Synthesis of nitrogen-containing heterocycles using exo- and endo-selective radical cyclizations onto enamides

Article abstract of DOI:10.1016/j.tet.2008.01.016

The effect of positional change of the carbonyl group of enamides on Bu₃SnH-mediated alkyl radical cyclization leading to five-, six-, seven-, and eight-membered nitrogen-containing heterocycles was examined. A 5-exo cyclization is generally preferred over a 6-endo ring closure in systems having an alkyl radical center on the enamide-acyl side chain, whereas enamides having an alkyl radical center opposite to the acyl side chain predominantly gave 6-endo cyclization products. These results suggest that the exo or endo selectivity of radical cyclization onto the alkenic bond of enamides can be controlled by positional change of the carbonyl group. For an understanding of these selectivities, heat of formation for each transition state was calculated. 6-endo-Selective radical cyclization was applied to the radical cascade, enabling a concise synthesis of a cylindricine skeleton. A 7- or 8-endo alkyl radical cyclization, however, predominated over a corresponding 6- or 7-exo ring closure regardless of the positional change of the carbonyl group of enamides.

Full text of DOI:10.1016/j.tet.2008.01.016

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2634e2641
www.elsevier.com/locate/tet
Synthesis of nitrogen-containing heterocycles using exo- and
endo-selective radical cyclizations onto enamides
Tsuyoshi Taniguchi a, Daigo Yonei a, Masamichi Sasaki a,
Osamu Tamura b, Hiroyuki Ishibashi a,
*
a Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology,
Kanazawa University, Kanazawa 920-1192, Japan
b Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan
Received 3 December 2007; received in revised form 26 December 2007; accepted 2 January 2008
Available online 6 January 2008
Abstract
The effect of positional change of the carbonyl group of enamides on Bu3SnH-mediated alkyl radical cyclization leading to five-, six-, seven-,
and eight-membered nitrogen-containing heterocycles was examined. A 5-exo cyclization is generally preferred over a 6-endo ring closure in
systems having an alkyl radical center on the enamide-acyl side chain, whereas enamides having an alkyl radical center opposite to the acyl side
chain predominantly gave 6-endo cyclization products. These results suggest that the exo or endo selectivity of radical cyclization onto the
alkenic bond of enamides can be controlled by positional change of the carbonyl group. For an understanding of these selectivities, heat of
formation for each transition state was calculated. 6-endo-Selective radical cyclization was applied to the radical cascade, enabling a concise
synthesis of a cylindricine skeleton. A 7- or 8-endo alkyl radical cyclization, however, predominated over a corresponding 6- or 7-exo ring
closure regardless of the positional change of the carbonyl group of enamides.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Cylindricine; Enamide; 6-endo Cyclization; Heterocycles; Radical cyclization
O
O
1. Introduction
Bu3SnH
ACN
Me
Me
Me
N
N
In recent years, radical cyclization has emerged as a valu-
able tool for the construction of carbo- and heterocyclic
compounds, including natural products.1 It has been recog-
nized that a 5-exo cyclization is generally preferred over
a 6-endo ring closure in systems having an alkenic bond at
the 5-position relative to the radical center. For example,
enamide 1, upon treatment with Bu3SnH in the presence of
azobis(cyclohexanecarbonitrile) (ACN), exclusively gave the
5-exo cyclization product 2 (Scheme 1).2
60%
I
2
1
O
O
Me
Me
N
N
•
•
3
4
O
O
Bu3SnH
ACN
68%
N
Et
N
Et
Formation of 2 was of particular interest since the primary
alkyl radical 3 was formed from 1 as an intermediate, though
6-endo cyclization of 1 might produce the more stable
Br
5
6
Scheme 1.
secondary a-acylamino radical 4. We previously reported, how-
ever, that similar treatment of enamide 5 gave the 6-endo
* Corresponding author. Tel.: þ81 76 234 4474; fax: þ81 76 234 4476.
E-mail address: isibasi@p.kanazawa-u.ac.jp (H. Ishibashi).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.016

T. Taniguchi et al. / Tetrahedron 64 (2008) 2634e2641
2635
O
N
Bu3SnH
ACN
O
Bu3SnH
O
Br
ACN
Et
N
Et
N
48%
N
Et
toluene
reflux
quant.
N
Et
Et
Br
Br
Me
O
O
7
8
3:1
9
17
18
Bu3SnH
ACN
O
R
O
N
N
Bu3SnH
42-77%
Br
R
ACN
O
10
11
toluene
reflux
Me
N
Me
N
N
Me
Scheme 2.
