Enantioselectivity and diastereoselectivity in reductive radical cyclization reactions of 3-(ω-iodoalkylidene)-piperidin-2-ones

Article abstract of DOI:10.1055/s-2006-942412

The E-configurated 3-(ω-iodoalkylidene)-piperidin-2-ones 1a-e were prepared from the corresponding ω-tert-butyldimethylsilyloxyalkanals 5a-e by aldol condensation with N-tert-butyloxycarbonylpiperidone, subsequent silyl deprotection and iododehydroxylatio

Full text of DOI:10.1055/s-2006-942412

2
206
PAPER
Enantioselectivity and Diastereoselectivity in Reductive Radical Cyclization
Reactions of 3-(w-Iodoalkylidene)-piperidin-2-ones
R
M
eductive Radica
l
Cyc
a
lization rtina Dressel, Tobias Aechtner, Thorsten Bach*
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +49(89)28913315; E-mail: thorsten.bach@ch.tum.de
Received 27 April 2006
Dedicated to Professor Dieter Hoppe on the occasion of his 65 birthday
th
In the course of a research program directed towards
Abstract: The E-configurated 3-(w-iodoalkylidene)-piperidin-2-
ones 1a–e were prepared from the corresponding w-tert-butyldi-
methylsilyloxyalkanals 5a–e by aldol condensation with N-tert-bu-
enantioselective photochemical reactions in solution1
0,11
we have studied the Norrish–Yang cyclization of N-(w-
1
2
tyloxycarbonylpiperidone, subsequent silyl deprotection and iodo- oxo-w-phenylalkyl)-substituted imidazolidinones. The
dehydroxylation. In the presence of tributylstannane as the reducing enantioselectivity determining step in this process is the
agent and of triethylborane as the initiator the iodides underwent a
reductive radical cyclization to the corresponding products rac-9a–
combination of two radical centers to give a cyclic tertiary
alcohol. We observed moderate to good enantioselectivi-
e (72–90% yield). The hydrogen abstraction occurred enantioselec-
ties (up to 60% ee) if the reaction was conducted in the
tively in the presence of the chiral complexing agent 2 in toluene as
presence of chiral lactam complexing agents, which bind
solvent (up to 88% ee). For substrates 1b and 1c, for which both the
radical cyclization and the hydrogen abstraction step were stereo-
the substrate via two hydrogen bonds. The fact that hydro-
genic, the insignificant change in diastereoselectivity indicated that gen bonding has not been previously employed for enan-
the cyclization step was not enantioselective. A 1:1 stoichiometry tiocontrol in radical reactions led us to study this
for the complex was proven by Job plot experiments. The enantiose-
lectivity of the reaction 1a → 9a was concentration dependent.
phenomenon more closely. The first class of radical pre-
cursors, which we have employed in pivotal experi-
Key words: cyclization, enantioselectivity, lactams, radical reac- ments,13 were the 3-(w-iodoalkylidene)-piperidin-2-ones
tions, supramolecular chemistry
1
depicted in Figure 1.
Although the chemistry of radicals is more than 100 years
old, its potential for the construction of enantiomerically
1
HN
I
X
pure compounds has been recognized only in recent
O
H
O
N
N
2
times. A breakthrough was achieved by the use of enan-
O
1
1
1
a
b
c
X = CH2
X = O
X = CMe2
1d X = CH2CH2
1e X = CH2CMe2
tiomerically pure, covalently attached auxiliaries,2
which allowed for high facial diastereoselectivities in
many radical reactions. Substrate- or auxiliary-induced
diastereoselective reactions have allowed the formation
and isolation of enantiomerically pure products, many of
which have been used as key intermediates in the synthe-
–4
2
Figure 1 Structure of the cyclization precursors 1 and of the chiral
complexing agent (template) 2.
2
,4
Reaction of the iodides in the presence of Bu SnH as re-
sis of natural products.
3
ducing agent was expected to yield the corresponding bi-
cyclic products in a 5- or 6-exo-cyclization. In all
instances, i.e. for 1a–e, the hydrogen abstraction step
leads to the formation of a stereogenic center. The cycliza-
tion step for compounds 1a,d,e does not generate a stereo-
genic center. It does so, however, for compounds 1b,c. As
source of chirality the complexing agent 214 was em-
ployed. In this account we report in detail the synthesis of
compounds 1 and their reductive cyclization. The stereo-
selectivity of the reactions was closely studied in the ab-
sence and in the presence of template 2. Further work was
directed towards a quantitative understanding of the bind-
ing mode (Job plot) and of the concentration dependence
of the enantioselectivity in the reaction of substrate 1a.
The auxiliary-free formation of enantiomerically pure
compounds is closely linked to studies on chiral Lewis ac-
ids as complexing agents in radical reactions. In this case,
5
the prochiral starting material is embedded in a chiral en-
vironment by noncovalent interactions enabling the direct
generation of enantiomerically pure or enriched products
6
without any additional cleavage step. Moreover, the fact
that Lewis acid coordination can increase the reactivity of
a given substrate in a radical reaction has been favorably
employed for the creation of catalytic enantioselective
7
radical reactions. Alternative methods for the direct pro-
duction of enantiomerically enriched radical reaction
8
products employ chiral hydrogen atom donors or chiral
9
transition-metal complexes.
The diols 3a–d, which were either commercially available
or were prepared following known procedures,15 were
monoprotected using stoichiometric amounts of tert-bu-
tyldimethylsilyl chloride (TBDMSCl) as the silylating
SYNTHESIS 2006, No. 13, pp 2206–2214
x
x.
x
x
.
2
0
0
6
Advanced online publication: 08.06.2006
DOI: 10.1055/s-2006-942412; Art ID: C01906SS
Georg Thieme Verlag Stuttgart · New York
©

PAPER
Reductive Radical Cyclization
2207
agent and NaH as the base (Scheme 1). Subsequent oxida- Table 1 Yields Achieved in the Individual Steps (Schemes 1 and 2)
Leading to the Radical Cyclization Products rac-9
tion of the remaining primary alcohol group in silyl ethers
1
6–19
4
a–d
achieved with NaOCl in the presence of catalytic amounts
of 2,2,6,6-tetramethylpiperidin-N-oxyl (Tempo) radi- 3a
to the corresponding aldehydes 5a–d was
Substrate 4 [%]
5 [%]
94
7 [%]a 8 [%]
1 [%]
79
rac-9 [%]
62
42
76
57
—
34
16
26
31
18
99
91
92
86
70
87
1
6,18,19
cal.
Aldehyde 5e was synthesized by Wittig
3
b
96
76
90b
89c
84
homologation of aldehyde 5c using methoxymethylphos-
phonium chloride as precursor for the ylide, which in turn 3c
96
68
was generated by treatment with butyl lithium. Hydrolysis
3
5
d
e
96
46
of alkenylmethyl ether 6 and subsequent re-protection
gave aldehyde 5e, which was employed without purifica-
tion for the subsequent aldol condensation.
—
60
72
a
b
c
Yield of pure unprotected E-product (see narrative).
dr = 50:50.
dr = 50:50.
