Stereoselective 6-exo cyclization of amidyl radicals. An experimental and theoretical study

Article abstract of DOI:10.1021/jo2014406

Unsaturated primary amidyl radicals of Z-configurations underwent efficient chemo- and stereoselective 6-exo cyclization reactions via chair-conformational transition states, leading to the predominant formations of 3,6-trans, 4,6-cis, or 5,6-trans substituted Δ-lactams. (Figure presented)

Full text of DOI:10.1021/jo2014406

NOTE
pubs.acs.org/joc
Stereoselective 6-Exo Cyclization of Amidyl Radicals. An Experimental
and Theoretical Study
Shunjun Zhuang,† Kun Liu,*,‡ and Chaozhong Li*,†
†Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. China
‡College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecule, Tianjin Normal University,
Tianjin 300387, P. R. China
S Supporting Information
b
ABSTRACT: Unsaturated primary amidyl radicals of Z-config-
urations underwent efficient chemo- and stereoselective 6-exo
cyclization reactions via chair-conformational transition states,
leading to the predominant formations of 3,6-trans, 4,6-cis, or
5,6-trans substituted δ-lactams.
itrogen-centered radicals are involved in a variety of useful
organic transformations.1 Amidyl radicals, in particular,
reactivity of amidyl radicals.9c While N-tert-butyl-substituted
hex-5-enamidyl radical underwent 1,5-hydrogen migration,
primary hex-5-enamidyl radicals underwent cyclization
exclusively.9c Furthermore, with vinylic halogen substitution,
the regioselectivity of 5-hexenamidyl radical cyclization could
be well controlled, leading to the regiospecific 6-exo and 7-endo
cyclization.9d The halogen effect also allows the direct use of
unsaturated amides as the substrates by inhibiting the compet-
ing ionic processes.14 This remarkable halogen effect was then
rationalized based on lone pair electron repulsion between the
halogen atom and the radical center and was successfully
extended to the control of regioselectivity in sulfonamidyl
and primary aminyl radical cyclizations.15 As an extension, we
set out to explore the control of stereoselectivity of 6-exo
cyclization.
Both (E)- and (Z)-6-iodo-2-methylhex-5-enamide (1a) were
first used as the model substrates. The (Z)-isomer was readily
prepared by the iodination of the 2-methylhex-5-ynamide with I2
followed by reduction with TsNHNH2.16 The (E)-alkenyl iodide
was synthesized via the hydroiodination of an alkyne with
Cp2ZrCl2/DIBALH (diisobutylaluminum hydride)/I2.17 (E)-
1a was then subjected to treatment with Pb(OAc)4 and I2 in
CH2Cl2 (0.03 M) at room temperature (rt) under UV irradia-
tion, a typical condition for the generation of amidyl radicals.9d
The 6-exo cyclization product 2a was thus obtained in 83% yield
as the 50:50 mixture of two stereoisomers (eq 1). On the other
hand, the reaction of the (Z)-isomer under the same conditions
gave 2a with the trans/cis ratio of 75:25. Switching Pb(OAc)4/I2
to other conditions such as diacetoxyiodobenzene (DIB)/I2
resulted in lower yields of cyclized products. However, the
trans/cis ratios remained unchanged. The CdC bond geometry
N
have gained increasing popularity in the past decade.1 The highly
reactive and electrophilic nature2 allows amidyl radicals to add to
electron-rich CdC double bonds leading to the direct construc-
tion of CÀN bonds.3À10 More importantly, the intramolecu-
lar addition provides a unique entry to various substituted
N-heterocycles,4À10 thus offering a great potential in the synthesis
of natural products such as alkaloids.10 On the other hand, the high
reactivity of amidyl radicals also imposes a significant challenge on
the control of chemo-, regio-, and stereoselectivity of cyclization.
While the efficiency and regioselectivity of cyclization of various
modes have been well investigated, the stereoselectivity of cycliza-
tion is far less explored for this type of radicals. In fact, only 5-exo
cyclization was studied by Clark et al., and poor to moderate
stereoselectivities were observed.11 It is certainly of interest to see
if high stereoselectivity could be achieved in other modes of
cyclization. However, the amidyl radical cyclization other than
5-membered ring closure suffers from the competing 1,5- or 1,6-
hydrogen migration processes12,13 (HofmannÀL€offlerÀFreytag
reactions) and sometimes from the poor regioselectivity, which
make the development of stereoselective reactions difficult. Here-
in, we report that efficient and highly stereoselective 6-exo
cyclization reactions can be successfully implemented for
amidyl radicals. Theoretical analysis in combination with
experimental results provides a clear understanding on the
control of stereoselectivity.
The cyclization of amidyl radicals in a 6-exo mode is rather
uncommon. Kinetic studies by Newcomb et al. indicated that
6-exo amidyl radical cyclization is about 2 orders of magnitude
slower than the corresponding 5-exo cyclization.2c Lessard and
co-workers reported the Bu3SnH-mediated 6-exo cyclization of
N-(phenylthio)cyclohept-4-enecarboxamide.7 During our re-
cent investigation on the behaviors of amidyl radical reactions,9
we found that the N-substituents play a crucial role in the
Received: July 14, 2011
Published: August 19, 2011
r
2011 American Chemical Society
8100
dx.doi.org/10.1021/jo2014406 J. Org. Chem. 2011, 76, 8100–8106
|

The Journal of Organic Chemistry
NOTE
thus has a significant impact on the stereoselectivity but no effect
on the efficiency and regioselectivity.18
Table 1. Stereoselectivity of 6-Exo Cyclization
To understand the effect of other halogen atoms, the vinylic
chloro-substituted amides (E)-3 and (Z)-3 were also prepared,
and their cyclization reactions were carried out under the above
conditions. For ease of characterization, the cyclized products
were then directly reduced with H3PO2/AIBN19 to give the
chlorides 4 (eq 2). Again, the trans/cis ratio of 4 was 50:50 in the
reaction of (E)-3 but 75:25 in the reaction of (Z)-3, indicating
that the chlorine atom had the same effect as the iodine atom in
controlling the stereoselectivity of cyclization.
On the basis of the above results, a number of (Z)-amides were
then screened, and the results are summarized in Table 1. The
reactions were clean in all cases, and the cyclized products were
obtained in high yields. The relative configurations of δ-lactams
were determined by the relevant proton coupling constants or by
the 2D NOESY experiments of representative examples (see the
Supporting Information). Interestingly, the α-carbonyl substitu-
ents R showed a remarkable influence on the product stereo-
selectivity. The ratio of trans to cis isomers increases when the
size of R increases (entries 1À4, Table 1). A higher stereose-
lectivity but in favor of the cis isomers was observed when the R
group was switched from the α-position to the β-position
(entries 5À7, Table 1). The minor isomers could be observed
from the crude 1H NMR but could not be isolated in a pure form.