O
O
20 (73%)
21 (15%)
19
trans : cis = 1.5 : 1
cyclization product 6 (Scheme 1).3 We also found that enamide
7 predominantly gave the 6-exo cyclization product 8, whereas
enamide 10 afforded the 7-endo cyclization product 11
(Scheme 2).4 These results strongly suggest that exo and endo
selectivities of radical cyclization onto the alkenic bond of
enamides can be controlled by positional change of the car-
bonyl group.
Bu3SnH
O
O
SePh
ACN
toluene
reflux
97%
Me
N
Me
N
O
O
22
23
trans : cis = 1 : 1.5
Scheme 4.
In this paper, we describe the effect of positional change
of the carbonyl group of enamides on the mode of Bu3SnH-me-
diated alkyl radical cyclization leading to five-, six-, seven-, and
eight-membered nitrogen-containing heterocycles. An applica-
tion of the 6-endo-selective cyclization to a concise synthesis of
a cylindricine skeleton is also described.5
13C NMR spectra of 18 and 21 showed the presence of a
quaternary carbon atom at 64.0 and 66.3 ppm, respectively.
These results clearly indicated that the mode of alkyl radical
cyclization of enamides could be altered by changing the
position of the carbonyl group of the enamides as in the cases
of compounds 1 and 5. Enamide 22, which was prepared from
the corresponding ethyl ester, underwent acyl radical cycliza-
tion to afford also the 6-endo cyclization product 23 (97%) as
a 1:1.5 mixture of trans and cis isomers (Scheme 4).10
2. Results and discussion
2.1. 5-exo Versus 6-endo alkyl radical cyclizations onto
enamide
Condensation of butylamine and acetaldehyde followed by
treatment of the resulting imine with acryloyl chloride and
successive treatment with diphenyl diselenide/sodium borohy-
dride gave enamide 12 (Scheme 3). Treatment of enamide 12
with Bu3SnH in the presence of ACN in boiling toluene
resulted in alkyl radical cyclization of enamide 12 to afford
the 5-exo cyclization product 136 in 78% yield. On the other
hand, similar treatment of enamide 14, prepared from 3-(phe-
nylseleno)propylamine and acetaldehyde, gave the 6-endo
cyclization product 157 (61%) along with the 5-exo cyclization
product 168 (29%). Similar treatment of enamide 17 exclu-
sively afforded the 5-exo cyclization product 18, whereas
enamide 19 gave the 6-endo cyclization product 209 (73%)
as a 1.5:1 mixture of trans and cis isomers, along with a small
quantity of the 5-exo cyclization product 21 (15%) (Scheme 4).
2.2. Calculation of heat of formation for transition state
For a better understanding of cyclization modes of 12, 14, 17,
and 19, heat offormation for each transition state (TS) was calcu-
lated by using 6-31G*.11 First, alkyl radical cyclization of model
radical A was computed for the exclusive formation of 5-exo
compound 13 from enamide 12 (Fig. 1). TS B was estimated to
α
-
-
α
N
N
N
Me
Me
Me
O
O
O
A
B
C
α = 109.3°
α = 95.5°
ΔE = 0.00 kcal/mol
ΔE = +4.04 kcal/mol
Me
Bu
SePh
Bu3SnH
ACN
toluene
reflux
78%
-
-
N
N
α
Bu
O
12
O
13
α
N
N
N
Me
Me
Me
Me
O
SePh
O
Bu3SnH
O
O
ACN
D
E
F
Me
N
Me
N
Me
N
toluene
reflux
α = 104.6°
α = 94.6°
O
O
ΔE = 0.00 kcal/mol
ΔE = +3.38 kcal/mol
15 (61%)
16 (29%)
14
Scheme 3.
Figure 1.

2636
T. Taniguchi et al. / Tetrahedron 64 (2008) 2634e2641
be more stable than TS C by ca. 4 kcal/mol, probably because TS
B forms an ideal trajectory angle for radical approach to the
double bond. The planarity of the amide bond makes TS C
a half-chair form, which may result in considerable strain
(see Supplementary data). The reason for the exclusive forma-
tion of 5-exo cyclization product 18 from 17 may be similar
to that for the formation of 13. Calculation of TSs for cycli-
zation of model radical D revealed that TS E for 5-exo cycli-
zation is 3.38 kcal/mol more stable than is TS F for 6-endo
cyclization.
Me
-
N
O
L
-
α
α
Me
N
O
N
O
Me
Since the energy difference between TS H and TS J is only
ca. 0.3 kcal/mol, both 5-exo cyclization product 16 and 6-endo
cyclization product 15 can be formed by cyclization of radical
G (Fig. 2). In contrast to TS C, TS J (and also K) providing 15
is a chair-type transition state. The predominance of 15 might
be partially due to the contribution of thermodynamic control
(stabilities of product radicals).11c The product radical J0 was
calculated to be ca. 39 kcal/mol more stable than TS J,
whereas radical H0 was estimated to be only ca. 31 kcal/mol
more stable than H.
