Syntheses of functionalized allylamines via lithiated intermediates

Article abstract of DOI:10.1002/ejoc.201400017

Lithiated allylamines are easily available by tin-lithium exchange from stannylated allylamines and are suitable nucleophiles for a wide range of conversions. With aldehydes and ketones, aminomethylated allyl alcohols are formed, whereas the reaction with α-brominated ketones gives rise to vinyl epoxides or aldehydes, depending on the reaction and workup conditions used. Copyright

Full text of DOI:10.1002/ejoc.201400017

FULL PAPER
DOI: 10.1002/ejoc.201400017
Syntheses of Functionalized Allylamines via Lithiated Intermediates
Samia Firdous[a] and Uli Kazmaier*[a]
Keywords: Organolithium compounds / Stannanes / Allylic compounds / Lithiation / Epoxides
Lithiated allylamines are easily available by tin–lithium ex-
change from stannylated allylamines and are suitable nu-
cleophiles for a wide range of conversions. With aldehydes
and ketones, aminomethylated allyl alcohols are formed,
whereas the reaction with α-brominated ketones gives rise to
vinyl epoxides or aldehydes, depending on the reaction and
workup conditions used.
lyzed conditions, the corresponding terminal (Z)-vinyl-
stannanes are formed with excellent selectivity.[8]
Introduction
Functionalized organometallics are extremely powerful
and useful tools in organic synthesis.[1] Owing to their high
reactivity, organolithium compounds bearing other func-
tional groups are highly interesting and have found wide-
spread applications in total synthesis.[2] In principle, func-
tionalized lithiated organic compounds can be obtained by
functional-group-directed (regio- and/or stereoselective) li-
thiation,[2,3] halogen–lithium exchange,[4] or by transmetal-
lation of other organometallics. As organostannanes are
relatively stable compounds and are easily accessible, it is
not surprising that they are popular starting materials for
the synthesis of organolithium compounds.[5]
Organostannanes can be obtained by hydrostannation of
alkenes and/or alkynes, although the control of the regio-
and stereoselectivity is not a trivial issue.[6] In principle,
three fundamentally different approaches can be used for
hydrostannation: a radical version and reactions in the pres-
ence of Lewis acids or transition metal catalysts. In general,
the radical process is the most unselective one and generates
mixtures of regio- and stereoisomers. Although the regiose-
lectivity is controlled by the stability of the intermediate
radical formed, the configuration of the remaining double
bond (for alkyne hydrostannation) is determined by the fi-
nal H-transfer step. In contrast, the transition-metal-cata-
lyzed version allows the transfer of the tin hydride from one
face of the double or triple bond (syn addition) and gener-
ates only regioisomers.[6] In general, with the most com-
monly used Pd catalysts, the tin moiety is transferred to the
sterically least hindered position of a double/triple bond,
but the selectivities are moderate in many cases, even for
terminal alkynes.[7] Therefore, the (E)-vinylstannanes are
obtained preferentially. Interestingly, under Lewis acid cata-
Recently, we developed a molybdenum catalyst that pro-
vides the opposite regioisomers.[9] Excellent regioselectivi-
ties are obtained for propargyl alcohol derivatives, such as
propargyl acetates and carbonates.[10] This is especially
interesting because these substrates cannot be obtained by
Pd-catalyzed hydrostannation (π-allyl intermediate forma-
tion), and the stannylated allyl alcohol derivatives are excel-
lent substrates, both for Stille couplings and for allylic alk-
ylations. For example, these carbonates can be used for the
incorporation of vinylstannane side chains into amino
acids[11] and even peptides,[12] which can subsequently be
modified by Stille couplings.[13] Recently, we reported that
stannylated allylic acetates and carbonates can also be sub-
jected to allylic aminations.[14] The stannylated allylamines
obtained can be either modified by Stille coupling or con-
verted into unsaturated β-lactams by tin–iodine exchange
and subsequent Pd-catalyzed carbonylation (Scheme 1).[15]
Scheme 1. Synthesis and reactions of stannylated allyl amines.
[a] Institute for Organic Chemistry, Saarland University,
P. O. Box 151150, 66041 Saarbrücken, Germany
E-mail: u.kazmaier@mx.uni-saarland.de
Results and Discussion
http://www.uni-saarland.de/lehrstuhl/kazmaier.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400017.
