67.1, 62.4, 52.0, 33.7, 25.9, 24.0, 20.9; IR
(neat) 3072, 2925 cmK1; LRMS (CI) m/z 165 (63), 136
(100); Anal. Calcd for C11H19N: C, 79.94; H, 11.59; Found:
C, 80.07; H, 11.57.
4.1.20. N-(p-Fluorobenzyl)-piperidine-3-methylphenyl-
silylmethane (27). The title compound was prepared
according to the general procedure for the preparation of 4
using 5 mol% of Cp*2LuMe$THF at 50 8C in a sealed tube.
The reaction was stopped at a 50% conversion after 14 h as
indicated by 1H NMR analysis. Workup and purification by
flash chromatography gave the title compound in 19% yield;
Rf 0.25 (10:90 MeOH/CH2Cl2); 1H NMR (500 MHz,
CDCl3) d 7.52–7.54 (m, 4H), 7.25–7.28 (m, 5H), 4.63–
4.65 (m, 1H), 3.37–3.40 (m, 2H), 2.78–2.83 (m, 1H), 2.55–
2.63 (m, 1H), 1.78–1.99 (m, 2H), 1.68–1.77 (m, 2H), 1.47–
1.53 (m, 2H), 0.78–0.92 (m, 2H), 0.76–0.78 (m, 1H), 0.28–
4.1.17. Pyrrolidine 24. The title compound was prepared
according to the general procedure for the preparation of 4
using 5 mol% of [CpT2MSLuMe]2 at room temperature in a
glovebox. The reaction was complete after 1 h as indicated
by GC analysis. Workup and purification by flash
chromatography gave the title compound in 88% yield; Rf
0.25 (10:90 MeOH/CH2Cl2); 1H NMR (500 MHz, CDCl3) d
7.50–7.59 (m, 2H), 7.31–7.39 (m, 3H), 4.82–4.87 (m, 1H),
4.73–4.78 (m, 1H), 4.32–4.38 (m, 1H), 3.21–3.27 (m, 1H),
2.95–3.01 (m, 1H), 2.52–2.59 (m, 1H), 2.19–2.27 (m, 1H),
1.98–2.05 (m, 1H),1.84–1.92 (m, 1H), 1.60–1.78 (m, 7H),
1.42–1.50 (m, 1H), 1.38–1.48 (m, 1H), 0.82–0.97 (m, 1H),
0.69–0.82 (m, 1H), 0.33 (s, 3H).
0.32 (m, 3H); 13C NMR (125 MHz, CDCl3) d 163.7 (JC–F
1.7 Hz), 135.2, 135.6, 130.7, 130.6, 117.8, 115.3 (JC–F
Z
Z
0.2 Hz), 65.1, 64.9, 55.9, 46.6, 39.6, 33.4, 33.2, 33.0, 25.7,
19.3, 19.3, K5.0, K5.1; 19F NMR (470 MHz, CDCl3) d K
116.8; IR (neat) 3052, 2942, 2117, 1447 cmK1; LRMS (CI)
m/z 327 (100), 262 (63); Anal. Calcd for C20H26FNSi: C,
73.35; H, 8.00; Found: C, 73.50; H, 7.88.
4.1.21. Pentafluorobenzyldiallylamine (29). Pentafluoro-
benzylallylamine was prepared from allylamine (0.571 g,
10.0 mmol) and pentafluorobenzaldehyde (1.96 g,
10.0 mmol) according to the general procedure for the
reductive amination of an aldehyde. The crude oil was
purified by flash column chromatography to afford the
secondary amine in 92% yield. The secondary amine was
alkylated acccording to the procedure for the preparation of
8 to afford the title compound as a clear, colorless oil in 96%
yield; Rf 0.24 (10:90 EtOAc/Hexane); 1H NMR (500 MHz,
4.1.18. Piperidine 25. The title compound was prepared
according to the general procedure for the preparation of 4
using 5 mol% of [CpT2MSLuMe]2 at room temperature in a
glovebox. The reaction was complete after 1 h as indicated
by GC analysis. Workup and purification by flash

G. A. Molander, J. A. C. Romero / Tetrahedron 61 (2005) 2631–2643
2641
CDCl3) d 5.81–5.86 (m, 2H), 5.21 (dd, JZ0.8, 17.2 Hz,
2H), 5.14 (ddd, JZ1.1, 1.7, 10.2 Hz, 2H), 3.69 (s, 2H), 3.10
(d, JZ6.3 Hz, 4H); 13C NMR (125 MHz, CDCl3) d 135.2,
117.8, 56.7, 44.4; 19F NMR (470 MHz, CDCl3) d K142.2
(dd, JZ9.4, 23.5 Hz), K156.2 (t, JZ21.1 Hz), K163.3
(ddd, JZ9.4, 14.1, 23.5 Hz); IR (neat) 3024, 2958,
1442 cmK1; LRMS (CI) m/z 277 (100), 212 (57); Anal.