M
N
α = 103.7°
ΔE = +2.11 kcal/mol
α = 104.1°
ΔE = +2.84 kcal/mol
-
-
α
α
Me
N
O
N
O
Me
P
O
Calculation of TSs MeP for cyclization of radical L gen-
erated from 19 was also conducted (Fig. 3). Among them, TS
O giving 6-endo cyclization product 20 exhibited the lowest
heat of formation, and this supports the main formation of
the 6-endo product 20. Perhaps owing to non-bonded interac-
tion, the trajectory angles in M and N are different from
ideal ones. For the formation of 5-exo cyclization product
21, the entropy effect might contribute to the distribution
of products.
α = 98.4°
ΔE = 0.000 kcal/mol
α = 98.8°
ΔE = +2.28 kcal/mol
Figure 3.
2.3. Synthesis of cyclindricine skeleton using endo-selective
cyclizations
The radical cascade consisting of 6-endo-trig and 5-endo-
trig cyclizations was next examined.12 Treatment of enamide
24, prepared by bromination of the corresponding alcohol,
with Bu3SnH/ACN afforded the cis-fused tricyclic compound
2513 in 30% yield (Scheme 5). The structure of 25 was
Me
-
N
O
G
Bu3SnH
ACN
Br
α
α
-
N
N
toluene
reflux
30%
Me
N
O
N
O
O
25
24
O
Me
O–
H
I
O2N
NO2
α = 107.4°
ΔE = 0.00 kcal/mol
α = 107.8°
ΔE = +2.09 kcal/mol
1) BH3 • THF
2) picric acid
quant.
N
H
NO2
-
-
26
α
α
Me
N
O
N
O
Me
Bu3SnH
K
J
O
SePh
O
ACN
α = 98.5°
ΔE = +0.32 kcal/mol
α = 99.1°
ΔE = +3.18 kcal/mol
toluene
reflux
37%
N
N
O
O
27
28
Me
N
Me
N
O
X = Cl: cylindricine A
X = OH: cylindricine C
X = OMe: cylindricine D
X = OAc: cylindricine E
X = SCN: cylindricine F
O
O
N
J'
H'
C6H13
ΔE = -31.20 kcal/mol
ΔE = -38.70 kcal/mol
X
Figure 2.
Scheme 5.

T. Taniguchi et al. / Tetrahedron 64 (2008) 2634e2641
2637
confirmed by an X-ray crystallographic analysis of the picrate
Bu3SnH
ACN
Br
26 (CCDC 262989) prepared by reduction of 25 with borane.
Enamide 27, which was prepared by the corresponding ethyl
ester, also gave the cis-fused compound 28 in 37% yield, the
structure of which was again confirmed by an X-ray crystallo-
graphic analysis (CCDC 262990). Compound 28 is a basic
structural element of cylindricines, which cause mortality in
a brine shrimp bioassay.14
The stereochemical outcome of the formation of the cis-
fused compounds 25 and 28 from 24 and 27, respectively,
can be explained by assuming their transition state for the
cyclizations. As depicted in Figure 4, two transition states Q
and R may be considered for the final step (5-endo-trig) of
the radical cascade. The A ring of Q which provides 25 and
28 is a chair form and that of R leading to the trans-fused
isomers 29 and 30 is a boat form. The 5-endo-trig cyclization
may proceed through transition state Q, in which the A ring
has a more favorable chair form, to give the observed cis-fused
compound 25 or 28. Indeed, calculation of TS Q and R
(transition state geometry by using 3-21G* followed by single
point calculation by 6-31G*) revealed that TS Q is 5.89 kcal/
mol more stable than is TS R.
N
N
N
toluene
reflux
Et
Et
Et
O
O
O
31
32 (77%)
33 (23%)
trans : cis = 1 : 1
Bu3SnH
ACN
Br
Me
N
Me
Me
toluene
reflux
N
N
O
O
O
36 (26%)
34
35 (73%)
trans : cis = 1 : 5.7
Scheme 6.
39 (46%) (Scheme 7). No 7-exo cyclization product was
formed.16 Enamide 40 gave the 8-endo cyclization product
41, but in low yield (7%) along with a considerable amount
of the simple reduction product 42 (84%).17 exo and endo
Selectivities were no longer observed for the alkyl radical
cyclization of enamides 31, 34, 37, and 40 having an alkenic
bond at the 6- or 7-position relative to the radical center.
This was probably associated with an increase in the entropy
effect.