On the basis of these previous results, we were interested
in the enlargement of the synthetic potential of stannylated
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Syntheses of Functionalized Allylamines via Lithiated Intermediates
amines 1 by converting them into the more reactive lithiated Table 1. Reactions of lithiated allylamines with aldehydes and
ketones.
allylamines. The preparation and reaction behavior of lithi-
ated and dilithiated allylamines have been studied by the
Barluenga group in great detail,[16] but not many synthetic
applications have been reported to date.[17]
In our initial experiments, we tried to obtain the required
lithiated allylamines by halogen–lithium exchange starting
Entry
R
RЈ
Product
Yield [%]
from the iodinated allylamine 2. This amine is easily access-
ible by our previous protocol (Scheme 2). Unfortunately, all
attempts to get satisfying results failed, although we varied
a wide range of reaction parameters, such as the tempera-
ture and the equivalents of nBuLi used. We tried to trap
the vinyllithium intermediate directly with benzaldehyde;
however, even under “optimized conditions”, a yield of only
6% could be obtained for the coupling product 3a. Clearly,
the halogen–lithium exchange of halogenated allylamines is
not the method of choice for the synthesis of lithiated
amines. This is in agreement with observations reported by
Barluenga et al.[16]
1
2
3
4
5
6
7
8
9
Ph
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
96
94
92
89
92
94
82
79
72
4-BrC6H4
4-ClC6H4
3-Pyridyl
Et
Ph(CH2)2
–(CH2)5–
Ph
Bn
Bn
Bn
the initial addition step should replace the bromine atom
to form amino-functionalized vinyl epoxides 4. These vinyl
epoxides are also highly interesting building blocks, which
can be subjected to allylic alkylations, for example.[18]
Interestingly, although we observed a clean conversion
by TLC, no product 4 could be obtained under our stan-
dard workup conditions (Scheme 3). We assumed that, even
if the vinyl epoxide formed, it might be too sensitive for
our workup protocol and would decompose. Therefore, we
quenched the reaction mixture with saturated NaCl solu-
tion and could indeed isolate the expected product 4a, al-
beit in only 30% yield. The yield could be improved further
by quenching the reaction with “wet methanol”; however,
we had problems with the reproducibility of our results.
Scheme 2. Generation of lithiated allylamine by iodine–lithium ex-
change.
Therefore, we decided to switch to the direct tin–lithium
exchange. Although, in general this exchange is relatively
fast and proceeds in most cases under very mild conditions
(–78 °C),[5,16] we observed that this is not the case with stan-
nylated tertiary amines such as 1a. Although, the metal ex-
change started at low temperature, it was not complete after
1 h at –30 °C, even with two equivalents of nBuLi. However,
complete transmetallation was observed at 0 °C, as deter-
mined by quenching the vinyllithium species with D2O
(100% D incorporation).
With this protocol in hand, we investigated a range of
different reactions of these lithiated tertiary amines. The re-
actions with aldehydes proceeded smoothly to form the ex-
Scheme 3. Syntheses of vinyl epoxides from α-bromo ketones.
Even the NMR samples changed with time; therefore we
pected amino-substituted secondary allyl alcohols 3 in ex- investigated the carbonyl addition–epoxidation–workup se-
cellent yield (Table 1). The reaction worked equally well for quence in more detail with simple nBuLi to gain infor-
aromatic, heteroaromatic, and aliphatic aldehydes (Table 1, mation on the stability of the phenyl-substituted epoxide
Entries 1–6). In all cases, two equivalents of aldehyde were under these conditions and to avoid problems arising from
used to achieve complete conversion of the vinyllithium in- the additional lability of the vinyl epoxide.
termediate (generated with two equivalents of nBuLi). The
We added nBuLi to phenacyl bromide at –78 °C and al-
side products formed from the excess reagents could easily lowed the mixture to warm to 0 °C over a period of 4 h
be removed by flash chromatography. The reaction is not (Scheme 4). The reaction was monitored by TLC. A clean
limited to aldehydes, but is also suitable for ketones reaction was observed; if the reaction was quenched at 0 °C,
(Table 1, Entries 7–9), although in this case the yields were the expected epoxide could be obtained in acceptable yield
slightly lower. All examples investigated gave yields in the and in pure form, as determined by NMR spectroscopy. No
range 72–82%.