When the trans-substituted cyclohexanecarboxamide (Z)-7 was
employed as the substrate, the bicyclic lactam 8 was secured in
81% yield as the only stereoisomer. Furthermore, with the
amides (Z)-9 bearing a substituent at the allylic position, the
corresponding trans-isomers 10 were obtained exclusively in
excellent yields (entries 9À12, Table 1). Surprisingly, although
the substitution at the allylic position in (Z)-9 significantly
encourages the 1,5-H migration by lowering the allylic CÀH
bond dissociation energies (BDEs), no products derived from
1,5-H migration could be detected even in the case of (Z)-9d
(R = Ph).
a Reaction conditions: alkenyl iodide (0.2 mmol), Pb(OAc)4 (0.7 mmol),
I2 (0.5 mmol), CH2Cl2 (6.6 mL), rt, hν, 1 h. b Isolated yield based on the
starting alkenyl iodide. c Determined by 1H NMR (400 MHz).
transition structures were fully optimized at the UB3LYP/6-31G**
level and the IEFPCM (the Polarizable Continuum Model using
the Integral Equation Formalism variant) model in dichloro-
methane. The default settings for IEFPCM in Gaussian09 were
used. Once convergence was reached, the harmonic vibration
frequencies were calculated at this point to confirm the geometry
obtained to be a true minimum or first-order saddle point. The
zero-point vibrational energy and thermal corrections were also
obtained at the UB3LYP/6-31G** level and the IEFPCM model,
from which the activation free energies can be calculated. Radicals
R-3E and R-3Z derived from substrates (E)-3 and (Z)-3 were
chosen as the models for the understanding of the effect of CdC
bond configuration on the stereoselectivity of cyclization. Radical
R-9Z derived from substrate 9d (with the iodine atom replaced by
chlorine atom) was also selected for computation in order to
understand the chemoselectivity between 1,5-H migration and
cyclization. The calculated activation free energies are summarized
in Table 2, and the computed transition-state structures are listed
in Figure 1 (also see the Supporting Information).
The above results have clearly shown that the 6-exo cyclization
of amidyl radicals can be efficient and highly stereoselective. To
gain further insight into the behaviors of amidyl radicals in 6-exo
cyclization, we turned to theoretical calculations for help. Ab
initio calculations were carried out with the Gaussian09 suite of
program.20 The density functional theory method was used,
which has been demonstrated to be a fairly accurate tool for
dealing with radical reactions.21 All equilibrium geometry and
8101
dx.doi.org/10.1021/jo2014406 |J. Org. Chem. 2011, 76, 8100–8106

The Journal of Organic Chemistry
NOTE
Table 2. Calculated (UB3LYP/6-31G**) Activation Free
Energies of 6-Exo Cyclization and 1,5-H Migration
the chlorine substitution does not have a significant steric influence on
the 1,5-H migration based on the structure of TS-9Z-M.
The vinylic halogen substituted substrates serve as a good model
for the study of stereoselectivity of amidyl radical cyclization. On the
basis of the structural difference between TS-3Z-trans and TS-3Z-
cis, it is conceivable that substituents other than a halogen atom
should have a similar effect in controlling the stereoselectivity of
cyclization.22,23 The structure of TS-9Z-M also reveals that the 1,5-H
migration from a tertiary CÀH is sterically unfavorable because it
requires one of the substituents to be at the axial position in the
transition states. This finding should be of important implications in
designing other modes of amidyl radical cyclization with the inhibi-
tion of the competing intramolecular hydrogen abstraction. These
are currently under investigation in our laboratory.
In summary, the above experiments in combination with theore-
tical calculations have clearly demonstrated that, with Z-configura-
tional vinylic halogen substitution, primary amidyl radicals undergo
efficient chemo-, regio-, and stereoselective 6-exo cyclization via
chairlike conformational transition states. The calculations offer a
quantitative view on the mechanism of 6-exo cyclization of amidyl
radicals, which will certainly allow more controlled and predictable
applications of this important type of reactions.
ΔGq (kcal/mol)
entry radical 6-exo cyclization 1,5-H migration calcd trans/cis ratio
1
2
3
R-3E
R-3Z
R-9Z
3.2 (3,6-trans),
3.3 (3,6-cis)
not calculated
not calculated
7.1
54:46
84:16
99:1
3.2 (3,6-trans),
4.2 (3,6-cis)
5.6 (5,6-trans),
8.4 (5,6-cis)
For the cyclization of radical R-3E, the two transition states,
TS-3E-trans and TS-3E-cis, both in chairlike conformations, are
of almost the same energy (entry 1, Table 2), in excellent
agreement with the observed 50:50 ratio of stereoisomers in
the cyclization of (E)-3. The distance between the internal vinylic
carbon and the nitrogen is longer in TS-3E-cis (2.73 Å) than in
TS-3E-trans (2.35 Å), which diminishes the steric unfavorable-
’ EXPERIMENTAL SECTION
ꢀ
(Z)-6-Iodo-2-methylhex-5-enamide ((Z)-1a). Typical Pro-
cedure. The benzene (3.5 mL) solution of morpholine (2.9 mL) was
added dropwise into the mixture of iodine (2.7 g, 10.8 mmol) and
benzene (35 mL) at 45 °C. The solution was stirred for 20 min, and
2-methylhex-5-ynamide (0.9 g, 7.2 mmol) was added dropwise. The
reaction mixture was stirred at 45 °C for 12 h. The resulting mixture was
then filtered, and the precipitate was washed with ether (30 mL). The
combined organic phase was washed with successively with saturated
aqueous NaCl solution, NaHSO4 solution (10%), and saturated
KHCO3 solution and then dried over anhydrous Na2SO4. After removal
of solvent in vacuo, the crude product was purified by column
chromatography on silica gel with hexane/acetone (3:1, v:1) as the
eluent to give 6-iodo-2-methylhex-5-ynamide (1.8 g, 98% yield) as a
white solid. The amide obtained was then added into the mixture of p-
toluenesulfonyl hydrazine (2.6 g, 14 mmol) and NaOAc (1.7 g, 21
mmol) in THF/H2O (1:1, v:v). The mixture was refluxed with stirring
for 12 h. After being cooled to rt, the solution was extracted with ether
(3 Â 20 mL), and the combined organic phase was dried over anhydrous
Na2SO4. The crude product was then purified by column chromatog-
raphy on silica gel with hexane/acetone (3:1 v/v) as the eluent to give
pure (Z)-1a as a white solid. Yield: 0.7 g (38%). Mp: 74À76 °C. IR
(KBr): ν (cmÀ1) 3348, 3168, 3053, 2967, 2931, 1662, 1630, 688, 657.
1H NMR (400 MHz, CDCl3): δ 1.19 (3H, d, J = 7.2 Hz), 1.45À1.59
(1H, m), 1.75À1.90 (1H, m), 2.13À2.23 (2H, m), 2.24À2.35 (1H, m),
5.56 (2H, br), 6.11À6.26 (2H, m). 13C NMR (100 MHz, CDCl3): δ
17.9, 32.2, 32.6, 40.1, 83.1, 140.5, 178.7. EIMS: m/z (rel intensity) 253
(M+, 0.6), 167 (8), 127 (4), 126 (23), 73 (100), 72 (14), 55 (6), 44 (23),
41 (10). HRMS: calcd for C7H12INO (M) 252.9964, found 252.9967.
(E)-6-Iodo-2-methylhex-5-enamide ((E)-1a). The hydroiodi-
nation of 2-(but-3-yn-1-yl)-2-methyl-1,3-dioxolane with Cp2ZrCl2/DI-
BALH/I2 was performed according to the literature procedure.17 The
product was then deprotected with 6 N HCl solution (1 mL) and MeOH
(10 mL) at rt for 12 h. After the usual workup, (E)-6-iodo-2-methylhex-
5-en-2-one was obtained in 39% yield (for two steps). The ketone was
cyanated with p-toluenesulfonylmethyl isocyanide/KOBut/DME to
give the homologous nitrile, which was then converted to amide (E)-
1a byhydrolysis with 30% H2O2 (30%)/NaOH (6 N) in EtOH according
to the conventional procedures. White solid. Mp: 76À78 °C. IR (KBr):
ꢀ
ness of the pseudoaxial chloromethylene moiety in TS-3E-cis.