2.4. 6-exo Versus 7-endo and 7-exo versus 8-endo alkyl
radical cyclizations onto enamide
H
Bu3SnH
ACN
Br
Treatment of enamide 31 with Bu3SnH/ACN afforded the
7-endo alkyl radical cyclization product 32 in 77% yield as
a 1:1 mixture of trans and cis stereoisomers (Scheme 6). No
expected 6-exo cyclization product was obtained. On the other
hand, similar treatment of enamide 34 afforded the expected
7-endo cyclization product 35 in 73% yield as a 1:5.7 mixture
of trans and cis stereoisomers.15
We further examined the mode of radical cyclization of
enamides 37 and 40. Enamide 37 afforded the 8-endo cycliza-
tion product 38 (11%) along with the simple reduction product
H
N
O
N
O
N
O
Et
Et
toluene
reflux
Et
38 (11%)
37
39 (46%)
Bu3SnH
ACN
H
Br
H
N
Me
Me
Me
toluene
reflux
N
N
O
O
O
40
41 (7%)
42 (84%)
Scheme 7.
H
The aryl radical cyclization of enamide 7 gave the 6-exo
cyclization product 8 in a high selectivity with reduction of
the entropy effect (Scheme 2), and therefore the cyclization
of 43 was examined in the hope that this compound might
result in the selective formation of a 7-exo cyclization product.
Enamide 43 was prepared by the treatment of N-ethyl-
N-[2-(phenylthio)ethyl]-o-bromophenylpropionamide with m-
chloroperbenzoic acid (mCPBA) followed by thermolysis of
the resulting sulfoxide. Treatment of 43 with Bu3SnH/ACN af-
forded the expected 7-exo cyclization product 44, but in low
yield (6%) along with the 8-endo product 45 (5%) (Scheme 8).
X
X
6-endo
N
N
O
O
X = H2, O
X
X
H
X
5-endo
A
N
N
O
A
O
Q
25: X = H2
E = 0.00 kcal/mol
(X = H2)
28: X = O
H
X
3. Conclusions
A
N
N
We revealed that the 5-exo and 6-endo selectivity for alkyl
radical cyclization onto the alkenic bond of enamide could be
controlled by positional change of the carbonyl group. Calcula-
tion of heat of formation for each transition state (TS) supported
these observations. 6-endo-Selective cyclization was applied to
O
O
R
29: X = H2
30: X = O
E = +5.89 kcal/mol
(X = H2)
Figure 4.

2638
T. Taniguchi et al. / Tetrahedron 64 (2008) 2634e2641
Bu3SnH
ACN
4.3. 1-Ethyl-1-azaspiro[4.5]decan-2-one (18)
O
O
O
N
N
N
toluene
reflux
N
Et
Et
General procedure for radical reaction: to a boiling
solution of 17 (90.0 mg, 0.346 mmol) in toluene (25 mL)
Br
Et
Me
44 (6%)
45 (5%)
43
was added dropwise
a solution of Bu3SnH (151 mg,
0.519 mmol) and ACN (17.0 mg, 0.0692 mmol) in toluene
(25 mL) over 3 h and the mixture was further heated at
reflux for 1 h. After evaporation of the solvent, the residue
was chromatographed on silica gel containing KF (10%)18
(hexane/AcOEt, 2:1) to give 18 (66.0 mg, 100%) as a color-
O
Et
46 (80%)
Scheme 8.
less oil: IR (CHCl3) n 1665 cmꢀ1 1H NMR (270 MHz,
;
CDCl3) d 1.03e1.13 (1H, m), 1.15 (3H, t, J¼7.3 Hz),
1.25e1.76 (9H, m), 1.89 (2H, t, J¼8.1 Hz), 2.34 (2H, t,
J¼8.1 Hz), 3.19 (2H, q, J¼7.3 Hz); 13C NMR (67.8 MHz,
CDCl3) d 15.3, 22.9, 25.0, 29.0, 29.3, 33.9, 35.3, 64.0,
174.3; HRMS calcd for C11H19NO: 181.1467. Found:
181.1471.
the radical cascade involving 5-endo-trig cyclization, giving
a concise synthesis of a cylindricine skeleton. A 7- or 8-endo al-
kyl radical cyclization predominated over a corresponding 6- or
7-exo cyclization regardless of the positional change of the car-
bonyl group of enamide. This was probably due to an increase in
the entropy effect. An application of the endo-selective cycliza-
tion to the radical cascade would be highly promising in natural
products’ synthesis. The results will be reported in due course.