NaH, TBDMSCl
HO
OH
HO
OTBDMS
r.t. (THF)
X
X
3
4
not only made racemic material available for comparison
but also allowed us to optimize the reaction conditions for
the projected enantioselective reaction in the presence of
2. It was conceived that an initiation with triethylborane
was ideally suited to conduct the radical cyclizations at
low temperature and that toluene was – as proven earlier
for photochemical reaction11 – the ideal solvent to in-
crease the hydrogen-bond association between complex-
ing agent 2 and the substrate as well as the putative radical
NaOCl [Tempo]
NaHCO3
°C (H2O–CH2Cl2)
5
a
X = CH2
5b X = O
X = CMe2
O
OTBDMS
X
0
5c
5
5d X = CH CH2
2
(
−
MeO)HCPPh3
78 °C (Et2O)
OTBDMS
MeO
5c
6
1
. p-TsOH, 50 °C
dioxane, H2O)
. TBDMSCl, im
DMF)
intermediate. Both prerequisites – BEt as initiator and
3
(
toluene as solvent – appeared to be given. Yields of the
radical cylization were very good at room temperature
2
OTBDMS
(
O
(
72–90%). It was not a big surprise that a facial diastereo-
selectivity in the reaction of substrates 1d,e was not ob-
served. Due to the single bond between the radical center
and the adjacent stereogenic center formed in the radical
cyclization step a free rotation is likely. Even if the rota-
tion was restricted and if preferred conformations existed,
the fact that the stereodifferentiating elements (X vs. CH2)
are two bonds away from the stereogenic center would
make any face differentiation unlikely.
5
e
Scheme 1 Synthesis of the intermediate aldehydes 5 from the diols
en route to the iodides 1 (Figure 1). The yields of the individual
3
steps are provided in Table 1.
Aldehydes 5 were used in the subsequent aldol condensa-
tion with piperidone or a protected derivative thereof. De-
spite extensive experimentation we did not find
appropriate reaction conditions allowing for a high-yield-
ing access to E-alkenes 7. Eventually, we settled on the
use of N-tert-butyloxycarbonyl(Boc)piperidone20 as nu-
cleophile precursor, which after deprotonation with LDA
underwent an aldol reaction with aldehydes 5. Acidic
R = TBDMS
R = H
7
8
TBAF
r.t. (THF)
HN
OR
X
O
work-up (sat. aq NH Cl-solution) delivered the desired N-
I , PPh , im
r.t. (THF)
3 3
Bu SnH [BEt ]
r.t. (toluene)
4
2
3
HN
deprotected condensation products together with the cor-
responding Z-isomers. Separation of the diastereoisomers
was facile and compounds 7 were obtained in low yields
X
1
O
rac-9
(
16–34%, Table 1). As stated above, attempts to conduct
Scheme 2 Preparation of iodides 1 from the silyl ethers 7 and sub-
sequent radical reaction to racemic exo-cyclization products rac-9.
The yields of the individual steps are provided in Table 1.
the reactions stepwise (aldol addition–elimination–depro-
tection) or to replace the nucleophile precursor by another
piperidone derivative proved to be less efficient overall.
Deprotection of silyl ethers 7 was readily achieved with After having established the suitability of the radical pro-
tetrabutylammonium fluoride (TBAF) in THF. The re-
maining primary alcohols 8 were converted into iodides 1
by using iodine and triphenylphosphine (Scheme 2,
Table 1). The subsequent radical cyclization proceeded
smoothly and in high yields. The corresponding products
rac-9 were obtained in racemic form. These experiments
cess we studied the same reactions in the presence of tem-
plate 2. The substrate concentration was identical in all
runs (50 mM) and the complexing agent was used in ex-
cess (125 mM, 2.5 equiv). Recovery yields of the com-
plexing agent were shown to be excellent and exceeded
consistently 90%. As a BEt -free initiation method was
3
Synthesis 2006, No. 13, 2206–2214 © Thieme Stuttgart · New York

2
208
M. Dressel et al.
PAPER
desirable (vide infra) and as it turned out that the initiation maximizing the reaction rate and minimizing the solvent
with BEt was not always feasible at low temperature, a polarity. On one hand, reactions with 50 mol% BEt were
3
3
photoinduced initiation was employed in some instances complete after one hour and reactions with 20 mol% after
method B, c = 10 mM, Scheme 3, light source: Original three hours. At room temperature and at –10 °C, reactions
(
Hanau TQ 150, duran filter). The reaction is depicted in could even be initiated with 10 mol% BEt and were fin-
3
Scheme 3 with the putative intermediate 10 and the results ished after six hours (entries 2 and 4). On the other hand,
of the study are summarized in Table 2.
the higher polarity due to the presence of BEt and its ox-
3
idation products resulted in a deterioration of the enantio-
meric excess. The effect was less dramatic at room
temperature (entries 1 and 2) and at –10 °C (entries 3 and
Bu3SnH
(toluene)
2
HN
HN
I
.
4
) but became significant when going from 50 mol% to 20
X
X
see Table 2
O
O
mol% at –78 °C (entries 5 and 6).
1
1
0
The switch to the nonpolar UV-initiation (method B, entry
7
) had no beneficial effect on the formation of 9a. It
HN
method A: initiation by BEt3
method B: initiation by UV light
λ > 300 nm)
proved, however, advantageous for optimizing the ee of
compound 9d, in which the increase from 61% ee (method
A, entry 12) to 75% ee (method B, entry 13) was signifi-
cant. The temperature effect is obvious for all enantiose-
H
X
O
(
9
Scheme 3 Enantioselective cyclization of iodide 1 to product 9 in lective versions and indicates a higher association of the
the presence of the chiral complexing reagent 2.
putative radical 10 to the template at lower temperature
(
1
cf. entries 1, 3 and 6; entries 11 and 12; entries 14 and
5). The reaction of substrate 1c to the corresponding
To our pleasant surprise the reaction of substrate 1a yield-
ed even at room temperature enantiomerically enriched
product 9 (Table 2, entries 1 and 2). The amount of BEt3
used for initiation resulted from a compromise between
product 9c according to method A proved as smooth as the
reactions of 1a (entries 9 and 10). Cyclization attempts
with 1b under these conditions failed, possibly due to sub-
Table 2 Yields and Enantioselectivities Achieved in the Reductive Radical Cyclization (Scheme 3) of Iodides 1
Entry
Substrate
1a
X
T [ °C]
25
Method
BEt [mol%]
9 [%]a
84
72
82
79
84
81
67
49
89
71
69
71
65
72
71
ee [%]b
38
44
40
55
41
84
64
–c
3
1
2
3
4
5
6
7
8
9
CH2
CH2
CH2
CH2
CH2
CH2
CH2
O
A
A
A
A
A
A
B
B
A
A
A
A
B
A
A
20
10
20
10
50
20
–
1a
25
1a
–10
–10
–78
–78
–60
–65
25
1a
1a
1a
1a
1b
–
1c
CMe2
CMe2
50
20
50
20
–
–d
1
1
1
1
1
0
1
2
3
4
5
1c
–78
25
–e
1d
CH CH
33
61
75
33
79
2
2
2
2
1d
CH CH
–78
–60
25
2
1d
CH CH
2
1e
CH CMe
50
20
2
2
2
1
1e
CH CMe
–78
2
a
Yield of isolated product. The reaction was carried out at a substrate concentration of 50 mM (method A) or 10 mM (method B), using Bu SnH
3
(
2 equiv) and 2 (2.5 equiv).
b
The ee values were calculated from the enantiomeric ratios, which were determined by HPLC analysis (9a,d: Daicel ChiralCel OD) or by
21
NMR shift experiments (9e).
c
The ee could not be determined (dr = 52:48).