Calcd for C13H12F5N: C, 56.32; H, 4.36; Found: C, 56.30;
H, 4.44.
residue was purified by flash column chromatography to
afford the title compound as a viscous oil in 93% yield; Rf
1
0.17 (5:95 EtOAc/Hexane); H NMR (500 MHz, CDCl3) d
6.94 (d, JZ0.5 Hz, 2H), 5.59–5.70 (m, 2H), 5.18 (t, JZ
1.2 Hz, 2H), 5.12 (dd, JZ1.4, 1.8 Hz, 2H), 3.77 (d, JZ
6.4 Hz, 4H), 2.61 (s, 6H), 2.30 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 142.4, 140.1, 133.1, 132.6, 131.9, 119.3, 47.9,
22.8, 20.9; IR (neat) 3048, 2928, 2116, 1442 cmK1; LRMS
(CI) m/z 279 (100), 239 (62); Anal. Calcd for C15H21NO2S:
C, 64.48; H, 7.58; Found: C, 64.59; H, 7.64.
4.1.22. 1-(N-Allyl-N-pentafluorobenzylamino)-2-methyl-
2-propene (30). Pentafluorobenzylallylamine was prepared
from allylamine (0.571g, 10.0 mmol) and pentafluoroben-
zaldehyde (1.96 g, 10.0 mmol) according to the general
procedure for the reductive amination of an aldehyde. The
crude oil was purified by flash column chromatography to
afford the secondary amine in 92% yield. The secondary
amine was alkylated acccording to the procedure for the
preparation of 8 to afford the title compund as a clear,
colorless oil in 89% yield; Rf 0.24 (10:90 EtOAc/Hexane);
1H NMR (500 MHz, CDCl3) d 5.78–5.85 (m, 1H), 5.20 (dd,
JZ1.6, 17.2 Hz, 1H), 5.13 (dd, JZ1.3, 10.1 Hz, 1H), 4.90
(s, 1H), 4.85 (s, 1H), 3.67 (s, 2H), 3.01 (d, JZ6.3 Hz, 2H),
2.94 (s, 2H), 1.69 (s, 3H); 13C NMR (125 MHz, CDCl3) d
143.3, 135.5, 117.5, 113.0, 60.7, 56.5, 44.8, 20.3; 19F NMR
(470 MHz, CDCl3) d K142.2 (dd, JZ7.1, 21.2 Hz),
K156.3 (t, JZ21.2 Hz), K163.3–K163.2 (m); IR (neat)
3024, 2914, 1456 cmK1; LRMS (CI) m/z 291 (100), 104
(87); Anal. Calcd for C14H14F5N: C, 57.53; H, 4.84; Found:
C, 57.42; H, 4.92.
4.1.25. (N-Mesitylsulfonyl)-piperidine-3-methanol (34).
(N-Mesitylsulfonyl)-piperidine-3-methylphenylsilylmethane
(33) was prepared according to the general procedure for the
preparation of 4 using 5 mol% of Cp*2LuMe$THF at 50 8C
in a sealed tube. The reaction was complete after five days
as indicated by 1H NMR analysis. Workup and purification
by flash chromatography afforded silane 33 in 57% yield.
The silane was oxidized according to a published method.5k
To a suspension of KH (0.021 g, 0.54 mmol) in 0.7 mL of
NMP was added cumene hydroperoxide (0.074 mL, 88%
solution, 0.43 mmol). After 20 min, the silane 33 (0.043 g,
0.11 mmol) in 0.7 mL of NMP was added dropwise via
cannula followed by tetrabutylammonium fluoride (0.056 g,
0.22 mmol). After stirring the mixture for 12 h at room
temperature; 1.4 mL of saturated Na2S2O3 was added and
the mixture was stirred for an additional 30 min at room
temperature. The mixture was then extracted with 3!1 mL
of t-BuOMe. The combined organic layers were washed
with 1!2 mL of saturated NaCl solution, dried with
MgSO4, filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography to yield the
title compound in 63% yield. The structure of the compound
was confirmed by X-ray crystallography; Rf 0.22 (10:90
4.1.23. (N-Pentafluorobenzyl)-piperidine-3-methyl-
phenylsilylmethane (31). The title compound was prepared
according to the general procedure for the preparation of 4
using 5 mol% of [Cp2TMSYMe]2 at 50 8C in a sealed tube.