4.4. N-(3-Bromopropyl)-N-cyclohex-1-en-1-ylacetamide (19)
A mixture of 3-(tert-butyldimethyl-silyloxy)propylamine19
(2.50 g, 13.2 mmol) and cyclohexanone (1.30 g, 13.2 mmol)
in benzene (30 mL) was heated under reflux with azeotropic
removal of water for 1.5 h. Triethylamine (2.40 g, 23.8 mmol)
and acetyl chloride (1.55 g, 19.8 mmol) were added at 0 ꢁC,
and the mixture was stirred at room temperature for 20 min.
The reaction mixture was washed with brine, dried (MgSO4),
and concentrated. THF (50 mL) was added to the residue,
a 1.0 M solution of tetrabutylammonium fluoride in THF
(16 mL, 15.8 mmol) was added to this solution, and the mixture
was stirred at room temperature for 1 h. The reaction mixture
was diluted with water and extracted with EtOAc, and the
organic layer was washed with brine, dried (MgSO4), and
concentrated. The residue was chromatographed on silica gel
(hexane/AcOEt, 1:1) to give N-cyclohex-1-en-1-yl-N-(3-hy-
droxypropyl)acetamide (1.40 g, 54%) as a colorless oil: IR
4. Experimental
4.1. General
Melting points are uncorrected. Infrared (IR) spectra were
recorded on a Shimadzu FTIR-8100 spectrophotometer for
solutions in CHCl3. 1H NMR and 13C NMR spectra were mea-
sured on a JEOL EX 500 (500 MHz) or a JEOL JNM-EX 270
(270 MHz) spectrometer. Chemical shifts (d) quoted are rela-
tive to tetramethylsilane. High resolution mass spectra
(HRMS) were obtained with a JEOL JMS-SX-102A mass
spectrometer. Column chromatography was carried out on
silica gel 60 N (Kanto Kagaku Co., Ltd., spherical, neutral,
63e210 mm) under pressure.
1
4.2. 3-Bromo-N-cyclohex-1-en-1-yl-N-ethylpropanamide (17)
(CHCl3) n 1625 cmꢀ1; H NMR (270 MHz, CDCl3) d 1.57e
1.81 (6H, m), 2.05 (3H, s), 2.07e2.17 (4H, m), 3.52e3.56
(4H, m), 4.12 (1H, br), 5.56e5.58 (1H, m); 13C NMR
(67.8 MHz, CDCl3) d 21.26, 21.33, 22.6, 24.6, 27.4, 30.4,
41.2, 58.0, 127.8, 138.6, 171.4. Anal. Calcd for C11H19NO2$1/
5H2O: C, 65.77; H, 9.73; N, 6.97. Found: C, 65.79; H, 9.88;
N, 6.98. To a solution of N-cyclohex-1-en-1-yl-N-(3-hydroxy-
propyl)acetamide (500 mg, 2.53 mmol) and triethylamine
(617 mg, 6.08 mmol) in toluene (10 mL) was added a solution
of methanesulfonyl chloride (348 mg, 3.04 mmol) in toluene
(10 mL) at 0 ꢁC, and the mixture was stirred at the same temper-
ature for 1 h. The reaction mixture was washed with brine, dried
(MgSO4), and concentrated. DMF (10 mL) and LiBr (2.20 g,
25.3 mmol) were added to the residue and the mixture was
stirred at room temperature for 3 h. The reaction mixture was
diluted with water and extracted with Et2O. The organic layer
was washed with brine, dried (MgSO4), and concentrated. The
residue was chromatographed on silica gel (hexane/AcOEt,
4:1) to give 19 (392 mg, 60%) as a colorless oil: IR (CHCl3)