The ee could not be determined (dr = 51:49).
The ee could not be determined (dr = 49:51).
d
e
Synthesis 2006, No. 13, 2206–2214 © Thieme Stuttgart · New York

PAPER
Reductive Radical Cyclization
2209
strate coordination to BEt . In this case, the photochemi- compound 2. To this end, a Job plot24 1H NMR analysis
3
cal initiation (method B, entry 8) was a viable alternative. for the association of 1a to complexing agent 2 was con-
It was disappointing to note that the enantiomeric excess ducted, the result of which is depicted in Figure 3. The
of the products 9b,c could not be assessed by the methods plot reveals the expected association and the 1:1 stoichio-
available to us. Neither HPLC nor GC separation attempts metry although the plot is not fully symmetrical.
on various chiral stationary columns nor NMR shift
2
1
experiments gave a significant separation of the four ste-
reoisomers formed. Diastereomer separation prior to ee
determination was not feasible either. From the continu-
ously low diastereoselectivities (dr @ 50:50) it can be con-
cluded, however, that the cyclization step is not selective.
As this statement already leads into a mechanistic discus-
sion the two selectivity-determining steps are depicted in
Figure 2.
The face differentiation in the hydrogen abstraction step
occurs presumably in the complex 2·10 of radical 10 and
template 2. An approach of the hydrogen atom donor
Figure 3 Job plot analysis of dNH (1a) in benzene-d at 20 °C for the
6
Bu SnH from the less shielded Si face is likely and this ap-
3
complex 1a/2.
proach is in line with the absolute configuration of prod-
2
2
ucts 9a,d,e. If the cyclization of radicals 11b (X = O) or
The possible association pathways of radical 10 are pro-
vided in Scheme 4. The association constant to substrate
1
1c (X = CMe ) was also diastereoselective and if the hy-
2
drogen abstraction step remained diastereoselective for
0b (X = O) or 10c (X = CMe ), which is a likely assump-
1
should be similar to the dimerization constant, while the
1
2
association to 2 should occur roughly with the association
constant for the complex 2·1. Unfortunately, it was not
possible to determine the dimerization constant (Kdim) of
tion, the selectivities of addition and hydrogen abstraction
should sum up and lead to a change in the diastereomeric
ratio. This is apparently not the case. Indeed, inspection of
molecular models shows that a differentiation of the two
enantiotopic faces in complexes 2·11b and 2·11c is not to
be expected.
1
substrate 1a by H NMR spectroscopy because the signals
for the amide NH and the olefinic proton of the starting
material overlapped. The precise determination of the as-
sociation constant (K ) for the association of 1a to sub-
a
strate 2 was consequently also not feasible.
H
SnBu3
Si
O
N
H
N
O
N
H
N
2
.
1
outside
3
1⋅10
10
complex [2 10]
⋅
H
O
H
O
X
X
Kdim
Ka
inside
.
O
N
O
N
Scheme 4 Association of the putative radical 10 to another molecu-
le of substrate 1 or to the chiral complexing agent 2.
2
⋅10
2⋅11
Figure 2 Structure of the putative complexes of radicals 10 and 11
with the complexing agent 2.
Reactions can occur enantioselectively only in complex
2
·10 while reactions of uncomplexed 10 and of complex
1
·10 should be not enantioselective due to the lack of a
2
3
The transition states, which ask for an attack at the exo- chiral environment. In a simplified version of this picture
cyclic carbon of the alkylidene piperdione from an angle – neglecting the association 1·10 – a straightforward equa-
of 105–107°, are similar for either outside or inside attack tion can be derived to calculate the enantiomeric excess
1c
(
Figure 2). In other words, while an inside attack (Re face (ee) as a function of concentration.1 In Figure 4 an arbi-
for X = O, Si face for X = CMe ) suffers from steric inter- trary value of K was chosen to obtain such a curve and to
2
a
action of the CH CH part of the chain, with the tetrahy- fit concentration dependent ee data (marked by an ×) for
2
2
dronaphthalene shield it favorably places the CH X part the conversion 1a → 9a. Up to a medium concentration
2
of the chain away from the bulky shield. Vice versa, the range the expected increase of enantiomeric excess (ee)
outside attack (Si face for X = O, Re face for X = CMe2) with increasing concentration was indeed observed. Sub-
is sterically favored because it minimizes the interaction sequently, the ee drops significantly presumably due to a
of the CH CH part with the shield, but it necessarily leads significant polarity change in the solution. The best ee of
2
2
to a disfavorable steric interaction of the CH X part and 88% was achieved at 100 mM. The product yield under
2
the tetrahydronaphthalene.
these conditions amounted to 78%.
Understandably, the association of the short-lived radical In summary, we have shown that the hydrogen abstraction
intermediates 10 and 11 to the complexing agent 2 were in radicals of type 10 proceeds with high enantioselectiv-
difficult to study. It was somewhat more feasible to have ity in the presence of complexing agent 2. As in previous
1
1
a closer look at the association of radical precursors 1a to studies, we assume that the association of the radical to
Synthesis 2006, No. 13, 2206–2214 © Thieme Stuttgart · New York

2
210
M. Dressel et al.
PAPER
4
5
b17 by oxidation whereas aldehyde 5e was prepared from aldehyde
c by a homologation sequence.
(
2-{[tert-Butyl(dimethyl)silyl]oxy}ethoxy)ethanal (5b)
Alcohol 4a (1.76 g, 8.00 mmol) and 2,2,6,6-tetramethylpiperidi-
noxyl radical (12.5 mg, 0.08 mmol) were dissolved in CH Cl
2
2
(
20 mL) and the solution was cooled to 0 °C. KBr (1.05 g,
8
4
.79 mmol) was dissolved in an aq NaHCO solution (5% w/w,
0 mL) and the solution was added to the reaction mixture. To the
3
vigourously stirred two-phase mixture was added dropwise aq
NaOCl (5.57 mL, 8.15 mmol, 5%) at 0 °C. After complete conver-
sion (TLC control) of the alcohol, the layers were separated and the
organic layer was extracted with CH Cl (30 mL). The combined
2
2
organic layers were washed with aq NaHCO (5% w/w, 15 mL) and
3
brine (15 mL). After filtration, the solvents were evaporated. The
crude product was obtained as colorless oil (1.68 g, 7.68 mmol,
Figure 4 Concentration dependence of the enantioselectivities (ee)
achieved in the cyclization 1a → 9a.
9
6%), which was directly used in the subsequent aldol condensation
step.
Rf 0.59 (P–EtOAc, 70:30).
the complexing agent 2 is favored over the competitive as-
1
H NMR (360 MHz, CDCl ): d = 9.71 (s, 1 H), 4.13 (s, 2 H), 3.79
3
3
3
sociation to lactam 1 or to itself. One major reason for this (t, J = 4.5 Hz, 2 H), 3.63 (t, J = 5.2 Hz, 2 H), 0.88 (s, 9 H), 0.05 (s,
preference is the fact that the complexing agent 2 shows 6 H).