1
EtOAc/Hexane); H NMR (500 MHz, CDCl3) d 6.94 (s,
1
2H), 3.49–3.55 (m, 3H), 3.35–3.42 (m, 1H), 2.83–2.90 (m,
1H), 2.68 (dd, JZ9.3, 12.3 Hz, 1H), 2.61 (s, 6H), 2.29 (s,
3H), 1.72–1.85 (m, 3H), 1.50–1.60 (m, 1H), 1.38 (br s, 1H),
1.13–1.21 (m, 1H); 13C NMR (125 MHz, CDCl3) d 142.3,
140.4, 131.9, 65.0, 47.0, 45.0, 38.0, 26.7, 23.9, 22.8, 20.9;
IR (KBr) 3304, 3075, 2925, 1226 cmK1; Anal. Calcd for
C15H23NO3S: C, 60.58; H, 7.79; Found: C, 60.65; H, 7.70.
The reaction was complete after 8 h as indicated by H
NMR analysis. Workup and purification by flash chroma-
tography gave the title compound in 97% yield; Rf 0.23
(10:90 MeOH/CH2Cl2); 1H NMR (500 MHz, CDCl3) d
7.48–7.51 (m, 2H), 7.24–7.37 (m, 3H), 4.37–4.40 (m, 1H),
3.69 (br s, 2 H), 2.70–2.81 (m, 2H), 1.90–2.00 (m, 1H),
1.65–1.78 (m, 3H), 1.51–1.60 (m, 1H), 1.40–1.51 (m, 1H),
0.68–0.90 (m, 3H), 0.32–0.34 (m, 3H); 13C NMR
(125 MHz, CDCl3) d 134.2, 134.2, 129.3, 127.9, 61.7,
61.6, 52.9, 52.9, 49.0, 33.3, 33.2, 32.9, 25.4, 19.3, 19.2,
K4.9, K5.1; 19F NMR (470 MHz, CDCl3) d K142.4 (m),
K156.5 (m), K163.5 (m); IR (neat) 3048, 2928, 2116,
1442 cmK1; LRMS (CI) m/z 399 (100), 384 (83), 334 (45);
Anal. Calcd for C20H22F5NSi: C, 60.13; H, 5.55; Found: C,
59.98; H, 5.60.
4.1.26. N-(tert-Butylcarbonyl)-3-isoquinolinemethanol
(37). The title compound was synthesized from 3-iso-
quinolinemethanol according to the procedure for the
preparation of 16. The title compound was isolated as a
1
viscous oil in 96% yield; Rf 0.28 (1:1 EtOAc/Hexane); H
NMR (500 MHz, CDCl3) d 7.10–7.20 (m, 4H), 4.69 (br s,
1H), 4.49 (br s, 1H), 4.31 (d, JZ16.5 Hz, 1H), 3.51 (br s,
2H), 3.03 (dd, JZ6.0, 15.9 Hz, 1H), 2.80 (d, JZ15.5 Hz,
1H), 1.74 (br s, 1H), 1.50 (s, 9H); 13C NMR (125 MHz,
CDCl3) d 133.7, 129.0, 127.3, 126.9, 126.8, 126.5, 80.82,
64.8, 52.4, 44.5, 30.6, 28.9, 21.4, 14.6; IR (neat) 3249, 3052,
2963, 1210, 1435 cmK1; LRMS (CI) m/z 262 (64), 205 (78),
57 (100); Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04;
Found: C, 68.59; H, 7.93.