To a solution of cyclohexanone (785 mg, 8.00 mmol) in tol-
uene (5 mL) was bubbled ethylamine at ꢀ78 ꢁC for 5 min, and
the mixture was heated in sealed tube at 110 ꢁC for 2.5 h. After
excess ethylamine was removed under reduced pressure, THF
(10 mL), NaHCO3 (1.00 g, 12.0 mmol), and 3-bromopropionyl
chloride (1.37 g, 8.00 mmol) were added to the residue at 0 ꢁC,
and the mixture was stirred at room temperature for 30 min. The
reaction mixture was diluted with water and extracted with
AcOEt. The organic phase was washed with brine, dried
(MgSO4), and concentrated. The residue was chromatographed
on silica gel (benzene/Et2O, 6:1) to give 17 (95.0 mg, 5%) as
a colorless oil: IR (CHCl3) n 1635 cmꢀ1; 1H NMR (270 MHz,
CDCl3) d 1.11 (3H, t, J¼7.1 Hz), 1.57e1.66 (2H, m),
1.71e1.79 (2H, m), 2.05e2.19 (4H, m), 2.85 (2H, t,
J¼6.9 Hz), 3.35e3.55 (2H, m), 3.64 (2H, t, J¼6.9 Hz),
5.61e5.64 (1H, m); 13C NMR (67.8 MHz, CDCl3) d 13.2,
21.42, 22.7, 24.7, 28.11, 28.13, 36.7, 40.3, 128.0, 137.8,
168.6. Anal. Calcd for C11H18BrNO: C, 50.78; H, 6.97; N,
5.38. Found: C, 50.91; H, 7.16; N, 5.56.
1
n 1680 cmꢀ1; H NMR (270 MHz, CDCl3) d 1.57e1.65 (2H,
m), 1.71e1.79 (2H, m), 2.01 (3H, s), 2.05e2.17 (6H, m), 3.41

T. Taniguchi et al. / Tetrahedron 64 (2008) 2634e2641
2639
(2H, t, J¼7.0 Hz), 3.50 (2H, t, J¼7.3 Hz), 5.59e5.63 (1H, m). It
10 min. Phenylselenyl chloride (1.72 g, 13.4 mmol) was added
to the solution and the mixture was stirred for 1 h. The reaction
mixture was diluted with a saturated aqueous solution of
NaHCO3 and extracted with AcOEt. The organic phase was
washed with brine, dried (MgSO4), and concentrated. The
residue was chromatographed on silica gel (benzene/Et2O,
6:1) to give 27 (641 mg, 40%) as a colorless oil: IR (CHCl3) n
was used in the next step without further purification.
4.5. 1-Acetyldecahydroquinoline (20) and 1-acetyl-1-
azaspiro[4.5]decane (21)
Following the general procedure, a boiling solution of 19
(150 mg, 0.577 mmol) in toluene (40 mL) was treated with a so-
lution of Bu3SnH (249 mg, 0.865 mmol) and ACN (28.0 mg,
0.115 mmol) in toluene (40 mL). After work-up, the residue
was chromatographed on silica gel containing KF (10%) (hex-
ane/AcOEt, 4:1). The first eluent gave 21 (15.3 mg, 15%) as
a colorless needles, mp 95e96 ꢁC (hexane): IR (CHCl3) n
1715, 1645, 1610 cmꢀ1
;
1H NMR (270 MHz, CDCl3)
d 1.55e1.64 (2H, m), 1.68e1.77 (2H, m), 2.07e2.17 (4H, m),
3.02 (2H, t, J¼7.3 Hz), 3.80 (2H, t, J¼7.3 Hz), 5.58e5.63
(2H, m), 6.34 (1H, dd, J¼16.8, 3.0 Hz), 6.44 (1H, dd, J¼16.8,
9.2 Hz), 7.33e7.43 (3H, m), 7.46e7.52 (2H, m); 13C NMR
(67.8 MHz, CDCl3) d 21.3, 22.6, 24.8, 28.0, 41.3, 45.8, 126.1,
127.3, 128.2, 128.8, 128.9, 129.3, 135.7, 137.7, 165.3, 198.5;
HRMS (FAB) calcd for C18H22NO2Se (MHþ): 364.0816.
Found: 364.0822.
1
1625 cmꢀ1; H NMR (270 MHz, CDCl3) d 1.23e1.33 (4H,
m), 1.57e1.91 (8H, m), 2.01 (3H, s), 2.61e2.73 (2H, m),
3.44 (2H, t, J¼6.6 Hz); 13C NMR (67.8 MHz, CDCl3) d 23.0,
24.5, 25.3, 25.5, 33.2, 36.3, 49.9, 66.3, 169.2; HRMS calcd
for C11H19NO: 181.1467. Found: 181.1475. The second eluent
gave a mixture of two stereoisomers (trans/cis¼1.5:1) of 20
4.7. (7aR*,11aR*)-Hexahydro-1H-pyrrolo[2,1-j]-quinoline-
3,7(2H,7aH)-dione (28)
(76.5 mg, 73%) as a colorless oil: IR (CHCl3) n 1620 cmꢀ1
;
1H NMR (270 MHz, CDCl3) d 1.00e1.89 [(12þ2/5)H, m],
2.05e2.12 (3/5H, m), 2.07 (3Hꢂ4/5, s), 2.10 (3Hꢂ1/5, s),
2.57 (1/5H, td, J¼13.3, 2.6 Hz), 3.04e3.33 [(1þ2/5)H, m],
3.53e3.74 (1H, m), 4.47e4.53 (1/5H, m), 4.63 (1/5H, dt,
J¼12.5, 3.8 Hz); HRMS calcd for C11H19NO: 181.1467.