1
1c
no self-association. Hydrogen abstraction reactions oc-
13
C NMR (90.6 MHz, CDCl ): d = 201.2 (d), 76.6 (t), 73.4 (t), 62.9
3
cur in the complex 2·10 with high enantioface differentia- (t), 25.9 (q), 18.3 (s), –5.3 (q).
tion. An activation of the radical 10 towards hydrogen
6
-{[tert-Butyl(dimethyl)silyl]oxy}-4,4-dimethylhexanal (5e)
abstraction in complex 2·10 cannot be ruled out and may
even enhance the efficiency of 2. Contrary to that, the cy-
clization of radical 11 to radical 10 is not sufficiently bi-
ased and occurs for the examples 1b and 1c, which we
studied, non-enantioselectively. Further substrates for
(Methoxymethyl)triphenylphosphonium chloride (7.03 g, 20.5
mmol) was suspended in anhyd Et O (80 mL) and cooled to 0 °C. A
2
solution of BuLi (8.20 mL, 20.5 mmol, 2.50 M in hexane) was add-
ed over 15 min. The reaction mixture was allowed to warm to r.t.
and stirred for 30 min. After cooling the resulting red suspension to
enantioselective radical reactions are currently being –78 °C, a solution of aldehyde 5c (3.89 g, 17.0 mmol) in anhyd
studied.
Et
O (40 mL) was added over 60 min. The reaction mixture was al-
2
lowed to warm to r.t. and stirred for 16 h. After addition of Et O
2
(
100 mL) and H O (50 mL), the aqueous layer was extracted with
2
All reactions involving water-sensitive chemicals were carried out
in flame-dried glassware with magnetic stirring under argon. THF
Et O (2 × 50 mL). The combined organic layers were washed with
a solution of aq H O (35%, 10 mL) and brine (20 mL) and dried
over Na SO . After filtration the solvent was evaporated and the
crude product was purified by flash chromatography (7.5 × 18 cm,
EtOAc) to give 6 a colorless liquid. R 0.88 (EtOAc). The product
was a mixture of E/Z-isomers (dr = 50:50), which was not further
characterized but used directly in the subsequent hydrolysis step.
2
2
2
and Et O were distilled from Na immediately prior to use. CH Cl
2
2
2
2 4
and N,N-diisopropylamine were distilled from CaH . All other
2
chemicals were either commercially available or prepared accord-
ing to the cited references. TLC: Merck glass sheets (0.25 mm silica
gel 60, F254), eluent given in brackets; detection by UV or colora-
f
tion with cerium ammonium molybdate (CAM) or KMnO . Flash
4
Enolether 6 (3.50 g, 12.8 mmol) was dissolved in dioxane–H O
(
The solution was stirred for 2 h at 50 °C and after cooling to r.t.
Et O (50 mL) was added. The organic layer was washed with sat. aq
NaHCO (5% w/w, 20 mL) and brine (15 mL). The extract was
dried over Na SO , filtered and concentrated. The resulting color-
2
chromatography was performed on silica gel 60 (Merck, 230–400
mesh) (approx. 50 g for 1 g of material to be separated) with the in-
dicated eluent. Common solvents for chromatography [pentane (P),
9:1, 150 mL) and p-TsOH·H O (3.57 g 19.3 mmol) was added.
2
2
Et O, EtOAc] were distilled prior to use. NMR: Bruker AV-360,
2
1
13
3
AV-500. H and C NMR spectra were recorded in CDCl at ambi-
3
2
4
ent temperature. Chemical shifts are reported relative to tetrameth-
ylsilane as internal standard. Apparent multiplets, which occur as a
result of the accidental equality of coupling constants of magneti-
cally non-equivalent protons, are marked as virtual (virt.). The mul-
tiplicities of the 13C NMR signals were determined by DEPT
less liquid was dissolved in anhyd DMF (20 mL), then imidazole
1.13 g, 16.6 mmol) and TBDMSCl (4.41 mL, 12.8 mmol, 2.90 M)
were added. After stirring for 2 h at r.t. Et O (30 mL) and H O
(
2
2
(
200 mL) were added and the aqueous layer was extracted with
Et O (2 × 30 mL). The combined organic layers were washed with
brine (15 mL) and dried over Na SO . Filtration and evaporation of
1
3
2
experiments. Overlaping signals in the C NMR spectra are marked
with an asterisk (*). IR: Perkin-Elmer 1600 FT-IR. GC-MS: Agilent
2
4
the solvent gave the crude aldehyde as a colorless liquid. R 0.72 (P–
f
6
890 (GC system), Agilent 5973 (Mass selective detector, EI).
EtOAc, 70:30). The crude aldehyde 5e was directly taken into the
aldol condensation step. The overall yield for the transformation
was calculated for the four steps going from 5c to 7e (vide infra).
HPLC: ChiralCel OD [250 × 4.60 mm], hexane–i-PrOH = 95:5,
flow rate: 1 mL/min. MS: Finnigan MAT 8200 (EI). Elemental
Analysis: Elementar Vario EL.
1
3
H NMR (360 MHz, CDCl ): d = 9.74 (t, J = 1.8 Hz, 1 H), 3.58 (t,
J = 6.4 Hz, 2 H), 2.43–2.40 (m, 2 H), 1.54–1.51 (m, 2 H), 1.39–
3
3
Aldehydes 5a–e
The literature-known aldehydes 5a, 5c,18 and 5d19 were prepared
by Tempo-catalyzed oxidation from the corresponding alcohols.
Analogously, aldehyde 5b was obtained from the known alcohol
16
1.36 (m, 2 H), 0.92 (s, 9 H), 0.90 (s, 6 H), 0.02 (s, 6 H).
13
C NMR (90.6 MHz, CDCl ): d = 202.8 (d), 58.2 (t), 44.1 (t), 35.1
3
(
t), 32.6 (t), 32.2 (s), 26.4 (q), 26.0 (q), 18.3 (s), –5.4 (q).
Synthesis 2006, No. 13, 2206–2214 © Thieme Stuttgart · New York

PAPER
Reductive Radical Cyclization
2211
Aldol Condensations of Aldehydes 5a–e; General Procedure
N,N-Di-isopropyl amine (1.70 equiv) was placed in a flame-dried
Schlenk flask. Under an argon atmosphere, anhyd THF (4.00 mL/
mmol aldehyde) was added and the solution was cooled to 0 °C. A
solution of n-BuLi (1.68 equiv, 2.50 M in hexane) was added over
Anal. Calcd for C H NO Si: C, 66.41; H, 10.84; N, 4.30. Found:
C, 66.13; H, 11.08; N, 4.41.
1
8
35
2
(E)-3-(6-{[tert-Butyl(dimethyl)silyl]oxy}hexylidene)piperidin-
2-one (7d)
3
0 min and the solution was stirred for 30 min at this temperature.
White solid, 31%; mp 52 °C; R 0.20 (EtOAc).
f
After cooling to –78 °C, a solution of N-Boc-protected piperidin-2-
one (1.20 equiv) in THF (2.00 mL/mmol aldehyde) was added. Af-
ter stirring the reaction mixture for 30 min at 0 °C, the solution was
cooled again to –78 °C and a solution of the aldehyde (1.00 equiv)
in THF (1.00 mL/mmol aldehyde) was added dropwise. The reac-
tion mixture was allowed to warm to r.t. and stirring was continued
IR (KBr): 3388 (br), 2932 (m), 2857 (m), 1670 (vs), 835 (m), 775
cm (w).