significant changes in the NMR spectrum were observed if
On the basis of the good results obtained with the the sample was stored for 30 min at room temperature, but
ketones, we next focused on reactions of α-bromo ketones. interestingly a complete conversion into the corresponding
In this case, one might expect that the alcoholate formed in aldehyde was observed on standing at room temperature
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S. Firdous, U. Kazmaier
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overnight. Probably, traces of DCl in the CDCl3 used initi- ene-derived bromo ketone did not provide the desired epox-
ated the isomerization by deuteration of the epoxide and ide, but directly formed the isomerized aldehyde (Table 2,
generation of a well-stabilized carbenium ion. On the basis Entry 5). The LiBr formed in the reaction probably acts as
of this assumption, one might assume that electron-donat- a Lewis acid catalyst and initiates the isomerization even
ing substituents on the aromatic ring should accelerate this under these reaction conditions. Comparable results were
isomerization by stabilization of the carbenium ion. This obtained with secondary bromo ketones, which gave access
effect was indeed observed in the reaction of the toluene- to the corresponding unsaturated ketones (Table 2, En-
derived α-bromo ketone. The yield of the expected epoxide tries 6 and 7).
was slightly lower than in the first case, but here the NMR
experiment has to be performed immediately after isolation
Table 2. Reactions of lithiated allylamines with α-bromo ketones.
of the epoxide. After 30 min at room temperature, the epox-
ide was already quantitatively converted into the corre-
sponding aldehyde.
Entry
Ar
R
Product
Yield [%]
1
2
3
4
5
6
7
Ph
H
H
H
H
H
Me
Me
4a
4b
4c
4d
5e
5f
71
76
75
72
56
62
51
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
Ph
4-BrC6H4
5g
Scheme 4. Formation and reaction behavior of phenyl-substituted
epoxides.
Finally, we tried to expand the spectrum of electrophiles
that can be reacted with the lithiated allylamines. If the vin-
yllithium compound is transmetalated, for example, to the
corresponding cuprate, subsequent 1,4-addition to unsatu-
rated carbonyl compounds should become possible. We
proved this option by using cyclohexenone as an acceptor,
and indeed the unsaturated amino ketone 6 was obtained
in acceptable yield (Scheme 5). Although this reaction is not
yet optimized, it clearly indicates that the synthetic poten-
tial of lithiated allylamines is high and justifies further in-
vestigations.
To prove if this isomerization is limited to terminal α-
bromo ketones, we also subjected a secondary bromide to
the same reaction conditions. The yield of the epoxide was
comparable to the previous examples, and the tendency to
undergo isomerization was intermediate. Here, around 20%
of isomerization was observed after 30 min. These results
might be an explanation for the reproducibility issues with
our vinyl epoxides, especially as these epoxides should be
even more sensitive than the saturated ones.
To avoid such side reactions, we changed the workup
procedure. Instead of quenching the reaction mixture with
aqueous solutions or alcohol, we added Celite or Isolute®
directly to the reaction mixture at 0 °C. After evaporation
of the solvent in vacuo, the crude product (absorbed on
the resin) was subjected directly to column chromatography.
And indeed, under these conditions, the desired vinyl epox-
ide 4a could be obtained in 71% yield (Table 2, Entry 1).
Interestingly, here the NMR sample of pure 4a in CDCl3
isomerized to 5a on standing. Therefore, CD2Cl2 was used
as the solvent for further NMR studies. As electron-with-
drawing substituents should “stabilize” the vinyl epoxides
Scheme 5. Further reactions of lithiated allylamines.
Conclusions
We have shown that lithiated allylamines, which are eas-
by destabilizing the intermediate carbenium ion, we investi- ily available by tin–lithium exchange from the stannylated
gated the reaction of several halogenated α-bromo ketones allylamines, are suitable nucleophiles for a wide range of
(Table 2, Entries 2–4). In all cases, the vinyl epoxides could conversions. Although the reactions with aldehydes and
be obtained in slightly better yields compared to those for ketones are unproblematic, clean, and fast, α-brominated
the unsubstituted phenyl ketone. Not surprisingly, the tolu- ketones need milder reactions conditions but can deliver
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Syntheses of Functionalized Allylamines via Lithiated Intermediates
1
(117 mg, 0.44 mmol). H NMR (CDCl3): δ = 1.46 (m, 2 H), 1.60
different products, depending on the reaction and workup
conditions. Further synthetic applications are under investi-
gation.
(m, 2 H), 2.29 (m, 2 H), 2.31 (m, 2 H), 2.77 (d, J = 12.4 Hz, 1 H),
3.00 (d, J = 12.8 Hz, 1 H), 4.95 (s, 1 H), 5.10 (s, 1 H), 5.30 (s, 1
H), 7.28–7.35 (m, 4 H) ppm. 13C NMR (CDCl3): δ = 23.9, 25.8,
54.1, 78.2, 117.1, 127.1, 128.1, 132.5, 142.3, 144.7 ppm. HRMS
(CI): calcd. for C15H21ClNO [M + H]+ 266.1306; found 266.1316.