Following the general procedure, a boiling solution of 27
(530 mg, 1.46 mmol) in toluene (70 mL) was treated with a so-
lution of Bu3SnH (649 mg, 2.20 mmol) and ACN (71.5 mg,
0.292 mmol) in toluene (70 mL). After work-up, the residue
was chromatographed on silica gel containing KF (10%)
(hexane/AcOEt, 1:1) to give 28 (113 mg, 37%) as colorless
crystals, mp 106e107 ꢁC (hexane): IR (CHCl3) n 1715,
1
Found: 181.1471. H NMR spectral data of 20 were identical
with those reported in the literature.19
1680 cmꢀ1 1H NMR (500 MHz, C6D6) d 0.76e1.88 (2H,
;
4.6. Se-Phenyl N-acryloyl-3-(cyclohex-1-en-1-ylamino)-
selenopropanoate (27)
m), 0.92 (1H, tt, J¼13.4, 3.7 Hz), 1.02 (1H, td, J¼13.4,
3.7 Hz), 1.17e1.28 (3H, m), 1.31e1.42 (3H, m), 1.83 (1H,
td, J¼14.0, 7.9 Hz), 1.91 (1H, dd, J¼14.7, 4.3 Hz), 2.03
(2H, t, J¼7.3 Hz), 2.10e2.15 (1H, m), 2.49 (1H, td, J¼13.4,
3.7 Hz), 4.26 (1H, ddd, J¼13.4, 7.9, 1.8 Hz); 13C NMR
(67.8 MHz, CDCl3) d 20.5, 21.7, 22.3, 29.0, 29.4, 32.4, 35.0,
39.7, 55.2, 64.6, 173.1, 207.3. Anal. Calcd for C12H17NO2:
C, 69.54; H, 8.27; N, 6.76. Found: C, 69.31; H, 8.42; N, 6.61.
Using a procedure similar to that described for the prepara-
tion of 19, b-alanine ethyl ester hydrochloride (3.00 g,
19.5 mmol) was condensed with cyclohexanone (9.47 g,
97.7 mmol) and the mixture was treated with acryloyl chloride
(2.67 g, 29.3 mmol) and triethylamine (3.56 g, 35.2 mmol). Af-
ter work-up, the crude material was chromatographed (hexane/
AcOEt, 6:1) to give ethyl N-acryloyl-3-(cyclohex-1-en-1-yl-
amino)propanoate (2.30 g, 47%) as a colorless oil: IR (CHCl3)
n 1730, 1645, 1615 cmꢀ1; 1H NMR (270 MHz, CDCl3) d 1.22
(3H, t, J¼7.3 Hz), 1.53e1.61 (2H, m), 1.67e1.75 (2H, m),
1.99e2.10 (4H, m), 2.55 (2H, t, J¼7.3 Hz), 3.73 (2H, t,
J¼7.3 Hz), 4.09 (2H, q, J¼7.3 Hz), 5.53e5.57 (2H, m), 6.29
(1H, dd, J¼16.8, 3.0 Hz), 6.41 (1H, dd, J¼16.8, 9.6 Hz); 13C
NMR (67.8 MHz, CDCl3) d 14.1, 21.4, 22.6, 24.8, 28.0, 33.0,
41.3, 60.4, 127.0, 128.37, 128.43, 137.8, 165.1, 171.7. Anal.
Calcd for C14H21NO3: C, 66.91; H, 8.42; N, 5.57. Found: C,
66.85; H, 8.52; N, 5.19. Ethyl N-acryloyl-3-(N-cyclohex-1-
en-1-ylamimo)propanoate (1.13 g, 4.48 mmol) was hydrolyzed
with NaOH (2 mL), and the resulting carboxylic acid was
treated with sodium hydride (60% oil suspension, 214 mg,
5.37 mmol) to give sodium salt of the corresponding carboxylic
acid. Diphenyl diselenide (2.80 g, 8.96 mmol) and tributylphos-
phine (1.81 g, 8.96 mmol) in THF (20 mL) were added to the
solution at room temperature, and the mixture was stirred for
3 h.20 To the reaction mixture was added sodium benzoate
(1.94 g, 13.4 mmol), and the mixture was further stirred for
4.8. 1-Ethyldecahydro-2H-1-benzazepin-2-one (32) and
N-cyclohex-1-en-1-yl-N-ethylbutanamide (33)
Following the general procedure, a boiling solution of 31