–1
1
3
H NMR (360 MHz, CDCl ): d = 6.90 (t, J = 7.7 Hz, 1 H), 6.60 (br
3
3
s, 1 H), 3.57 (t, J = 6.4 Hz, 2 H), 3.35–3.33 (m, 2 H), 2.46 (t,
3
3
3
J = 5.4 Hz, 2 H), 2.13 (virt. quint., J ≈ J = 7.2 Hz, 2 H), 1.80 (virt.
3
3
quint., J ≈ J = 6.1 Hz, 2 H), 1.51–1.43 (m, 2 H), 1.41–1.28 (m, 4
H), 0.87 (s, 9 H), 0.02 (s, 6 H).
for 16 h. After the reaction mixture was diluted with sat. aq NH Cl
4
solution (2.00 mL/mmol aldehyde), Et O (7.50 mL/mmol alde-
2
hyde) was added. The aqueous layer was extracted twice with Et O
13
2
C NMR (90.6 MHz, CDCl ): d = 167.2 (s), 141.6 (d), 138.0 (s),
3
(
1.50 mL/mmol aldehyde). The combined organic layers were
6
3.0 (t), 42.0 (t), 32.6 (t), 28.0 (t), 25.9 (q), 25.7 (t), 24.9 (t), 23.9 (t),
washed with brine and dried over Na SO . After filtration, the sol-
2
4
22.3 (t), 18.5 (s), –5.3 (q).
vent was evaporated and the crude product was purified by flash
chromatography (P–EtOAc, 40:60 → EtOAc).
+
HRMS (EI): m/z [M ] calcd for C H NO Si: 311.2281; found:
1
7
33
2
3
11.2278.
(
E)-3-[5-{[tert-Butyl(dimethyl)silyl]oxy}pentylidene)-
(
E)-3-(6-{[tert-Butyl(dimethyl)silyl]oxy}-4,4-dimethylhexyl-
piperidin-2-one (7a)
White solid, 34%; mp 51 °C; R 0.22 (EtOAc).
IR (KBr): 3178 (m), 1670 (vs), 1624 (vs), 1097 (s), 836 cm–1 (s).
idene)piperidin-2-one (7e)
White solid, 18% over 4 steps; mp 61 °C; R 0.28 (EtOAc).
f
f
IR (KBr): 3388 (br), 2932 (m), 2857 (m), 1670 (vs), 835 (m), 775
cm (m).
1
3
H NMR (360 MHz, CDCl ): d = 6.80 (t, J = 7.3 Hz, 1 H), 6.60 (br
–1
3
3
s, 1 H), 3.57 (t, J = 6.0 Hz, 2 H), 3.35–3.23 (m, 2 H), 2.43 (t,
1
3
3
3
3
H NMR (360 MHz, CDCl
3
): d = 6.83 (t, J = 7.5 Hz, 1 H), 6.10 (br
J = 5.5 Hz, 2 H), 2.10 (virt. q, J ≈ J = 7.2 Hz, 2 H), 1.80 (virt.
3
3
3
s, 1 H), 3.65 (t, J = 7.7 Hz, 2 H), 3.36–3.32 (m, 2 H), 2.47 (t,
quint., J ≈ J = 6.1 Hz, 2 H), 1.58–1.38 (m, 4 H), 0.85 (s, 9 H), 0.01
(
3
3
J = 5.4 Hz, 2 H) 2.11–2.06 (m, 2 H), 1.84 (q, J = 5.6 Hz, 2 H),
.51–1.47 (m, 2 H), 1.34–1.29 (m, 2 H), 0.90 (s, 6 H), 0.89 (s, 9 H),
0.02 (s, 6 H).
s, 6 H).
1
1
3
C NMR (90.6 MHz, CDCl ): d = 167.4 (s), 139.0 (d), 128.4 (s),
3
6
1
2.8 (t), 41.9 (t), 32.4 (t), 27.5 (t), 25.9 (q), 24.9 (t), 24.2 (t), 22.7 (t),
8.5 (s), –5.3 (q).
1
3
C NMR (90.6 MHz, CDCl ): d = 166.6 (s), 139.7 (d), 127.9 (s),
3
6
0.0 (t), 44.0 (t), 42.0 (t), 41.0 (t), 32.2 (s), 27.3 (q), 26.0 (q), 24.3
Anal. Calcd for C H NO Si: C, 64.59; H, 10.50. Found: C, 64.24;
H, 10.65.
1
6
31
2
(t), 22.8 (t), 22.7 (t), 18.3 (s), –5.3 (q).
Anal. Calcd for C H NO Si: C, 67.20; H, 10.98; N, 4.12. Found:
1
9
37
2
C, 66.89; H, 10.88; N, 4.19.
(
E)-3-[2-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethoxy)eth-
ylidene]piperidin-2-one (7b)
White solid, 16%; mp 119 °C; R 0.21 (EtOAc).
Deprotection of Compounds 7a–e; General Procedure
f
Compounds 7a–e (1.00 equiv) were dissolved in THF (4.40 mL/
mmol lactam) and a TBAF solution (2.00 equiv, 1.00 M in THF)
was added in one portion. After stirring for 4 h, silica gel was added,
the solvent was removed in vacuo and the crude product was puri-
fied by flash chromatography (EtOAc–acetone, 60:40).
IR (KBr): 3184 (br), 2954 (m), 2857 (m), 1674 (vs), 1628 (m), 1095
(
s), 836 cm–1 (m).
1
3
H NMR (360 MHz, CDCl ): d = 6.97 (t, J = 7.9 Hz, 1 H), 6.11 (br
3
3
3
s, 1 H), 4.20 (d, J = 8.0 Hz, 2 H), 3.75 (t, J = 10.4 Hz, 2 H), 3.51
(
3
3
t, J = 10.3 Hz, 2 H), 3.36–3.31 (m, 2 H), 2.50 (t, J = 7.1 Hz, 2 H),
(
E)-3-(5-Hydroxypentylidene)piperidin-2-one (8a)
1
.88–1.82 (m, 2 H), 0.88 (s, 9 H), 0.05 (s, 6 H).
White solid, 99%; mp 58–59 °C; R 0.13 (EtOAc–acetone, 60:40).
1
3
f
C NMR (90.6 MHz, CDCl ): d = 166.3 (s), 134.13 (d), 131.3 (s),
3
IR (KBr): 3384 (br), 1670 (vs), 1622 (vs), 1066 cm–1 (s).
7
1
0.2 (t), 66.4 (t), 63.7 (t), 30.3 (t), 42.1 (t), 25.9 (q), 24.6 (t), 24.1 (t),
8.3 (s), –5.2 (q).
1
H NMR (360 MHz, CDCl ): d = 7.03 (br s, 1 H), 6.67 (t,
3
3
3
J = 7.3 Hz, 1 H), 3.55 (t, J = 6.1 Hz, 2 H), 3.31–3.21 (m, 2 H),
Anal. Calcd for C H NO Si: C, 60.16; H, 9.76; N, 4.68. Found: C,
15
29
3
3
3
2
.82 (br s, 1 H), 2.40 (t, J = 5.6 Hz, 2 H), 2.10 (virt. quint., J ≈
3 3
6
0.19; H, 9.93; N, 4.86.