Experimental Section
2-(Piperidin-1-ylmethyl)-1-(pyridin-3-yl)prop-2-en-1-ol (3d): Allyl
alcohol 3d was obtained from 1 (200 mg, 0.48 mmol) and 3-pyridyl-
carbaldehyde (103 mg, 0.96 mmol) after flash chromatography
(hexanes/ethyl acetate 9:1 to 1:1) as a yellow oil in 89% yield
(99 mg, 0.42 mmol). 1H NMR (CDCl3): δ = 1.43 (m, 2 H), 1.58
(m, 4 H), 2.30 (m, 2 H), 2.52 (m, 2 H), 2.82 (d, J = 12.8 Hz, 1 H),
2.99 (d, J = 12.4 Hz, 1 H), 4.97 (s, 1 H), 5.10 (s, 1 H), 5.36 (s, 1
H), 7.25 (t, J = 7.6 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 8.48 (dd,
J = 4.8, 1.6 Hz, 1 H), 8.61 (d, J = 2.4 Hz, 1 H) ppm. 13C NMR
(CDCl3): δ = 23.9, 25.8, 54.1, 62.5, 76.8, 117.3, 123.0, 133.5, 138.9,
147.9, 148.2 ppm. HRMS (CI): calcd. for C14H21N2O [M + H]+
233.1648; found 233.1754.
General Remarks: All reactions were performed in oven-dried glass-
ware (70 °C) under an atmosphere of nitrogen. Dried solvents were
distilled before use: tetrahydrofuran (THF) was distilled from Na/
benzophenone, dry N,N-dimethylformamide (DMF) was pur-
chased from Sigma–Aldrich. The products were purified by flash
chromatography on silica gel columns (Macherey–Nagel 60, 0.063–
0.2 mm). Mixtures of ethyl acetate and hexanes were generally used
as eluents. Analytical TLC was performed on precoated silica gel
plates (Macherey–Nagel, Polygram® SIL G/UV254). Visualization
was accomplished with UV-light, KMnO4 solution, or iodine. 1H
and 13C NMR spectra were recorded with a Bruker AC-400
[400 MHz (1H) and 100 MHz (13C)] spectrometer with samples in
CDCl3 or CD2Cl2. Chemical shifts are reported in ppm relative to
tetramethylsilane (TMS), and CHCl3 or CD2Cl2 were used as in-
ternal standards. Mass spectra were recorded with a Finnigan
MAT 95 spectrometer at the Saarland University by using the CI
or EI technique.
2-(Piperidin-1-ylmethyl)pent-1-en-3-ol (3e): Allyl alcohol 3e was ob-
tained from 1 (200 mg, 0.48 mmol) and propionaldehyde (56 mg,
0.96 mmol) after flash chromatography (hexanes/ethyl acetate 9:1
to 1:1) as a colorless oil in 92% yield (81 mg, 0.44 mmol). 1H NMR
(CDCl3): δ = 0.88 (t, J = 7.6 Hz, 3 H), 1.42 (m, 2 H), 1.54 (m, 4
H), 1.68 (q, J = 7.6 Hz, 2 H), 2.33 (m, 2 H), 2.50 (m, 2 H), 2.82
(d, J = 12.4 Hz, 1 H), 3.23 (d, J = 12.5 Hz, 1 H), 4.03 (t, J =
6.9 Hz, 1 H), 4.87 (s, 1 H), 4.99 (s, 1 H) ppm. 13C NMR (CDCl3):
δ = 10.2, 24.0, 25.8, 29.4, 54.1, 63.0, 78.0, 115.1, 144.7 ppm. HRMS
(CI): calcd. for C11H22NO [M + H]+ 184.1696; found 184.1684.
General Procedure for Reactions of Lithiated Allylamines with Alde-
hydes and Ketones: A solution of α-stannylated allylamine 1 in dry
THF was cooled to 0 °C. A solution of nBuLi (1.6 m, 2 equiv.) in
hexane was added slowly at 0 °C. The reaction was monitored by
TLC. On completion of the Sn–Li exchange, a solution of the alde-
hyde or the ketone (2.0 equiv.) in dry THF was added. The reaction
mixture was stirred at 0 °C for 1 h and it was then quenched with
1 n HCl. The layers were separated, and the aqueous phase was
extracted with diethyl ether. The combined organic layers were
washed with NaHCO3 and/or brine and dried with Na2SO4, and
the solvents were evaporated in vacuo. The crude products ob-
tained were purified by column chromatography (silica, hexanes/
ethyl acetate) to yield the corresponding alcohols 3.