For the cyclization of radical R-3Z, the two computed transition
states, TS-3Z-trans and TS-3Z-cis, are also in chairlike conformations
(Figure 1). The Z-configuration of CdC bond now results in the
steric hindrance between the chlorine atom and the axial β-carbonyl
ꢀ
hydrogen in TS-3Z-cis, their distance being estimated to be 2.89 Å.
As a result, TS-3Z-cis is 1.0 kcal/mol higher in energy than TS-3Z-
trans, which corresponds to the trans/cis ratio of 84:16 in the cyclized
products 4if we assume that the cyclization is kinetically controlled, in
good agreement with the experimental value (75:25).
The chairlike conformational transition state TS-3Z-trans well
explains the preference of 3,6-trans, 4,6-cis, and 5,6-trans configura-
tions in the cyclized products. It is also reasonable that, when the
substituent on the alkyl chain of substrate gets closer to the vinyl
group, the transition state similar to TS-3Z-cis will face more steric
hindrance and the energy difference between the two transition states
will become larger. This accounts for the higher stereoselectivity in
the cyclization of (Z)-5 and (Z)-9. Moreover, when the substituent
gets bulkier, the transition-state conformations become more rigid.
This may increase the steric instability of the disfavored transition
state similar to TS-3Z-cis, which in turn enlarges the energy differ-
ence. These analyses are in excellent qualitative agreement with the
experimental data.
In the case of radical R-9Z, the activation free energy is
computed to be 5.6 kcal/mol for 6-exo cyclization with 5,6-trans
stereochemistry and 7.1 kcal/mol for 1,5-H migration, indicating that
cyclization predominates, consistent with the experimental observa-
tions. Similar to TS-3Z-trans, the transition state for 5,6-trans
cyclization of R-9Z is in a chair conformation with both the phenyl
and chloromethylene group at the equatorial positions. On the other
hand, the transition state for 1,5-H migration, TS-9Z-M, is in a half-
chair conformation with the vinyl group at the pseudoaxial position,
resulting in an enhanced steric congestion in the transition state.
Therefore, although the CÀH BDE becomes much lower because of
the phenyl substitution, the 6-exo cyclization still prevails. Note that
8102
dx.doi.org/10.1021/jo2014406 |J. Org. Chem. 2011, 76, 8100–8106

The Journal of Organic Chemistry
NOTE
Figure 1. Computed (UB3LYP/6-31G**) transition-state structures.
ν (cmÀ1) 3350, 3172, 2965, 2932, 1663, 1633, 1460, 942. 1H NMR (400
MHz, CDCl3): δ 1.16 (3H, d, J = 7.2 Hz), 1.41À1.56 (1H, m), 1.71À1.84
(1H, m), 2.04À2.16 (2H, m), 2.21À2.33 (1H, m), 5.50 (2H, br), 6.04
(1H, d, J = 14.4 Hz), 6.43À6.54 (1H, m). 13C NMR (100 MHz, CDCl3):
δ 17.9, 32.5, 33.7, 39.8, 75.3, 145.6, 178.4. EIMS: m/z (rel intensity) 253
(M+, 0.6), 167 (9), 126 (19), 73 (100), 72 (16), 57 (6), 55 (8), 44 (25),
41 (10). Anal. Calcd for C7H12INO: C, 33.22; H, 4.78; N, 5.53. Found: C,
33.57; H, 4.88; N, 5.46.
1635, 1460, 1317, 737. 1H NMR (400 MHz, CDCl3): δ 1.17 (3H, d, J =
6.8 Hz), 1.43À1.55 (1H, m), 1.73À1.86 (1H, m), 2.17À2.36 (3H, m),
5.58 (1H, br), 5.73 (1H, q, J = 7.2 Hz), 5.88 (1H, br), 6.03 (1H, d, J = 7.2
Hz). 13C NMR (100 MHz, CDCl3): δ 17.8, 24.9, 32.6, 40.2, 118.7,
130.9, 178.8. EIMS: m/z (rel intensity) 161 (M+, 0.5), 75 (12), 73 (100),
72 (17), 55 (10), 53 (6), 44 (38), 42 (9), 41 (13). Anal. Calcd for
C7H12ClNO: C, 52.02; H, 7.48; N, 8.67. Found: C, 52.23; H, 7.52;
N, 8.60.
(Z)-2-Ethyl-6-iodohex-5-enamide ((Z)-1b). Yellowish solid.
Mp: 58À60 °C. IR (KBr): ν (cmÀ1) 3369, 3180, 3064, 2963, 2935,
1655, 1617, 1277, 643. 1H NMR(400 MHz, CDCl3): δ0.94(3H, t, J =7.2
Hz), 1.45À1.69 (3H, m), 1.71À1.86 (1H, m), 2.00À2.11 (1H, m), 2.17
(2H, q, J = 7.2 Hz), 5.55 (1H, br), 5.83 (1H, br), 6.10À6.25 (2H, m). 13C
NMR (100 MHz, CDCl3): δ 11.9, 26.0, 30.7, 32.8, 48.1, 83.1, 140.6,
177.9. EIMS: m/z (rel intensity) 140 (M+ À I, 33), 167 (11), 87 (100), 72
(89), 55 (20), 53 (6), 44 (25), 41 (15). Anal. Calcd for C8H14INO: C,
35.97; H, 5.28; N, 5.24. Found: C, 36.24; H, 5.45; N, 5.12.
(Z)-6-Iodo-2-isopropylhex-5-enamide ((Z)-1c). White solid.
Mp: 52À54 °C. IR (KBr): ν (cmÀ1) 3386, 3190, 2959, 2926, 1651,
1278, 652; 1H NMR (400 MHz, CDCl3): δ 0.97 (6H, d, J = 5.6 Hz),
1.58À1.69 (1H, m), 1.71À1.91 (3H, m), 2.06À2.26 (2H, m), 5.49 (1H,
br), 5.63 (1H, br), 6.12À6.26 (2H, m). 13C NMR (100 MHz, CDCl3): δ
20.4, 20.7, 28.2, 30.7, 33.1, 53.5, 83.0, 140.8, 177.6. EIMS: m/z (rel
intensity) 281 (M+, 2), 154 (27), 101 (58), 86 (100), 72 (14), 55 (15),
44 (23), 43 (12), 41 (21). HRMS: calcd for C9H16INO (M) 281.0277,
found 281.0273.
(Z)-6-Iodo-3-methylhex-5-enamide ((Z)-5a). White solid.
Mp: 65À67 °C. IR (KBr): ν (cmÀ1) 3357, 3177, 3058, 2952, 2920,
1659, 1628, 1415, 1278, 666. 1H NMR (400 MHz, CDCl3): δ
0.96À1.05 (3H, m), 1.95À2.32 (5H, m), 5.58 (2H, br), 6.13À6.32
(2H, m). 13C NMR (100 MHz, CDCl3): δ 19.7, 30.1, 41.5, 42.7, 84.2,
139.3, 174.9. EIMS: m/z (rel intensity) 126 (M+ À I, 58), 67 (11), 59
(100), 55 (11), 44 (48), 43 (19), 42 (11), 41 (33). HRMS: calcd for
C7H12INO (M) 252.9964, found 252.9965.
(Z)-3-Ethyl-6-iodohex-5-enamide ((Z)-5b). White solid. Mp:
57À59 °C. IR (KBr): ν (cmÀ1) 3353, 3177, 3059, 2961, 2931, 1666,
1626, 1411, 1269, 648. 1H NMR (400 MHz, CDCl3): δ 0.92 (3H, t, J =
7.2 Hz), 1.30À1.50 (2H, m), 1.95À2.35 (5H, m), 5.59 (2H, br),
6.12À6.31 (2H, m). 13C NMR (100 MHz, CDCl3): δ 11.1, 26.5,
36.1, 38.5, 40.1, 84.1, 139.4, 175.1. EIMS: m/z (rel intensity) 140 (M+ À
I, 72), 167 (10), 141 (8), 81 (12), 59 (100), 55 (15), 44 (32), 41 (16).