3
J = 7.3 Hz, 2 H), 1.77 (virt. quint., J ≈ J = 6.0 Hz, 2 H), 1.58–1.38
(
m, 4 H).
(
E)-3-(5-{[tert-Butyl(dimethyl)silyl]oxy}-3,3-dimethylpentyl-
idene)piperidin-2-one (7c)
13
C NMR (90.6 MHz, CDCl ): d = 167.0 (s), 138.8 (d), 128.4 (s),
3
White solid, 26%; mp 82 °C; R 0.28 (EtOAc).
f
62.2 (t), 41.7 (t), 32.2 (t), 27.4 (t), 24.7 (t), 24.2 (t), 22.5 (t).
IR (KBr): 3184 (br), 2954 (m), 2857 (m), 1674 (vs), 1628 (m), 1095
(
+
HRMS (EI): m/z [M ] calcd for C H NO : 183.1259; found:
1
0
17
2
s), 836 cm–1 (m).
1
83.1260.
1
3
H NMR (500 MHz, CDCl ): d = 6.95 (t, J = 7.9 Hz, 1 H), 6.09 (br
3
3
(E)-3-[2-(2-Hydroxyethoxy)ethylidene]piperidin-2-one (8b)
White solid, 91%; mp 95 °C, R 0.09 (EtOAc–acetone, 60:40).
s, 1 H), 3.65 (t, J = 7.3 Hz, 2 H), 3.36–3.33 (m, 2 H), 2.46–2.42 (m,
3
2
H), 2.05 (t, J = 7.9 Hz, 2 H), 1.85–1.81 (m, 2 H), 1.50 (t,
J = 7.6 Hz, 2 H), 0.92 (s, 6 H), 0.86 (s, 9 H), 0.02 (s, 6 H).
f
3
IR (KBr): 3426 (s, br), 3173 (s, br), 3018 (m), 2924 (m), 1670 (vs),
1621 (s), 1031 cm (m).
–
1
1
3
C NMR (90.6 MHz, CDCl ): d = 167.2 (s), 136.9 (d), 129.3 (s),
3
6
0.0 (t), 44.5 (t), 42.1 (t), 40.6 (t), 33.7 (t), 27.3 (q), 25.9 (q), 24.5
1
H NMR (360 MHz, CDCl ): d = 7.10 (br s, 1 H), 6.84 (t,
J = 10.1 Hz, 1 H), 4.14 (d, J = 10.1 Hz, 2 H), 3.68–3.62 (m, 4 H),
3
(
t), 22.7 (s), 18.3 (s), –5.3 (q).
3
3
3
.59–3.50 (m, 4 H), 1.93–1.65 (m, 2 H).
Synthesis 2006, No. 13, 2206–2214 © Thieme Stuttgart · New York

2
212
M. Dressel et al.
PAPER
1
3
3
3
C NMR (90.6 MHz, CDCl ): d = 166.7 (s), 134.3 (d), 130.9 (s),
quint., J ≈ J = 7.3 Hz, 2 H), 1.87–1.73 (m, 4 H), 1.58–1.47 (m, 2
3
7
0.9 (t), 67.7 (t), 63.5 (t), 30.5 (t), 42.2 (t), 24.9 (t).
H).
+
13
HRMS (EI): m/z [M ] calcd for C H NO : 185.1052; found:
C NMR (90.6 MHz, CDCl ): d = 167.2 (s), 141.6 (d), 138.0 (s),
9
15
3
3
1
85.1053.
63.0 (t), 42.0 (t), 32.6 (t), 28.0 (t), 25.7 (t), 23.9 (t), 22.3 (t).
+
HRMS (EI): m/z [M ] calcd for C H INO: 293.0277; found:
1
0
16
(
(
E)-3-(5-Hydroxy-3,3-dimethylpentylidene)piperidin-2-one
8c)
2
93.0275.
White solid, 92%; mp 83–86 °C; R 0.07 (EtOAc–acetone, 60:40).
f
(
E)-3-[2-(2-Iodoethoxy)ethylidene]piperidin-2-one (1b)
IR (KBr): 3426 (s, br), 3173 (s, br), 3018 (m), 2924 (m), 1670 (vs),
1
Yellow solid, 76%; mp 54–56 °C; R 0.17 (EtOAc).
f
621 (s), 1031 cm–1 (m).
IR (KBr): 3458 (s, br), 2956 (m), 2865 (m), 1676 (vs), 1631 (s),
1
3
–1
H NMR (500 MHz, CDCl ): d = 6.95 (t, J = 7.8 Hz, 1 H), 6.13 (br
1485 (m), 848 cm (m).
3
3
s, 1 H), 3.69 (t, J = 7.4 Hz, 2 H), 3.37–3.34 (m, 2 H), 2.47–2.43 (m,
1
H NMR (360 MHz, CDCl ): d = 6.95–6.92 (m, 1 H), 6.21 (s, 1 H),
H) 2.06 (d, 3J = 7.9 Hz, 2 H) 1.86–1.83 (m, 2 H), 1.56 (t,
3
2
3
3
4
2
.19 (d, J = 6.1 Hz, 2 H), 3.71 (t, J = 6.6 Hz, 2 H), 3.38–3.35 (m,
3
J = 7.4 Hz, 2 H), 0.95 (s, 6 H).
3
3
H), 3.24 (t, J = 6.8 Hz, 2 H), 2.49 (t, J = 5.4 Hz, 2 H), 1.87 (virt.
1
3
3
3
C NMR (90.6 MHz, CDCl ): d = 167.4 (s), 137.1 (d), 129.6 (s),
quint., J ≈ J = 6.2 Hz, 2 H).
13
3
6
2.1 (t), 44.6 (t), 42.0 (t), 41.1 (t), 33.9 (t), 27.2 (q), 24.5 (t), 22.7 (s).
C NMR (90.6 MHz, CDCl ): d = 165.9 (s), 134.5 (d), 130.7 (s),
3
Anal. Calcd for C H NO : C, 68.21; H, 10.02; N, 6.63. Found: C,
71.2 (t), 66.8 (t), 30.2 (t), 42.0 (t), 22.5 (t), 2.5 (t).
12
21
2
6
7.97; H, 10.00; N, 6.42.
+
HRMS (EI): m/z [M ] calcd for C H INO : 295.0069; found:
9
14
2
2
95.0056.
(
E)-3-(6-Hydroxyhexylidene)piperidin-2-one (8d)
White solid, 86%; mp 83 °C; R 0.21 (EtOAc–acetone, 60:40).
f
(
E)-3-(5-Iodo-3,3-dimethylpentylidene)piperidin-2-one (1c)
IR (KBr): 3289 (s, br), 2934 (m), 2864 (m), 1672 (vs), 1632 (s),
1
Yellow solid, 68%; mp 74–76 °C; R 0.20 (EtOAc).
f
053 cm–1 (m).
IR (KBr): 3461 (s, br), 2953 (m), 2862 (m), 1674 (vs), 1635 (s),
1
–1
H NMR (360 MHz, CDCl ): d = 6.91 (br s, 1 H), 6.88 (t,
1476 (m), 842 cm (m).