4.1.24. N, N-Diallylmesitylsulfonamide (32). To diallyl-
amine in CH2Cl2 at 0 8C was added triethylamine. The
solution was stirred for 30 min before adding a solution of
2-mesitylenesulfonyl chloride in CH2Cl2 dropwise via
cannula. The clear solution became cloudy and the mixture
was warmed to room temperature over two hours. The
reaction was quenched with 15 mL of water and the organic
layer was separated. The aqueous layer was washed with
3!5 mL of CH2Cl2. The organic layers were combined and
washed with 15 mL of saturated NaCl. The layers were
separated and the organic layer was dried with MgSO4,
filtered, and the solvent was removed in vacuo. The crude
4.1.27. N-(tert-Butylcarbonyl)-3-isoquinolinecarbalde-
hyde (38). The title compound was synthesized from 37
according to the procedure for the preparation of 18. The
title compound was isolated as a mixture of rotamers in 87%
yield; Rf 0.20 (20:80 EtOAc/Hexane); 1H NMR (500 MHz,

2642
G. A. Molander, J. A. C. Romero / Tetrahedron 61 (2005) 2631–2643
CDCl3) d 9.49 (d, JZ21.2 Hz, 1H), 7.09–7.19 (m, 4H),
4.82, (br s, 0.5H), 4.70 (s, 0.5H), 4.68 (s, 0.5H), 4.51–4.59
(m, 1H), 4.46 (br s, 0.5H), 3.21–3.24 (m, 0.5H), 3.10 (br s,
1H), 1.53 (br s, 5H), 1.51, (br s, 5H); 13C NMR (125 MHz,
CDCl3) d 201.0, 200.3, 128.4, 127.7, 127.3, 127.1, 127.0,
126.9, 126.3, 126.2, 81.2, 60.4, 60.3, 59.1, 45.0, 44.3, 29.3,
28.3, 14.2; IR (neat) 3048, 2928, 1694, 1221 cmK1; LRMS
(CI) m/z 261 (4), 231 (56), 57 (100); Anal. Calcd for
C15H19NO3: C, 68.94; H, 7.33; Found: C, 69.07; H, 7.40.
(45); Anal. Calcd for C14H17N: C, 84.37; H, 8.60; Found: C,
84.23; H, 8.67.
4.1.31. Acetate 42. In a sealed tube initially prepared in the
glovebox, Cp*2LuMe$THF (10 mg, 5.0 mol%) was dis-
solved in cyclohexane (1.0 mL). To this solution was added
N-allyl-3-vinylisoquinoline (74 mg, 0.37 mmol) and
methylphenylsilane (55 mg, 0.45 mmol). The reaction was
stirred at room temperature for 12 h. GC analysis of the
crude reaction mixture indicated that the reaction was
complete. The clear, colorless solution was diluted with
diethyl ether and filtered through a small plug of silica to
remove the catalyst and concentrated by rotary evaporation.
The crude product was oxidized according to the procedure
for the preparation of 51. The resulting crude alcohol was
dissolved in 2.5 mL of CH2Cl2 and to the clear solution was
added triethylamine (0.14 g, 0.19 mL, 1.4 mmol). After
stirring at room temperature for 10 min, acetyl chloride
(0.11 g, 0.10 mL, 1.4 mmol) was added dropwise via
syringe. The solution was stirred for 15 min, after which
the reaction was complete as determined by TLC analysis.
The reaction was quenched with 2 mL of water and the
layers were separated. The aqueous layer was extracted with
2!1 mL of CH2Cl2. The combined organic extracts were
washed with 1!3 mL of saturated NaCl solution, dried with
Na2SO4, filtered, and concentrated in vacuo. GC analysis of
the crude acetate indicated that the fused nitrogen hetero-
cycle was a 5:4 mixture of diastereomers. The crude oil was
purified by flash column chromatography to afford the title
compound as a mixture of diastereomers in 52% overall
4.1.28. N-(tert-Butylcarbonyl)-3-vinylisoquinoline (39).
The title compound was synthesized from 38 according to
the procedure for the preparation of 20. The title compound
was isolated as a clear, colorless oil in 98% yield; Rf 0.28
(30:70 EtOAc/Hexane); 1H NMR (500 MHz, CDCl3) d
7.09–7.26 (m, 4H), 5.66 (ddd, JZ5.2, 10.5, 17.2 Hz, 1H),
5.00–5.07 (m, 2H), 4.97, (br s, 1H), 4.74 (d, JZ16.7 Hz,
1H), 4.32 (d, JZ16.7 Hz, 1H), 3.13 (dd, JZ5.9, 15.9 Hz,
1H), 2.80 (dd, JZ1.8, 15.7 Hz, 1H), 1.50 (s, 9H); 13C NMR
(125 MHz, CDCl3) d 155.0, 136.9, 133.3, 132.9, 128.6,
126.5, 126.2, 126.0, 115.8, 79.9, 51.4, 43.4, 33.4, 28.5; IR
(neat) 2976, 2861, 1694 cmK1; LRMS (CI) m/z 259 (15),
203 (48), 57 (100); Anal. Calcd for C16H21NO2: C, 74.10;
H, 8.16; Found: C, 73.99; H, 8.32.