5-Phenyl-2-(piperidin-1-ylmethyl)pent-1-en-3-ol (3f): Allyl alcohol 3f
was obtained from 1 (200 mg, 0.48 mmol) and 3-phenylpropional-
dehyde (129 mg, 0.96 mmol) after flash chromatography (hexanes/
ethyl acetate 9:1 to 1:1) as a pale yellow oil in 94% yield (117 mg,
1
0.45 mmol). H NMR (CDCl3): δ = 1.35 (m, 2 H), 1.48 (m, 4 H),
1.76–1.92 (m, 2 H), 2.28 (m, 2 H), 2.42 (m, 2 H), 2.51–2.74 (m, 2
H), 2.79 (d, J = 12.5 Hz, 1 H), 3.18 (d, J = 12.5 Hz, 1 H), 4.10 (m,
1 H), 4.82 (s, 1 H), 4.94 (s, 1 H), 7.09–7.20 (m, 5 H) ppm. 13C
NMR (CDCl3): δ = 24.0, 25.8, 32.1, 38.4, 54.1, 63.3, 75.6, 115.1,
125.6, 128.2, 128.4, 142.2, 145.0 ppm. HRMS (CI): calcd. for
C17H26NO [M + H]+ 260.2009; found 260.2018.
1-Phenyl-2-(piperidin-1-ylmethyl)prop-2-en-1-ol (3a): Allyl alcohol
3a was obtained from 1 (200 mg, 0.48 mmol) and benzaldehyde
(102 mg, 0.96 mmol) after flash chromatography (hexanes/ethyl
acetate 9:1 to 1:1) as a pale yellow liquid in 96% yield (107 mg,
1-[3-(Piperidin-1-yl)prop-1-en-2-yl]cyclohexanol (3g): Tertiary allyl
alcohol 3g was obtained from 1 (200 mg, 0.48 mmol) and cyclohex-
anone (94 mg, 0.96 mmol) after flash chromatography (hexanes/
ethyl acetate, 9:1) as a pale yellow oil in 82% yield (88 mg,
1
0.46 mmol). H NMR (CDCl3): δ = 1.37 (m, 2 H), 1.50 (m, 2 H),
2.20 (m, 2 H), 2.43 (m, 2 H), 2.65 (d, J = 12.8 Hz, 1 H), 2.93 (d, J
= 12.8 Hz, 1 H), 4.84 (s, 1 H), 5.02 (s, 1 H), 5.23 (s, 1 H), 7.22 (m,
5 H) ppm. 13C NMR (CDCl3): δ = 23.9, 25.8, 54.0, 62.3, 78.8,
116.5, 125.5, 126.7, 127.9, 143.6, 145.1 ppm. HRMS (CI): calcd.
for C15H22NO [M + H]+ 232.1695; found 232.1702.
1
0.39 mmol). H NMR (CDCl3): δ = 1.30–1.70 (m, 16 H), 2.37 (m,
4 H), 3.04 (s, 2 H), 4.83 (s, 1 H), 4.98 (s, 1 H) ppm. 13C NMR
(CDCl3): δ = 21.9, 24.0, 25.8, 25.9, 38.0, 53.9, 63.7, 73.3, 113.0,
150.2 ppm. HRMS (CI): calcd. for C14H26NO [M + H]+ 224.2009;
found 224.1975.
1-(4-Bromophenyl)-2-(piperidin-1-ylmethyl)prop-2-en-1-ol (3b): Allyl
alcohol 3a was obtained from 1 (200 mg, 0.48 mmol) and 4-bromo-
benzaldehyde (178 mg, 0.96 mmol) after flash chromatography
(hexanes/ethyl acetate 9:1 to 1:1) as a pale yellow oil in 94% yield
1,2-Diphenyl-3-(piperidin-1-ylmethyl)but-3-en-2-ol
(3h):
Allyl
alcohol 3h was obtained from 1 (200 mg, 0.48 mmol) and benzyl
phenyl ketone (188 mg, 0.96 mmol) after flash chromatography
(hexanes/ethyl acetate, 9:1) as a pale yellow oil in 79% yield
1
(140 mg, 0.45 mmol). H NMR (CDCl3): δ = 1.38 (m, 2 H), 1.52
(m, 2 H), 2.22 (m, 2 H), 2.46 (m, 2 H), 2.69 (d, J = 12.8 Hz, 1 H),
2.92 (d, J = 12.8 Hz, 1 H), 4.87 (s, 1 H), 5.03 (s, 1 H), 5.20 (s, 1 H),
7.19–7.22 (m, 2 H), 7.37–7.39 (m, 2 H) ppm. 13C NMR (CDCl3):
δ = 23.9, 25.8, 54.1, 62.4, 78.3, 117.0, 120.6, 127.5, 131.0, 142.9,
144.7 ppm. HRMS (CI): calcd. for C15H21BrNO [M + H]+
310.0801; found 310.0796.