3
3
3
J = 7.6 Hz, 1 H), 3.62 (t, J = 6.4 Hz, 2 H), 3.36–3.31 (m, 2 H),
1
3
H NMR (360 MHz, CDCl ): d = 6.93 (t, J = 7.3 Hz, 1 H), 6.29 (br
3
3
3
2
(
.46–2.43 (m, 2 H), 2.13 (virt. quint., J ≈ J = 7.2 Hz, 2 H), 1.83
3
s, 1 H), 3.37–3.34 (m, 2 H), 3.14 (t, J = 7.0 Hz, 2 H), 2.46 (t,
3
3
virt. quint., J ≈ J = 6.3 Hz, 2 H), 1.63–1.29 (m, 6 H).
3
3
3
J = 7.1 Hz, 2 H), 2.04 (d, J = 7.9 Hz, 2 H), 1.93 (t, J = 7.1 Hz, 2
1
3
3
3
C NMR (90.6 MHz, CDCl ): d = 167.2 (s), 141.6 (d), 138.0 (s),
H), 1.85 (virt. quint., J ≈ J = 6.9 Hz, 2 H), 0.93 (s, 6 H).
13
3
6
3.0 (t), 42.0 (t), 32.6 (t), 28.0 (t), 25.7 (t), 24.9 (t), 23.9 (t), 22.3 (t).
C NMR (90.6 MHz, CDCl ): d = 166.2 (s), 134.9 (d), 130.3 (s),
3
+
HRMS (EI): m/z [M ] calcd for C H NO : 197.1416; found:
47.3 (t), 42.0 (t), 40.0 (t), 37.0 (s), 26.3 (q), 24.6 (t), 22.8 (t), 0.4 (t).
1
1
19
2
1
97.1414.
Anal. Calcd for C H INO: C, 44.87; H, 6.82; N, 4.36. Found: C,
1
2
20
4
4.53; H, 6.70; N, 4.32.
(
E)-3-(6-Hydroxy-4,4-dimethylhexylidene)piperidin-2-one (8e)
White solid, 70%; mp 95 °C; R 0.19 (EtOAc–acetone, 60:40).
f
(
E)-3-(6-Iodohexylidene)piperidin-2-one (1d)
IR (KBr): 3289 (s, br), 2932 (m), 2859 (m), 1672 (vs), 1624 (s),
1
Yellow solid, 46%; mp 72 °C; R 0.18 (EtOAc).
f
053 cm–1 (m).
IR (KBr): 3380 (s, br), 2922 (m), 2857 (m), 1670 (vs), 1621 (m),
1
3
–1
H NMR (360 MHz, CDCl ): d = 6.86 (t, J = 7.5 Hz, 1 H), 5.92 (br
1168 cm (m).
3
3
s, 1 H), 3.72 (t, J = 7.8 Hz, 2 H), 3.39–3.35 (m, 2 H), 2.50 (t,
1
3
H NMR (360 MHz, CDCl ): d = 6.97 (t, J = 7.4 Hz, 1 H), 6.79 (br
3
3
3
J = 5.6 Hz, 2 H) 2.15–2.08 (m, 2 H), 1.88 (q, J = 5.3 Hz, 2 H),
3
s, 1 H), 3.44–3.40 (m, 2 H), 3.17 (t, J = 7.0 Hz, 2 H), 2.48–2.46 (m,
1
.58–1.52 (m, 2 H), 1.39–1.34 (m, 2 H), 0.94 (s, 6 H).
2
H) 2.23–2.19 (m, 2 H), 1.91–1.87 (m, 2 H), 1.85–1.81 (m, 2 H),
1
3
C NMR (90.6 MHz, CDCl ): d = 167.2 (s), 141.6 (d), 138.0 (s),
1.58–1.33 (m, 4 H).
3
6
2
3.0 (t), 42.0 (t), 32.6 (t), 28.0 (t), 25.7 (t), 25.5 (s), 24.9 (t), 23.9 (t),
2.3 (t).
13
C NMR (90.6 MHz, CDCl ): d = 164.2 (s), 144.4 (d), 132.0 (s),
3
4
2.2 (t), 33.1 (t), 30.2 (t), 28.1 (t), 27.3 (t), 23.2 (t), 21.5 (t), 6.6 (t).
Anal. Calcd for C H NO : C, 69.29; H, 10.29; N, 6.22. Found: C,
+
13
23
2
HRMS (EI): m/z [M ] calcd for C H INO: 307.0433; found:
1
1
18
6
9.01; H, 10.43; N, 6.43.
3
07.0430.
Iodination of Compounds 8a–e; General Procedure
To a solution of the alcohol 8 (1.00 equiv) in anhyd THF (10.0 mL/
(
E)-3-(6-Iodo-4,4-dimethylhexylidene)piperidin-2-one (1e)
Yellow solid, 60%; mp 91–93 °C; R 0.18 (EtOAc).
f
mmol alcohol) were added successively Ph P (1.10 equiv), imida-
3
IR (KBr): 3340 (s, br), 2991 (m), 2854 (m), 1660 (vs), 1621 (m),
1
zole (2.10 equiv) and I (1.15 equiv) at r.t. The reaction mixture was
2
–
1
173 cm (m).
stirred for 2 h, then silica gel was added and the solvent was evapo-
rated. The crude product was purified by flash chromatography
1
3
H NMR (500 MHz, CDCl ): d = 6.82 (t, J = 7.4 Hz, 1 H), 5.83 (br
3
(EtOAc).
3
s, 1 H), 3.37–3.34 (m, 2 H), 3.13 (t, J = 8.2 Hz, 2 H), 2.48 (t,
3
J = 5.8 Hz, 2 H) 2.09–2.04 (m, 2 H), 1.94–1.91 (m, 2 H), 1.89–1.84
(
E)-3-(5-Iodopentylidene)piperidin-2-one (1a)
(m, 2 H), 1.34–1.31 (m, 2 H), 0.92 (s, 6 H).
Yellow solid, 79%; mp 63–65 °C; R 0.14 (EtOAc).
f
13
C NMR (90.6 MHz, CDCl ): d = 161.3 (s), 139.1 (d), 132.2 (s),
3
–
1
IR (KBr): 3166 (s, br), 1670 (vs), 1618 (s), 1410 (m), 1337 cm (s).
4
7.2 (t), 42.1 (t), 40.0 (t), 35.8 (t), 26.9 (q), 26.3 (s), 24.4 (t), 22.8
1
(t), 22.6 (t).
H NMR (360 MHz, CDCl ): d = 7.87–6.73 (m, 2 H), 3.35–3.25 (m,
3
3
3
2
H), 3.14 (t, J = 6.9 Hz, 2 H), 2.43 (t, J = 5.5 Hz, 2 H), 2.12 (virt.
+
HRMS (EI): m/z [M ] calcd for C H INO: 335.0746; found:
1
3
22
3
35.0741.
Synthesis 2006, No. 13, 2206–2214 © Thieme Stuttgart · New York

PAPER
Reductive Radical Cyclization
2213
Racemic Reductive Radical Cyclization Reactions of Com-
pounds 1a–e; General Procedure
3-(4,4-Dimethylcyclohexyl)piperidin-2-one (rac-9e)
White solid, 72%; mp 81–83 °C; R 0.19 (EtOAc).
f
To a solution of the iodide (c = 50 mM) in toluene (Merck, Uvasol)
tributylstannane (2.00 equiv) and triethylborane (0.5 equiv) were
added at ambient temperature. The reaction mixture was stirred un-
til the conversion was complete (TLC control) and then silica gel
was added. The solvent was evaporated and the crude product was
purified by flash chromatography (EtOAc).