HRMS: calcd for C8H14INO (M) 267.0120, found 267.0121.
(Z)-6-Iodo-3-isopropylhex-5-enamide ((Z)-5c). White solid.
Mp: 84À86 °C. IR (KBr): ν (cmÀ1) 3359, 3185, 3059, 2960, 2894, 1666,
1626, 1431, 1409, 1270, 652. 1H NMR(400 MHz, CDCl3): δ 0.91 (6H, d,
J = 6.8 Hz), 1.69À1.81 (1H, m), 2.00À2.30 (5H, m), 5.54 (1H, br), 5.77
(1H, br), 6.13À6.27 (2H, m). 13C NMR (100 MHz, CDCl3): δ 19.1,
19.2, 30.0, 36.4, 37.2, 40.2, 83.9, 140.2, 175.3. EIMS: m/z (rel intensity)
154 (M+ À I, 49), 95 (20), 69 (10), 59 (100), 55 (14), 44 (30), 43 (24),
41 (32). HRMS: calcd for C9H16INO (M) 281.0277, found 281.0274.
(1R*,2S*)-2-((Z)-3-Iodoallyl)cyclohexanecarboxamide ((Z)-7).
White solid. Mp: 114À116 °C. IR (KBr): ν (cmÀ1) 3366, 3182, 3064,
2929, 2852, 1659, 1623, 1444, 1416, 1286, 669, 613. 1H NMR
(400 MHz, CDCl3): δ 0.93À1.10 (1H, m), 1.13À1.34 (2H, m),
1.44À1.57 (1H, m), 1.65À1.95 (6H, m), 1.98À2.10 (1H, m),
2.19À2.30 (1H, m), 5.58 (1H, br), 5.76 (1H, br), 6.11À6.28 (2H,
m). 13C NMR (100 MHz, CDCl3): δ 25.5, 25.6, 30.8, 31.1, 38.4, 39.8,
51.1, 83.8, 139.4, 178.0. EIMS: m/z (rel intensity) 293 (M+, 4), 167
(22), 166 (100), 107 (20), 81 (24), 79 (20), 72 (22), 67 (21), 55 (21).
Anal. Calcd for C10H16INO: C, 40.97; H, 5.50; N, 4.78. Found: C,
41.07; H, 5.38; N, 4.73.
(Z)-6-Iodo-2-phenylhex-5-enamide ((Z)-1d). White solid.
Mp: 61À63 °C. IR (KBr): ν (cmÀ1) 3404, 3295, 3183, 3061, 2944,
1
2914, 1647, 1446, 1406, 701, 625. H NMR (400 MHz, CDCl3): δ
1.83À1.96 (1H, m), 2.05À2.19 (2H, m), 2.25À2.38 (1H, m), 3.40 (1H,
t, J = 7.2 Hz), 5.41 (1H, br), 5.66 (1H, br), 6.10À6.26 (2H, m),
7.25À7.40 (5H, m). 13C NMR (100 MHz, CDCl3): δ 31.1, 32.9, 52.0,
83.3, 127.6, 128.1, 129.1, 139.4, 140.3, 175.6. EIMS: m/z (rel intensity)
315 (M+, 2), 188 (16), 167 (8), 136 (9), 135 (100), 118 (21), 115 (8),
91 (31), 44 (10). HRMS: calcd for C12H14INO (M) 315.0120, found
315.0125.
(E)-6-Chloro-2-methylhex-5-enamide ((E)-3). White solid.
Mp: 66À68 °C. IR (KBr): ν (cmÀ1) 3358, 3176, 2967, 2928, 1663,
1636, 1463, 1420, 924. 1H NMR (400 MHz, CDCl3): δ 1.15 (3H, d, J =
7.2 Hz), 1.40À1.53 (1H, m), 1.70À1.83 (1H, m), 2.01À2.17 (2H, m),
2.21À2.33 (1H, m), 5.55 (1H, br), 5.70À6.10 (3H, m). 13C NMR (100
MHz, CDCl3): δ 17.8, 28.6, 33.1, 39.9, 117.6, 133.0, 178.7. EIMS: m/z
(rel intensity) 161 (M+, 0.3), 75 (11), 73 (100), 72 (20), 55 (6), 53 (6),
44 (40), 42 (7), 41 (14). HRMS: calcd for C7H12ClNO (M) 161.0607,
found 161.0610.
(Z)-6-Iodo-4-methylhex-5-enamide ((Z)-9a). White solid.
Mp: 69À71 °C. IR (KBr): ν (cmÀ1) 3341, 3163, 3059, 2954, 2920,
1664, 1633, 1455, 1414, 1164, 699. 1H NMR (400 MHz, CDCl3): δ 1.02
(3H, d, J = 6.8 Hz), 1.57À1.87 (2H, m), 2.21 (2H, t, J = 7.6 Hz),
(Z)-6-Chloro-2-methylhex-5-enamide ((Z)-3). White solid.
Mp: 78À80 °C. IR (KBr): ν (cmÀ1) 3338, 3166, 2970, 2933, 1666,
8103
dx.doi.org/10.1021/jo2014406 |J. Org. Chem. 2011, 76, 8100–8106

The Journal of Organic Chemistry
NOTE
2.46À2.63 (1H, m), 5.53 (2H, br), 5.91 (1H, dd, J = 9.2 Hz, 7.2 Hz), 6.19
(1H, d, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): δ 19.5, 31.5, 33.6,
39.2, 81.5, 145.9, 175.3. EIMS: m/z (rel intensity) 126 (M+ À I, 74), 67
(15), 59 (100), 55 (22), 54 (17), 53 (27), 44 (54), 41 (23). HRMS: calcd
for C7H12INO (M) 252.9964, found 252.9967.
(1H, br). 13C NMR (100 MHz, CDCl3): δ À16.0, 17.9, 25.2, 25.6, 34.8,
60.8, 176. EIMS: m/z (rel intensity) 252 (M+ À I, 0.7), 127 (4), 113 (7),
112 (100), 82 (7), 69 (19), 56 (4), 42 (4), 41 (12). HRMS: calcd for
C7H11I2NO (M) 378.8930, found 378.8931. The structure was further
confirmed by its 2D NOESY experiments.
(Z)-4-Ethyl-6-iodohex-5-enamide ((Z)-9b). White solid. Mp:
54À56 °C. IR (KBr): ν (cmÀ1) 3343, 3165, 3064, 2960, 2919, 1666,
1627, 1455, 1411, 1254, 697. 1H NMR (400 MHz, CDCl3): δ 0.90 (3H,
t, J = 7.2 Hz), 1.27À1.69 (3H, m) 1.78À1.93 (1H, m) 2.14À2.30 (2H,
m) 2.32À2.48 (1H, m) 5.5 (2H, br) 5.86 (1H, dd, J = 9.2 Hz, 7.6 Hz)
6.30 (1H, d, J = 7.6 Hz). 13C NMR (100 MHz, acetone-d6) δ 11.0, 27.1,
29.7, 32.9, 46.0, 82.5, 145.3, 174.4. EIMS: m/z (rel intensity) 140 (M+ À
I, 88), 95 (21), 68 (24), 67 (32), 59 (100), 56 (40), 44 (63), 41 (39).