1
(122 mg, 0.38 mmol). H NMR (CDCl3): δ = 1.41 (m, 2 H), 1.54
(m, 2 H), 2.11 (m, 2 H), 2.62 (d, J = 12.4 Hz, 1 H), 2.94 (d, J =
12.4 Hz, 1 H), 3.23 (d, J = 12.8 Hz, 1 H), 3.36 (d, J = 13.2 Hz, 1
H), 5.13 (s, 1 H), 5.48 (s, 1 H), 6.96–7.40 (m, 10 H) ppm. 13C NMR
(CDCl3): δ = 24.0, 25.8, 47.5, 64.4, 79.7, 114.7, 125.7, 125.8, 126.2,
128.0, 130.9, 137.6, 146.5, 147.9 ppm. HRMS (CI): calcd. for
C22H28NO [M + H]+ 322.2165; found 322.2145.
1-(4-Chlorophenyl)-2-(piperidin-1-ylmethyl)prop-2-en-1-ol (3c): Allyl
alcohol 3c was obtained from 1 (200 mg, 0.48 mmol) and 4-chloro-
benzaldehyde (135 mg, 0.96 mmol) after flash chromatography
(hexanes/ethyl acetate 9:1) as a pale yellow oil in 92% yield
2-Benzyl-1-phenyl-3-(piperidin-1-ylmethyl)but-3-en-2-ol (3i): Allyl
alcohol 3i was obtained from 1 (200 mg, 0.48 mmol) and dibenzyl
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S. Firdous, U. Kazmaier
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ketone (202 mg, 0.96 mmol) after flash chromatography (hexanes/
ethyl acetate, 9:1) as a pale yellow oil in 72% yield (116 mg,
3-(Piperidin-1-ylmethyl)-2-p-tolylbut-3-enal (5e): Aldehyde 5e was
obtained from 1 (200 mg, 0.48 mmol) and 4-methylphenacyl brom-
0.34 mmol). 1H NMR (CDCl3): δ = 1.07–1.19 (m, 6 H), 1.69 (m, 4 ide (121 mg, 0.57 mmol) after flash chromatography (hexanes/ethyl
H), 2.23 (s, 2 H), 2.82–2.92 (m, 1 H), 4.91 (s, 1 H), 4.93 (s, 1 H),
acetate 1:0 to 9:1) as a yellow oil in 56% yield (69 mg, 0.26 mmol).
7.08–7.21 (m, 10 H) ppm. 13C NMR (CDCl3): δ = 23.8, 25.6, 49.4, 1H NMR (CD2Cl2): δ = 1.45 (m, 2 H), 1.57 (m, 4 H), 2.34 (s, 1
53.5, 64.9, 79.2, 115.1, 125.8, 127.3, 131.3, 137.9, 146.5 ppm.
HRMS (C23H29NO). HRMS (CI): calcd. for C23H30NO [M + H]+
336.2249; found 336.2290.
H), 2.39 (m, 4 H), 3.12 (m 2 H), 4.47 (s, 1 H), 5.55 (s, 1 H), 5.85
(s, 1 H), 7.07–7.20 (m, 5 H), 9.62 (d, J = 2.0 Hz, 1 H) ppm. 13C
NMR (CD2Cl2): δ = 21.3, 24.8, 26.5, 54.6, 59.2, 67.6, 118.3, 129.2,
130.1, 134.2, 137.7, 191.7, 201.5 ppm. HRMS (CI): calcd. for
C17H24NO [M + H]+ 258.1852; found 258.1838.
General Procedure for Reactions of Lithiated Allylamines with α-
Bromo Ketones: A solution of α-stannylated allylamine 1 in dry
Et2O or THF was cooled to 0 °C, and a solution of nBuLi (a 1.6 m,
1.2 equiv.) in hexane was added slowly at the same temperature.
The reaction was monitored by TLC. After Sn–Li exchange was
complete, the reaction mixture was cooled to –78 °C, and the α-
bromo ketone (1.2 equiv.) was added as an ethereal solution. The
reaction mixture was further stirred at –78 °C for 1 h, before it was
warmed slowly to 0 °C. After complete consumption of the ketone,
Celite or Isolute® was added to the reaction mixture (to avoid aque-
ous workup), and the solvent was evaporated in vacuo. The crude
product (absorbed on the resin) was directly subjected to column
chromatography.