IR (KBr): 3346 (br), 2823 (m), 1656 (vs), 1634 (m), 1149 cm–1 (m).
1
H NMR (360 MHz, C D ): d = 6.57 (br s, 1 H), 2.53–2.51 (m, 2 H),
6
6
2
1
.27–2.21 (m, 1 H), 2.06–2.00 (m, 1 H), 1.54–1.50 (m, 1 H), 1.40–
.09 (m, 11 H), 0.89 (s, 6 H).
13
C NMR (90.6 MHz, C D ): d = 167.8 (s), 45.5 (t), 42.0 (d), 39.9
6
6
(
d), 39.7 (s), 33.5 (t), 30.1 (t), 26.6 (t), 24.3 (t), 22.6 (q).
3
-Cyclopentylpiperidin-2-one (rac-9a)
Anal. Calcd for C H NO: C, 74.59; H, 11.07; N, 6.69. Found: C,
1
3
23
White solid, 87%; mp 69–71 °C; R 0.16 (EtOAc).
f
7
4.31; H, 10.59; N, 7.01.
IR (KBr): 3190 (m), 1654 (vs), 1497 (m), 530 cm–1 (m).
1
Enantioselective Reductive Radical Cyclization Reactions
Method A); General Procedure
To a solution of the iodide (c = 50 mM) and the chiral complexing
H NMR (360 MHz, CDCl ): d = 6.33–6.31 (m, 1 H), 3.30–3.16 (m,
H), 2.43–2.22 (m, 2 H), 1.90–1.42 (m, 10 H), 1.38–1.23 (m, 1 H),
.22–1.08 (m, 1 H).
3
(
2
1
agent 2 (2.50 equiv) in toluene (Merck, Uvasol) tributylstannane
1
3
C NMR (90.6 MHz, CDCl ): d = 175.1 (s), 44.3 (d), 42.4 (t), 40.7
3
(
2.00 equiv) and triethylborane (0.10–0.50 equiv) were added at the
(
d), 30.3 (t), 28.7 (t), 25.4 (t), 25.1 (t), 23.3 (t), 21.3 (t).
given temperature. The reaction mixture was stirred until the con-
version was complete (TLC control) and then silica gel was added.
The solvent was evaporated and the crude product was purified by
flash chromatography (P–EtOAc, 50:50 → EtOAc). The chiral
Anal. Calcd for C H NO: C, 71.81; H, 10.25. Found: C, 71.91; H,
1
1
0
17
0.25.
3
-(Tetrahydrofuran-3-yl)piperidin-2-one (rac-9b and rac-9b¢)
complexing agent 2 is less polar [R 0.57 (EtOAc)] than the piperi-
f
White solid, 90%; mixture of diastereoisomers, dr = 50:50; R 0.20
din-2-ones and could be easily recovered (>90%) by flash chroma-
f
(
EtOAc).
tography.
IR (KBr): 3334 (m, br), 2831 (m), 1673 (vs), 1168 cm–1 (m).
Enantioselective Reductive Radical Cyclization Reactions
(Method B); General Procedure
To a solution of the iodide (c = 10 mM) and the chiral complexing
1
H NMR (360 MHz, CDCl ): d = 5.85 (br s, 1 H), 3.90–3.84 (m, 2
3
H), 3.78–3.61 (m, 2 H), 3.31–3.28 (m, 2 H), 2.80–2.73 (m, 1 H),
2
1
.61–2.54 (m, 1 H), 2.36–2.17 (m, 2 H), 2.04–1.89 (m, 2 H), 1.61–
.55 (m, 2 H).
agent 2 (2.50 equiv) in toluene (Merck, Uvasol) tributylstannane
(
2.00 equiv) was added. The reaction mixture was irradiated at
1
3
300 nm (TQ 150, duran) for 2.5 h at the given temperature. After
silica gel was added, the solvent was evaporated and the crude prod-
uct was purified by flash chromatography (P–EtOAc, 50:50 →
EtOAc).
C NMR (90.6 MHz, CDCl ): d = 173.8/173.8 (s), 72.6/71.0 (t),
3
6
8.5/67.6 (t), 44.3/43.7 (d), 42.3/42.3 (t), 40.8/40.1 (d), 30.7/30.3
(
t), 25.0/24.1 (t), 21.6/21.4 (t).
+
HRMS (EI): m/z [M ] calcd for C H NO : 169.1103; found:
9
15
2
1
69.1102.
3
-Cyclopentylpiperidin-2-one (9a)
HPLC [ChiralCel OD, 215 nm]: t = 16.5 min.
R
3
-(3,3-Dimethylcyclopentyl)piperidin-2-one (rac-9c and rac-9c¢)
[
[
a]D20 +33.2 (c 0.34 in CH Cl ) [84% ee].
2 2
White solid, 89%; mixture of diastereoisomers, dr = 50:50; R 0.28
f
(
EtOAc).
20
a]D +45.8 (c 0.6 in MeOH) [84% ee].
IR (KBr): 3331 (br), 2995 (m), 1611 (vs), 1115 (m), 748 (m), 836
-
1
3-Cyclohexylpiperidin-2-one (9d)
(
s), 652 cm (s).
HPLC [ChiralCel OD, 215 nm]: t = 17.9 min
1
R
H NMR (360 MHz, CDCl ): d = 5.72 (br s, 1 H), 3.27–3.25 (m, 2
3
[
a]D20 +51.0 (c 0.26 in CH Cl ) [75% ee].
H), 2.62–2.52 (m, 1 H), 2.28–2.25 (m, 1 H), 1.88–1.82 (m, 2 H),
2 2
1
.81–1.62 (m, 4 H), 1.61–1.22 (m, 4 H), 1.00 (s, 3 H), 0.96 (s, 3 H).
3
-(4,4-Dimethyl-cyclo-hexyl)piperidin-2-one (9e)
1
3
C NMR (90.6 MHz, CDCl ): d = 173.2/173.2 (s), 45.4/44.1 (t),
20
3
[
a]D +6.5 (c 0.05 in CH Cl ) [79% ee].
2 2
4
4.8/44.7 (d), 42.4/42.4 (t), 40.8/40.5 (t), 40.1/40.0 (d), 38.7/38.3
(
2
s), 30.4/30.3 (q), 29.9/28.4 (t), 29.3/29.3 (q), 23.5/23.5 (t), 21.3/
1.3 (t).
Acknowledgment
+
HRMS (EI): m/z [M ] calcd for C H NO: 195.1623; found:
1
2
21
Our research was supported by the Deutsche Forschungsgemein-
schaft (Schwerpunktprogramm 1179 Organokatalyse) and by the
Fonds der Chemischen Industrie.
1
95.1623.
3
-Cyclohexylpiperidin-2-one (rac-9d)
White solid, 84%; mp 95 °C; R 0.21 (EtOAc).
f
IR (KBr): 3372 (br), 2835 (m), 1675 (vs), 1621 (m), 1168 cm–1 (m). References
1
H NMR (360 MHz, CDCl ): d = 7.05 (br s, 1 H), 3.29–3.36 (m, 2
3
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(
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1
1
1
19
(
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Synthesis 2006, No. 13, 2206–2214 © Thieme Stuttgart · New York