Anal. Calcd for C8H14INO: C, 35.97; H, 5.28; N, 5.24. Found: C, 36.21;
H, 5.28; N, 5.22.
(Z)-6-Iodo-4-isopropylhex-5-enamide ((Z)-9c). White solid.
Mp: 34À36 °C. IR (KBr): ν (cmÀ1) 3345, 3190, 3059, 2958, 2920,
1662, 1606, 1455, 1406, 1264, 710. 1H NMR (400 MHz, CDCl3): δ 0.90
(3H, d, J = 6.8 Hz), 0.94 (3H, d, J = 6.8 Hz), 1.55À1.77 (2H, m),
1.85À1.95 (1H, m), 2.12À2.35 (3H, m), 5.60 (2H, br), 5.92 (1H, dd, J =
7.6 Hz, 10 Hz), 6.34 (1H, d, J = 7.6 Hz). 13C NMR (100 MHz, acetone-
d6) δ 18.8, 19.9, 27.3, 31.6, 33.1, 50.4, 83.4, 143.7, 174.3. EIMS: m/z (rel
intensity) 154 (M+ À I, 92), 137 (34), 95 (29), 67 (45), 59 (100), 44
(65), 43 (37), 41 (69). HRMS: calcd for C9H16INO (M) 281.0277,
found 281.0287.
(3R*,6S*)-6-(Diiodomethyl)-3-ethylpiperidin-2-one (trans-2b).
White solid. Mp: 129À131 °C. IR (KBr): ν (cmÀ1) 3189, 3075, 2959, 2934,
1646, 1402, 1316, 1090, 818. 1H NMR (400 MHz, CDCl3):δ 0.94 (3H, t, J=
7.2 Hz), 1.38À1.62 (3H, m), 1.90À2.05 (2H, m), 2.11À2.29 (2H, m),
3.07À3.16 (1H, m), 5.15 (1H, d, J = 3.2 Hz), 6.61 (1H, br). 13C NMR (100
MHz, CDCl3): δ À14.3, 11.1, 23.5, 24.1, 29.3, 42.0, 60.7, 175.1. EIMS: m/z
(rel intensity) 266 (M+ À I, 6), 127 (14), 126 (100), 83 (41), 82 (11), 56
(10), 55 (34), 42 (9), 41 (30). HRMS: calcd for C8H13I2NO (M) 392.9087,
found 392.9092.
(3S*,6S*)-6-(Diiodomethyl)-3-ethylpiperidin-2-one (cis-2b).
White solid. Mp: 100À102 °C. IR (KBr): ν (cmÀ1) 3186, 3065, 2959,
2868, 1660, 1409, 1299, 1093. 1H NMR (400 MHz, CDCl3): δ 1.01 (3H, t,
J = 7.2 Hz), 1.53À1.74 (2H, m), 1.78À2.04 (4H, m), 2.22À2.32 (1H, m),
3.19À3.29 (1H, m), 5.13 (1H, d, J =4.0 Hz), 6.27 (1H, br). 13C NMR(100
MHz, CDCl3): δ À16.2, 12.0, 22.1, 24.8, 25.4, 41.7, 60.8, 175.4. EIMS: m/z
(rel intensity) 266 (M+ À I, 1), 365 (8), 127 (14), 126 (100), 112 (13), 83
(30), 82 (9), 55 (19), 41 (18). HRMS: calcd for C8H13I2NO (M)
392.9087, found 392.9080.
(3S*,6S*)-6-(Diiodomethyl)-3-isopropylpiperidin-2-one
(trans-2c). White solid. Mp: 120À122 °C. IR (KBr): ν (cmÀ1) 3174,
1
3050, 2958, 2869, 1657, 1415, 1304, 1091, 838. H NMR (400 MHz,
(Z)-6-Iodo-4-phenylhex-5-enamide ((Z)-9d). White solid.
Mp: 62À64 °C. IR (KBr): ν (cmÀ1) 3382, 3196, 3056, 3026, 2947,
CDCl3): δ 0.85 (3H, d, J = 6.8 Hz), 0.98 (3H, d, J = 7.2 Hz), 1.33À1.47
(1H, m), 1.62 (1H, qd, J = 13.2 Hz, 2.8 Hz), 1.79À1.98 (1H, m),
2.18À2.30 (2H, m), 2.53À2.68 (1H, m), 3.10À3.22 (1H, m), 5.13 (1H,
d, J = 3.2 Hz), 6.18 (1H, br). 13C NMR (100 MHz, CDCl3): δ À14.5,
17.5, 18.8, 20.3, 27.4, 29.3, 46.5, 60.6, 174.9. EIMS: m/z (rel intensity)
280 (M+ À I, 25), 140 (100), 98 (27), 97 (56), 69 (50), 55 (35), 43 (28),
41 (84). HRMS: calcd for C9H15I2NO (M) 406.9243, found 406.9240.
(3S*,6S*)-6-(Diiodomethyl)-3-phenylpiperidin-2-one (trans-
2d). White solid. Mp: 156À158 °C. IR (KBr): ν (cmÀ1) 3200, 3078,
1
2930, 1644, 1490, 1451, 1419, 1297, 710, 697. H NMR (400 MHz,
CDCl3): δ 2.07À2.30 (4H, m), 3.69 (1H, q, J = 8.0 Hz), 5.44 (1H, br),
5.68 (1H, br), 6.24À6.35 (2H, m), 7.19À7.36 (5H, m). 13C NMR (100
MHz, CDCl3): δ 30.5, 33.4, 50.1, 83.0, 126.9, 127.5, 128.9, 142.0, 143.7,
175.4. EIMS: m/z (rel intensity) 188 (M+ À I, 16), 171 (100), 143 (64),
129 (61), 128 (39), 116 (53), 115 (87), 59 (56), 44 (34). HRMS: calcd
for C12H14NO (M À I) 188.1075, found 188.1079.
Typical Procedure for the 6-Exo Cyclization of Amidyl
Radicals. (Z)-6-Iodo-2-methylhex-5-enamide ((Z)-1a, 51 mg, 0.20
mmol) was added into the mixture of Pb(OAc)4 (0.31 g, 0.70 mmol)
and iodine (0.13 g, 0.50 mmol) in dichloromethane (6.6 mL) at rt under
nitrogen atmosphere. The mixture was irradiated with stirring at rt for 1
h with the aid of a 125 W high-pressure mercury lamp. The mercury
lamp was then turned off, and saturated aqueous Na2S2O3 (5.0 mL) was
added into the reaction solution. The resulting mixture was then
extracted with dichloromethane (3 Â 10 mL). The combined organic
phase was dried over anhydrous Na2SO4. After removal of the solvent
under reduced pressure, the crude products were purified by column
chromatography on silica gel with petroleum ether/acetone (4:1 v/v) as
the eluent to give separately the pure trans-2a (47 mg, 63% yield) and cis-
2a (15 mg, 20% yield).
1
2981, 2959, 1656, 1491, 1405, 1306, 756, 700. H NMR (400 MHz,
CDCl3): δ 1.57À1.71 (1H, m), 1.98À2.12 (1H, m), 2.14À2.24 (1H,
m), 2.26À2.36 (1H, m), 3.25À3.35 (1H, m), 3.48À3.58 (1H, m), 5.17
(1H, d, J = 3.2 Hz), 6.67 (1H, br), 7.18À7.40 (5H, m). 13C NMR
(100 MHz, CDCl3): δ À15.3, 28.8, 29.4, 48.4, 61.1, 127.2, 128.5, 128.7,
139.9, 173.5. EIMS: m/z (rel intensity) 441 (M+, 0.4), 314 (11), 175
(13), 174 (100), 129 (11), 115 (12), 104 (16), 103 (21), 91 (20).