3-Phenyl-4-(piperidin-1-ylmethyl)pent-4-en-2-one (5f): Ketone 5f
was obtained from 1 (200 mg, 0.48 mmol) and α-bromopropio-
phenone (121 mg, 0.57 mmol) after flash chromatography (hex-
anes/ethyl acetate 1:0 to 9:1) as a yellow oil in 62% yield (76 mg,
1
0.30 mmol). H NMR (CDCl3): δ = 1.49 (m, 2 H), 1.51 (m, 4 H),
1.95 (s, 1 H), 2.33 (m, 4 H), 3.06 (m 2 H), 5.47 (s, 1 H), 5.76 (s, 1
H) 7.46 (m, 5 H) ppm. 13C NMR (CDCl3): δ = 14.9, 24.1, 25.8,
54.0, 58.1, 60.3, 118.1, 127.5, 127.9, 128.4, 133.0, 171.0, 200.6 ppm.
HRMS (CI): calcd. for C17H24NO [M + H]+ 258.1852; found
258.1857.
3-(4-Bromophenyl)-4-(piperidin-1-ylmethyl)pent-4-en-2-one
(5g):
1-[2-(2-Phenyloxiran-2-yl)allyl]piperidine (4a): Epoxide 4a was ob-
tained from 1 (200 mg, 0.48 mmol) and phenacyl bromide (115 mg,
0.57 mmol) after flash chromatography (hexanes/ethyl acetate 1:0
Ketone 5g was obtained from 1 (200 mg, 0.48 mmol) and α,4-di-
bromopropiophenone (166 mg, 0.57 mmol) after flash chromatog-
raphy (hexanes/ethyl acetate 1:0 to 9:1) as a yellow oil in 51% yield
(80 mg, 0.24 mmol). 1H NMR (CD2Cl2): δ = 1.42 (m, 2 H), 1.56
(m, 4 H), 2.38 (m, 4 H), 2.95 (m 2 H), 3.11 (s, 1 H), 5.54 (s, 1 H),
5.85 (s, 1 H), 7.61 (m, 2 H), 7.82 (m, 2 H) ppm. 13C NMR
(CD2Cl2): δ = 24.8, 26.5, 32.2, 54.6, 67.7, 118.5, 128.2, 130.0, 132.0,
132.3, 136.3, 200.0 ppm. HRMS (CI): calcd. for C17H23BrNO [M
+ H]+ 336.0957; found 336.0969.
1
to 9:1) as a yellow oil in 71% yield (83 mg, 0.34 mmol). H NMR
(CD2Cl2): δ = 1.44 (m, 2 H), 1.58 (m, 4 H), 2.40 (m, 4 H), 2.69 (d,
J = 5.4 Hz, 1 H), 2.93 (d, J = 5.6 Hz, 1 H), 3.13 (s, 2 H), 5.56 (s,
1 H), 5.86 (s, 1 H), 7.36 (m, 5 H) ppm. 13C NMR (CD2Cl2): δ =
24.8, 26.5, 54.6, 55.8, 60.7, 67.6, 118.7, 126. 5, 127.8, 128.7, 134.1,
141.0 ppm. HRMS (CI): calcd. for C16H22NO [M + H]+ 244.1696;
found 244.1680.
3-[3-(Piperidin-1-yl)prop-1-en-2-yl]cyclohexanone (6): A solution of
α-stannylated allylamine 1 (250 mg, 0.60 mmol) in dry THF (1 mL)
was cooled to 0 °C, and nBuLi (0.7 mL, 1.6 m in hexane, 1.2 mmol)
was slowly added at 0 °C. The reaction was monitored by TLC. On
completion of Sn–Li exchange, the reaction mixture was cooled to
–78 °C, and a slurry of CuBr·Me2S (123 mg, 0.6 mmol) in dry THF
(1 mL) at –78 °C was added. The reaction mixture was stirred at
–78 °C for 1 h and then slowly warmed to 0 °C. The reaction mix-
ture was again cooled to –78 °C, and a solution of 2-cyclohexenone
(115 mg, 1.2 mmol) in dry THF (1.5 mL) was added slowly to af-
ford a yellow solution. The reaction mixture was stirred until all of
the starting material was consumed (TLC). After quenching of the
reaction with saturated NH4Cl/NH4OH solution (25 mL), the lay-
ers were separated, and the aqueous layer was extracted with di-
ethyl ether (3ϫ 25 mL). The combined organic layers were dried
with MgSO4 and concentrated in vacuo. The crude product was
purified by column chromatography (silica, hexanes/ethyl acetate
9:1) to provide amino ketone 6 (77 mg, 0.35 mmol, 58%) as a color-
less oil. 1H NMR (CDCl3): δ = 1.14–2.27 (m, 19 H), 2.85 (m, 2 H),
4.85 (s, 1 H), 4.96 (s, 1 H) ppm. 13C NMR (CDCl3): δ = 22.6, 25.9,
36.2, 38.5, 48.1, 54.5, 60.8, 106.9, 147.4, 212.15 ppm. HRMS:
calcd. for C14H24NO [M + H]+ 222.1852; found 222.1846.