4.1.29. N-Allyl-3-vinylisoquinoline (40). The title com-
pound was synthesized from 39 according to the procedure
for the preparation of 22. The title compound was isolated as
a clear, colorless oil in 92% yield; Rf 0.23 (10:90 EtOAc/
Hexane); 1H NMR (500 MHz, CDCl3) d 7.08–7.12 (m, 4H),
5.88–5.96 (m, 1H), 5.78–5.85 (m, 1H), 5.16–5.31 (m, 4H),
4.06 (d, JZ8.5 Hz, 1H), 3.87 (d, JZ8.5 Hz, 1H), 3.09–3.14
(m, 1H), 3.05 (ddd, JZ0.8, 7.4, 14.0 Hz, 1H), 2.88–2.94 (m,
1H), 2.79–2.84 (m, 1H), 2.55–2.60 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 139.4, 136.3, 135.6, 134.7, 128.7,
128.2, 126.2, 125.5, 118.1, 117.5, 66.6, 57.6, 46.2, 28.9; IR
(neat) 3048, 2934 cmK1; LRMS (CI) m/z 199 (100), 104
(87); Anal. Calcd for C14H17N: C, 84.37; H, 8.60; Found: C,
84.63; H, 8.92.
1
yield; Rf 0.23 (5:95 EtOAc/Hexane); H NMR (500 MHz,
CDCl3) d 7.20–7.32 (m, 4H), 4.33 (dd, JZ5.6, 11.0 Hz,
1H), 4.13 (dd, JZ5.6, 11.0 Hz, 1H), 3.71 (d, JZ15.1 Hz,
1H), 3.42 (d, JZ13.5 Hz, 1H), 2.59–2.68 (m, 2H), 2.22–
2.28 (m, 1H), 2.01 (s, 2H), 1.68–1.79 (m, 2H), 1.58–1.66
(m, 1H), 1.42–1.48 (m, 1H), 1.34–1.40 (m, 1H) 1.10–1.12
(m, 3H); 13C NMR (125 MHz, CDCl3) d 171.2, 139.9,
128.7, 128.1, 126.7, 66.7, 58.5, 54.8, 48.3, 40.0, 23.7, 22.7,
21.0; IR (neat) 3025, 2928, 1635, 1220 cmK1; HRMS calcd
for C16H21NO2: 259.1572, found: 259.1669; LRMS (CI)
m/z 259 (69), 217 (100).
4.1.30. N-Allyl-1-vinylisoquinoline (41). To 3,4-dihydro-
isoquinoline (0.394 g, 3.0 mmol) in 15.0 mL of THF was
added an excess of allyl bromide (3.0 mL). The mixture was
stirred for 2 h before adding vinylmagnesium bromide
(6.0 mL, 1.0 M in THF, 6.0 mmol) via syringe. The mixture
was refluxed for one hour. The mixture was cooled to room
temperature, quenched with 5 mL of water, and the layers
were separated. The aqueous layer was extracted with 3!
2 mL of Et2O. The combined organic extracts were washed
with 3!10 mL of saturated NaCl solution, dried with
MgSO4, filtered, and concentrated in vacuo. The crude oil
was purified by flash column chromatography to afford the
title compound as a clear, colorless oil in 78% yield; Rf 0.27
(10:90 EtOAc/Hexane); 1H NMR (500 MHz, CDCl3) d
7.06–7.14 (m, 4H), 5.87–5.97 (m, 1H), 5.77–5.86 (m, 1H),
5.17–5.30 (m, 4H), 4.06 (d, JZ8.5 Hz, 1H), 3.47 (ddd, JZ
1.4, 5.4, 13.9 Hz, 1H), 3.09–3.14 (m, 1H), 3.05 (ddd, JZ
0.8, 7.4, 14.0 Hz, 1H), 2.88–2.94 (m, 1H), 2.79–2.84 (m,
1H), 2.55–2.60 (m, 1H); 13C NMR (125 MHz, CDCl3) d
139.4, 136.3, 135.6, 134.7, 128.7, 128.2, 126.2, 125.5,
118.1, 117.5, 66.6, 57.6, 46.2, 28.9; IR (neat) 3032,
2928 cmK1; LRMS (CI) m/z 199 (100), 185 (24), 158
Acknowledgements
We thank the National Institutes of Health (GM48480) for
their generous support of this program.
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