HRMS: calcd for C12H13I2NO (M) 440.9087, found 440.9089.
(4S*,6S*)-6-(Diiodomethyl)-4-methylpiperidin-2-one (cis-
6a). White solid. Mp: 156À158 °C. IR (KBr): ν (cmÀ1) 3288, 2994,
1
2950, 2910, 1658, 1615, 1450, 1300, 745, 692. H NMR (400 MHz,
CDCl3): δ 1.03À1.18 (4H, m), 1.88À2.22 (3H, m), 2.36À2.47 (1H,
m), 3.09À3.19 (1H, m), 5.16 (1H, d, J = 3.2 Hz), 6.76 (1H, br). 13C
NMR (100 MHz, CDCl3): δ À14.1, 21.1, 26.5, 37.1, 39.4, 60.1, 173.1.
EIMS: m/z (rel intensity) 379 (M+, 0.2), 113 (7), 112 (100), 82 (4), 69
(43), 56 (5), 42 (6), 41 (15), 40 (4). HRMS: calcd for C7H11I2NO (M)
378.8930, found 378.8934.
(4S*,6S*)-6-(Diiodomethyl)-4-ethylpiperidin-2-one (cis-
6b). White solid. Mp: 121À123 °C. IR (KBr): ν (cmÀ1) 3191,
3081, 2957, 2916, 1655, 1405, 1304, 816. 1H NMR (400 MHz,
CDCl3): δ 0.95 (3H, t, J = 7.6 Hz), 1.07 (1H, q, J = 12.0 Hz),
1.34À1.46 (2H, m), 1.78À2.00 (2H, m), 2.13À2.25 (1H, m),
2.43À2.53 (1H, m), 3.12À3.21 (1H, m), 5.16 (1H, d, J = 3.2 Hz),
6.49 (1H, br). 13C NMR (100 MHz, CDCl3): δ À15.1, 11.0, 28.5,
33.0, 35.4, 37.4, 60.4, 172.9. EIMS: m/z (rel intensity) 266 (M+ À I,
0.5), 127 (11), 126 (100), 83 (47), 82 (5), 56 (7), 55 (13), 42 (4), 41
(17). HRMS: calcd for C8H13I2NO (M) 392.9087, found 392.9091.
(4S*,6S*)-6-(Diiodomethyl)-4-isopropylpiperidin-2-one
(cis-6c). White solid. Mp: 138À140 °C. IR (KBr): ν (cmÀ1) 3228,
(3R*,6S*)-6-(Diiodomethyl)-3-methylpiperidin-2-one (trans-
2a). White solid. Mp: 134À136 °C. IR (KBr): ν (cmÀ1) 3192, 3090,
2957, 2927, 1662, 1617, 1490, 1406, 1315, 1278, 1101, 814. 1H NMR
(400 MHz, CDCl3): δ 1.23 (3H, d, J = 7.6 Hz), 1.40À1.65 (2H, m),
1.93À2.03 (1H, m), 2.17À2.25 (1H, m), 2.26À2.38 (1H, m),
3.10À3.18 (1H, m), 5.15 (1H, d, J = 3.2 Hz), 6.54 (1H, br). 13C
NMR (100 MHz, CDCl3): δ À14.3, 16.4, 27.9, 29.4, 36.0, 61.0, 175.8.
EIMS: m/z (rel intensity) 379 (M+, 0.3), 127 (5), 113 (7), 112 (100), 82
(7), 69 (25), 56 (5), 42 (5), 41 (16). HRMS: calcd for C7H11I2NO (M)
378.8930, found 378.8929. The structure was further confirmed by its
2D NOESY experiments.
(3S*,6S*)-6-(Diiodomethyl)-3-methylpiperidin-2-one (cis-
2a). White solid. Mp: 132À134 °C. IR (KBr): ν (cmÀ1) 3221, 2962,
2929, 1676, 1612, 1401, 1299, 1199, 779. 1H NMR (400 MHz, CDCl3):
δ 1.31 (3H, d, J = 7.2 Hz), 1.64À1.77 (2H, m), 1.90À2.07 (2H, m),
2.42À2.58 (1H, m), 3.14À3.27 (1H, m), 5.15 (1H, d, J = 4.0 Hz), 6.51
8104
dx.doi.org/10.1021/jo2014406 |J. Org. Chem. 2011, 76, 8100–8106

The Journal of Organic Chemistry
NOTE
1
2963, 2912, 1672, 1619, 1475, 1384, 1295, 765. H NMR (400 MHz,
CDCl3): δ 0.90À0.98 (6H, m), 1.11 (1H, q, J = 10.8 Hz), 1.51À1.64
(1H, m), 1.67À1.79 (1H, m), 1.96À2.04 (1H, m), 2.14À2.24 (1H, m),
2.39À2.49 (1H, m), 3.06À3.16 (1H, m), 5.19 (1H, d, J = 3.2 Hz), 6.76
(1H, br). 13C NMR (100 MHz, CDCl3): δ À15.1, 19.1, 19.6, 31.8, 33.2,
34.9, 37.4, 60.5, 173.2. EIMS: m/z (rel intensity) 280 (M+ À I, 0.3), 141
(10), 140 (100), 97 (43), 69 (5), 67 (5), 55 (7), 43 (10), 41 (25).
HRMS: calcd for C9H15I2NO (M) 406.9243, found 406.9245. The
structure was further confirmed by its 2D NOESY experiments.
(3S*,4aS*,8aR*)-3-(Diiodomethyl)octahydroisoquinolin-
(20 mL) at rt under nitrogen atmosphere. The mixture was irradiated
with stirring at rt for 1 h with the aid of a 125 W high-pressure mercury
lamp. The mercury lamp was then turned off, and the resulting mixture
was passed through a short silica gel column and washed with ethyl
acetate. The combined organic phase was concentrated in vacuo, and the
crude product was dissolved in ethanol (18 mL). Sodium bicarbonate
(0.60 g, 7.2 mmol), H3PO2 (50% aqueous solution, 0.66 mL, 6.0 mmol),
and AIBN (12 mg) were added successively. The mixture was refluxed
for 5 h and then cooled down to rt. Brine (30 mL) was added, and the
solution was extracted with ethyl acetate (30 mL Â 2). The combined
organic phase was dried over anhydrous Na2SO4. After the removal of
solvent under reduced pressure, the crude product was purified by
column chromatography on silica gel with petroleum/acetone (4:1 v/v)
as the eluent to give separately the pure trans-4 (45 mg, 46% yield) and
cis-4 (45 mg, 46% yield).
(3R*,6S*)-6-(Chloromethyl)-3-methylpiperidin-2-one (trans-
4). White solid. Mp: 90À92 °C. IR (KBr): ν (cmÀ1) 3250, 2971, 2933,
2869, 1668, 1625, 1471, 1400, 1302, 1267, 759, 737. 1H NMR (400 MHz,
CDCl3): δ 1.24 (3H, d, J = 7.2 Hz), 1.43À1.58 (2H, m), 1.94À2.10 (2H,
m), 2.26À2.40 (1H, m), 3.39 (1H, dd, J = 11.2, 8.0 Hz), 3.57 (1H, dd, J =
11.2, 4.0 Hz), 3.61À3.71 (1H, m), 6.09 (1H, br). 13C NMR (100 MHz,
CDCl3): δ16.8, 26.4, 28.3, 36.1, 48.3, 54.5, 175.3. EIMS: m/z(rel intensity)
161 (M+, 4), 113 (10), 112 (100), 84 (5), 69 (32), 56 (4), 42 (5), 41 (8).