1-{2-[2-(4-Fluorophenyl)oxiran-2-yl]allyl}piperidine (4b): Epoxide 4b
was obtained from 1 (200 mg, 0.48 mmol) and 4-fluorophenacyl
bromide (124 mg, 0.57 mmol) after flash chromatography (hexanes/
ethyl acetate 1:0 to 9:1) as a colorless oil in 76% yield (95 mg,
1
0.36 mmol). H NMR (CD2Cl2): δ = 1.43 (m, 2 H), 1.56 (m, 4 H),
2.38 (m, 4 H), 2.65 (d, J = 5.3 Hz, 1 H), 2.92 (d, J = 5.3 Hz, 1 H),
3.11 (m, 2 H), 5.54 (s, 1 H), 5.84 (s, 1 H), 7.24 (m, 2 H), 7.46 (m,
2 H) ppm. 13C NMR (CD2Cl2): δ = 24.8, 26.5, 54.6, 55.9, 60.3,
67.7, 118.6, 128. 4, 131.8, 140.2, 146.0, 164.7 ppm. HRMS (CI):
calcd. for C16H21FNO [M + H]+ 262.1602; found 262.1109.
1-{2-[2-(4-Bromophenyl)oxiran-2-yl]allyl}piperidine (4c): Epoxide 4c
was obtained from 1 (200 mg, 0.48 mmol) and 4-bromophenacyl
bromide (158 mg, 0.57 mmol) after flash chromatography (hexanes/
ethyl acetate 1:0 to 9:1) as a yellow oil in 72% yield (113 mg,
1
0.35 mmol). H NMR (CD2Cl2): δ = 1.43 (m, 2 H), 1.56 (m, 4 H),
2.38 (m, 4 H), 2.66 (d, J = 5.3 Hz, 1 H), 2.91 (d, J = 5.3 Hz, 1 H),
3.11 (m, 2 H), 5.54 (s, 1 H), 5.84 (s, 1 H), 7.02 (m, 2 H), 7.33 (m,
2 H) ppm. 13C NMR (CD2Cl2): δ = 24.6, 26.3, 54.4, 55.6, 60.1,
67.5, 118.3, 128.1, 128.2, 136.7 (s, C Ar), 136.8, 161.1 ppm. HRMS
(CI): calcd. for C16H21BrNO [M + H]+ 322.0801; found 322.0799.
1-{2-[2-(4-Chlorophenyl)oxiran-2-yl]allyl}piperidine (4d): Epoxide
4d was obtained from 1 (200 mg, 0.48 mmol) and 4-chlorophenacyl
bromide (133 mg, 0.57 mmol) after flash chromatography (hexanes/
ethyl acetate 1:0 to 9:1) as a colorless oil in 75% yield (100 mg,
Supporting Information (see footnote on the first page of this arti-
cle): Copies of NMR spectra of all new compounds.
1
0.36 mmol). H NMR (CD2Cl2): δ = 1.42 (m, 2 H), 1.56 (m, 4 H),
Acknowledgments
2.39 (m, 4 H), 2.65 (d, J = 5.3 Hz, 1 H), 2.92 (d, J = 5.3 Hz, 1 H),
3.11 (s, 2 H), 5.54 (s, 1 H), 5.84 (s, 1 H), 7.31 (m, 5 H) ppm. 13C
NMR (CD2Cl2): δ = 24.8, 26.5, 54.8, 55.9, 60.2, 67.7, 118.5, 128.1,
128.8, 133.4, 139.7, 153.8 ppm. HRMS (CI): calcd. for
C16H21ClNO [M + H]+ 278.1306; found 278.1334.
Financial support by the Deutsche Forschungsgemeinschaft
(DFG) is gratefully acknowledged. Mr. C. Bukovec is thanked for
initial experiments.
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3182–3187

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Received: January 3, 2014
Published Online: April 8. 2014
Eur. J. Org. Chem. 2014, 3182–3187
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3187