Anal. Calcd for C7H12ClNO: C, 52.02; H, 7.48; N, 8.67. Found: C, 52.10;
H, 7.48; N, 8.76.
1(2H)-one (8). White solid. Mp: 172À174 °C. IR (KBr): ν (cmÀ1
)
3191, 3074, 2939, 2913, 2853, 1655, 1402, 1300. 1H NMR (400 MHz,
CDCl3): δ 1.04À1.35 (5H, m), 1.55À1.68 (1H, m), 1.70À1.92 (4H,
m), 2.05À2.15 (1H, m), 2.30À2.40 (1H, m), 3.17À3.27 (1H, m), 5.13
(1H, d, J = 2.8 Hz), 6.13 (1H, br). 13C NMR (100 MHz, CDCl3): δ
À14.2, 25.5, 26.0, 26.6, 32.9, 36.4, 36.8, 45.8, 60.2, 174.4. ESI-MS m/z
419.5 (M+ + H). HRMS: calcd for C10H16I2NO (M + H) 419.9316,
found 419.9325. The structure was further confirmed by its 2D NOESY
experiments.
(5S*,6S*)-6-(Diiodomethyl)-5-methylpiperidin-2-one (trans-
10a). White solid. Mp: 114À116 °C. IR (KBr): ν (cmÀ1) 3366, 2961,
2931, 1652, 1460, 1388, 1300, 632. 1H NMR (400 MHz, CDCl3): δ 1.03
(3H, d, J = 6.8 Hz), 1.48À1.83 (3H, m), 2.33À2.48 (2H, m), 2.77 (1H, d, J
= 8.4 Hz), 5.46 (1H, d, J = 1.6 Hz), 6.09 (1H, br). 13C NMR (100 MHz,
CDCl3): δ À17.0, 17.8, 27.7, 31.3, 35.1, 67.5, 172.5. EIMS: m/z (rel
intensity) 379 (M+, 0.05), 113 (7), 112 (100), 70 (7), 69 (7), 56 (6), 55
(30), 42 (9), 41 (17). HRMS: calcd for C7H11I2NO (M) 378.8930, found
378.8933. The structure was further confirmed by its 2D NOESY
experiments.
(5S*,6S*)-6-(Diiodomethyl)-5-ethylpiperidin-2-one (trans-
10b). White solid. Mp: 74À76 °C. IR (KBr): ν (cmÀ1) 3440, 3184,
3063, 2963, 2929, 1682, 1409, 1099, 826. 1H NMR (400 MHz, CDCl3): δ
0.98 (3H, t, J = 7.2 Hz), 1.22À1.36 (1H, m), 1.38À1.48 (1H, m),
1.50À1.64 (2H, m), 1.87À1.97 (1H, m), 2.28À2.48 (2H, m), 2.93 (1H,
d, J = 7.6 Hz), 5.47 (1H, d, J = 2.4 Hz), 6.23 (1H, br). 13C NMR (100
MHz, CDCl3): δ À15.9, 11.0, 23.6, 24.8, 31.0, 40.6, 65.8, 172.5. EIMS:m/
z (rel intensity) 266 (M+ À I, 0.4), 127 (11), 126 (100), 84 (9), 83 (4), 69
(5), 55 (25), 42 (8), 41 (20). HRMS: calcd for C8H13INO (M À I)
266.0042, found 266.0044.
(5R*,6S*)-6-(Diiodomethyl)-5-isopropylpiperidin-2-one
(trans-10c). White solid. Mp: 86À88 °C. IR (KBr): ν (cmÀ1) 3204,
3094, 2963, 2920, 1662, 1628, 1423, 1304, 1198, 805. 1H NMR (400
MHz, CDCl3): δ 0.87 (3H, d, J = 6.8 Hz), 1.02 (3H, d, J = 6.8 Hz),
1.33À1.45 (1H, m), 1.54À1.68 (1H, m), 1.70À1.85 (2H, m),
2.27À2.51 (2H, m), 3.04 (1H, d, J = 8.0 Hz), 5.47 (1H, d, J = 2.4
Hz), 6.13 (1H, br). 13C NMR (100 MHz, CDCl3): δ À14.8, 16.9,
18.8, 21.4, 27.5, 31.2, 44.9, 63.8, 172.6. EIMS: m/z (rel intensity) 280
(M+ À I, 0.2), 141 (10), 140 (100), 111 (10), 98 (10), 69 (10), 55
(22), 43 (12), 41 (27). HRMS: calcd for C9H15INO (M À I)
280.0198, found 280.0203.
(3S*,6S*)-6-(Chloromethyl)-3-methylpiperidin-2-one (cis-
4). White solid. Mp: 104À106 °C. IR (KBr): ν (cmÀ1) 3199, 3085,
1
2957, 2935, 2868, 1661, 1617, 1486, 1437, 1325, 814. H NMR (400
MHz, CDCl3): δ 1.25 (3H, d, J = 7.2 Hz), 1.56À1.67 (1H, m),
1.69À1.81 (1H, m), 1.84À1.97 (2H, m), 2.40À2.52 (1H, m), 3.44
(1H, dd, J = 11.2, 8.0 Hz), 3.55 (1H, dd, J = 11.2, 4.8 Hz), 3.61À3.71
(1H, m), 6.16 (1H, br). 13C NMR (100 MHz, CDCl3): δ 17.6, 23.1,
26.1, 35.4, 47.8, 53.7, 175.7. EIMS: m/z (rel intensity) 161 (M+, 0.8),
113 (7), 112 (100), 84 (5), 69 (36), 56 (6), 55 (4), 42 (10), 41 (15).
Anal. Calcd for C7H12ClNO: C, 52.02; H, 7.48; N, 8.67. Found: C,
52.33; H, 7.43; N, 8.75.
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H, 13C NMR and
S
b
2D NOESY spectra, DFT calculation data and complete refer-
ence.20 This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: clig@mail.sioc.ac.cn; bnulk@yahoo.com.cn.
(5R*,6S*)-6-(Diiodomethyl)-5-phenylpiperidin-2-one (trans-
10d). White solid. Mp: 146À148 °C. IR (KBr): ν (cmÀ1) 3436, 3360,
3059, 3024, 2983, 2941, 1655, 1451, 759, 700, 638. 1H NMR (400 MHz,
CDCl3): δ 1.91À2.01 (1H, m), 2.15À2.31 (1H, m), 2.50À2.68 (3H,
m), 3.28 (1H, d, J = 9.6 Hz), 4.94 (1H, d, J = 1.2 Hz), 6.24 (1H, br),
7.22À7.28 (2H, m), 7.32À7.43 (3H, m). 13C NMR (100 MHz, CDCl3):
δ À16.7, 27.5, 31.9, 47.0, 67.0, 127.4, 128.3, 129.5, 139.4, 172.1. EIMS:
m/z (rel intensity) 314 (M+ À I, 100), 174 (57), 127 (24), 117 (82), 115
(54), 104 (63), 103 (24), 91 (31). Anal. Calcd for C12H13I2NO: C,
32.68; H, 2.97; N, 3.18. Found: C, 33.02; H, 3.10; N, 3.06.
’ ACKNOWLEDGMENT
This project was supported by the National Natural Science
Foundation of China (Grant Nos. 20832006 and 21072211) and
by the National Basic Research Program of China (973 Program)
(Grant Nos. 2010CB833206 and 2011CB710805).
’ REFERENCES
(1) For reviews, see: (a) Stella, L. Angew. Chem., Int. Ed. Engl. 1983,
22, 337–350. (b) Esker, J. L.; Newcomb, M. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Ed.; Academic Press: New York, 1993; Vol.
58, pp 1À45. (c) Zard, S. Z. Synlett 1996, 1148–1154. (d) Fallis, A. G.;
Brinza, I. M. Tetrahedron 1997, 53, 17543–17594. (e) Stella, L. In Radicals
in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
Typical Procedure for the 6-Exo Cyclization Followed by
Reduction with H3PO2/AIBN. (E)-6-Chloro-2-methylhex-5-enam-
ide ((E)-3, 97 mg, 0.60 mmol) was added into the mixture of Pb(OAc)4
(0.93 g, 2.1 mmol) and iodine (0.40 g, 1.5 mmol) in dichloromethane
8105
dx.doi.org/10.1021/jo2014406 |J. Org. Chem. 2011, 76, 8100–8106

The Journal of Organic Chemistry
NOTE
2001; Vol. 2, pp 407À424. (f) Zard, S. Z. Chem. Soc. Rev. 2008, 37,
1603–1618.
(23) The effect of the CdC geometry of vinyl silyl ethers on the
stereoselectivity of 5-exo aminyl radical cyclization was recently
reported; see: (a) Zhai, H.; Zlotorzynska, M.; Sammis, G. M. Chem.
Commun. 2009, 5716–5718. (b) Zlotorzynska, M.; Zhai, H.; Sammis,
G. M. J. Org. Chem. 2010, 75, 864–872.
(2) For kinetic studies, see: (a) Sutcliffe, R.; Ingold, K. U. J. Am.
Chem. Soc. 1982, 104, 6071–6075. (b) Esker, J. L.; Newcomb, M.
Tetrahedron Lett. 1993, 34, 6877–6880. (c) Horner, J. H.; Musa, O. M.;
Bouvier, A.; Newcomb, M. J. Am. Chem. Soc. 1998, 120, 7738–7748.
(d) Martinez, E.; Newcomb, M. J. Org. Chem. 2006, 71, 557–561.
(3) (a) Guin, J.; M€uck-Lichtenfeld, C.; Grimme, S.; Studer, A. J. Am.
Chem. Soc. 2007, 129, 4498–4503. (b) Kemper, J.; Studer, A. Angew.
Chem., Int. Ed. 2005, 44, 4914–4917. (c) Walton, J. C.; Studer, A. Acc.
Chem. Res. 2005, 38, 794–802.
(4) (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Choi, H.-S.; Yoon,
W. H.; He, Y.; Fong, K. C. Angew. Chem., Int. Ed. 1999, 38, 1669–1675.
(b) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int. Ed.
2000, 39, 625–628. (c) Nicolaou, K. C.; Baran, P. S.; Kranich, R.; Zhong,
Y.-L.; Sugita, K.; Zou, N. Angew. Chem., Int. Ed. 2001, 40, 202–206.
(d) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt,
K. W.; Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233–2244.
(5) Janza, B.; Studer, A. J. Org. Chem. 2005, 70, 6991–6994.
(6) Gagosz, F.; Moutrille, C.; Zard, S. Z. Org. Lett. 2002, 4,
2707–2709.
(7) Gaudreault, P.; Drouin, C.; Lessard, J. Can. J. Chem. 2005, 83,
543–545.
(8) Clark, A. J.; Fullaway, D. R.; Murphy, N. P.; Parekh, H. Synlett
2010, 610–614.
(9) (a) Tang, Y.; Li, C. Org. Lett. 2004, 6, 3229–3231. (b) Lu, H.; Li,
C. Tetrahedron Lett. 2005, 46, 5983–5985. (c) Chen, Q.; Shen, M.; Tang,
Y.; Li, C. Org. Lett. 2005, 7, 1625–1627. (d) Hu, T.; Shen, M.; Chen, Q.;
Li, C. Org. Lett. 2006, 8, 2647–2650. (e) Yuan, X.; Liu, K.; Li, C. J. Org.
Chem. 2008, 73, 6166–6171.
(10) (a) Biechy, A.; Hachisu, S.; Quiclet-Sire, B.; Ricard, L.; Zard,
S. Z. Tetrahedron 2009, 65, 6730–6738. (b) Biechy, A.; Hachisu, S.; Quiclet-
Sire, B.; Ricard, L.; Zard, S. Z. Angew. Chem., Int. Ed. 2008, 47, 1436–1438.
(c) Callier-Dublanchet, A.-C.; Cassayre, J.; Gagosz, F.; Quiclet-Sire, B.;
Sharp, L. A.; Zard, S. Z. Tetrahedron 2008, 64, 4803–4816. (d) Sharp, L.;
Zard, S. Z. Org. Lett. 2006, 8, 831–834. (e) Cassayre, J.; Gagosz, F.; Zard,
S. Z. Angew. Chem., Int. Ed. 2002, 41, 1783–1785.
(11) (a) Clark, A. J.; Peacock, J. L. Tetrahedron Lett. 1998, 39,
6029–6032. (b) Clark, A. J.; Deeth, R. J.; Wongtap, H. Synlett 1999,
444–446.
(12) Barton, D. H. R.; Beckwith, A. L. J.; Goosen, A. J. Chem. Soc.
1965, 181–190.
ꢀ
(13) For recent selected examples, see: (a) Martín, A.; Pꢀerez-Martín,
I.; Suꢀarez, E. Org. Lett. 2005, 7, 2027–2030. (b) Reddy, L. R.; Reddy,
B. V. S.; Corey, E. J. Org. Lett. 2006, 8, 2819–2821. (c) Francisco, C. G.;
ꢀ
Herrera, A. J.; Martín, A.; Pꢀerez-Martín, I.; Suꢀarez, E. Tetrahedron Lett.
2007, 48, 6384–6388. (d) Chen, K.; Richter, J. M.; Baran, P. S. J. Am.
Chem. Soc. 2008, 130, 7247–7249.
(14) Hu, T.; Liu, K.; Shen, M.; Yuan, X.; Tang, Y.; Li, C. J. Org. Chem.
2007, 72, 8555–8558.
(15) (a) Lu, H.; Chen, Q.; Li, C. J. Org. Chem. 2007, 72, 2564–2569.
(b) Liu, F.; Liu, K.; Yuan, X.; Li, C. J. Org. Chem. 2007, 72, 10231–10234.
(16) Coleman, R. S.; Garg, R. Org. Lett. 2001, 3, 3487–3490.
(17) Amans, D.; Bellosta, V.; Cossy, J. Org. Lett. 2007, 9, 4761–4764.
(18) For a review on stereoselective transformations controlled by
geometry of CdC bonds in terms of allylic 1,3-strain, see: Hoffmann,
R. W. Chem. Rev. 1989, 89, 1841–1860.
(19) Yorimitsu, H.; Shinokubo, H.; Oshima, K. Bull. Chem. Soc. Jpn.
2001, 74, 225–235.
(20) Frisch, M. J. Gaussian 09, revision A.02; Gaussian Inc.: Wall-
ingford, CT, 2009. See the Supporting Information for the full reference.
(21) For a review, see: Schiesser, C. H.; Skidmore, M. A. In Radicalsin
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
2001; Vol. 1, pp 337À359.
(22) The effect of the CdC geometry of α,β-unsaturated esters on
the stereoselectivity of alkyl radical cyclization was reported. See:
Hanessian, S.; Dhanoa, D. S.; Beaulieu, P. L. Can. J. Chem. 1987, 65,
1859–1866.
8106
dx.doi.org/10.1021/jo2014406 |J. Org. Chem. 2011, 76, 8100–8106