(180 mg, 0.346 mmol) in toluene (30 mL) was treated with a so-
lution of Bu3SnH (286 mg, 0.984 mmol) and ACN (32.0 mg,
0.131 mmol) in toluene (30 mL). After work-up, the residue
was chromatographed on silica gel containing KF (10%) (hex-
ane/AcOEt, 1:1). The first eluent gave 33 (30.0 mg, 23%) as
a colorless oil: IR (CHCl3) n 1630 cmꢀ1; 1H NMR (270 MHz,
CDCl3) d 0.91 (3H, t, J¼7.4 Hz), 1.15 (3H, t, J¼7.3 Hz),
1.60e1.78 (6H, m), 2.07e2.18 (4H, m), 2.22 (2H, t,
J¼7.3 Hz), 3.42e3.63 (2H, m), 5.57e5.59 (1H, m); 13C NMR
(67.8 MHz, CDCl3) d 13.4, 13.9, 19.2, 21.6, 22.8, 24.7, 28.3,
35.5, 40.2, 127.1, 138.5, 172.0; HRMS calcd for C12H21NO:
195.1623. Found: 195.1622. The second eluent gave 32
(98.0 mg, 77%) as a colorless oil: IR (CHCl3) n 1615 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d 1.12 (3Hꢂ1/2, t, J¼7.1 Hz),
1.13 (3Hꢂ1/2, t, J¼7.1 Hz), 1.25e2.04 (13H, m), 2.42 (1/2H,
t, J¼13.9 Hz), 2.53 (1/2H, ddd, J¼14.6, 10.0, 3.9 Hz), 2.58 (1/

2640
T. Taniguchi et al. / Tetrahedron 64 (2008) 2634e2641
2H, dd, J¼14.6, 7.3 Hz), 2.75 (1/2H, ddd, J¼15.1, 9.8, 5.1 Hz),
3.18 (1/2H, dt, J¼13.0, 3.2 Hz), 3.21 (1/2H, dq, J¼13.9,
7.1 Hz), 3.27 (1/2H, td, J¼11.2, 3.2 Hz), 3.32 (1/2H, dq,
J¼13.9, 7.1 Hz), 3.45 (1/2H, dq, J¼13.9, 7.1 Hz), 3.68 (1/2H,
dq, J¼13.9, 7.1 Hz); 13C NMR (67.8 MHz, CDCl3) d 13.4,
14.9, 16.2, 19.8, 23.5, 25.8, 26.1, 26.7, 27.2, 29.5, 29.6, 30.3,
31.0, 34.1, 34.3, 36.2, 38.4, 39.1, 40.4, 44.7, 60.9, 63.2, 173.2,
174.6; HRMS calcd for C12H21NO: 195.1623. Found: 195.1629.
J¼7.1 Hz), 1.25 (3Hꢂ9/20, d, J¼7.4 Hz), 1.52 (9/20H, dd,
J¼6.6, 4.3 Hz), 1.71 (3Hꢂ11/20, d, J¼7.4 Hz), 2.54 (11/20H,
dd, J¼16.8, 8.7 Hz), 2.74e2.87 (1H, m), 2.93e3.14 [(2þ11/
20)H, m], 3.29e3.42 (11/20H, m), 3.60e3.77 [(1þ9/20)H, m],
4.63 (9/20H, q, J¼7.4 Hz), 7.09e7.37 (4H, m); 13C NMR
(67.8 MHz, CDCl3) d 12.7, 13.7, 18.6, 23.6, 29.4, 34.9, 35.5,
39.1, 42.8, 46.8, 59.0, 60.7, 126.1, 127.1, 127.3, 128.28, 128.33,
128.4, 128.5, 128.8, 130.6, 137.7, 139.4, 141.8, 173.1, 173.2;
HRMS calcd for C13H17NO: 203.1310. Found: 203.1307. The
third eluent gave 45 (5.0 mg, 5%) as colorless oil: IR (CHCl3)
4.9. (6aR*,10aS*)-1-Ethyldodecahydro-1-benzazocin-2(1H)-
one (38) and N-cyclohex-1-en-1-yl-N-ethylpentanamide (39)
n 1630 cmꢀ1 1H NMR (270 MHz, CDCl3) d 0.93 (3H, t,
;
J¼7.1 Hz), 2.82e2.88 (2H, m), 2.97e3.08 (2H, m), 3.10 (2H, t,
J¼6.8 Hz), 3.14 (2H, q, J¼7.1 Hz), 3.70 (2H, t, J¼6.8 Hz),
7.02e7.31 (4H, m); 13C NMR (67.8 MHz, CDCl3) d 12.7, 30.5,
34.7, 37.0, 41.5, 46.2, 126.9, 127.3, 130.1, 130.5, 136.4, 138.5,
172.4; HRMS calcd for C13H17NO: 203.1310. Found: 203.1304.
Following the general procedure, a boiling solution of 37
(200 mg, 0.694 mmol) in toluene (30 mL) was treated with a so-
lution of Bu3SnH (303 mg, 1.04 mmol) and ACN (34.0 mg,
0.139 mmol) in toluene (30 mL). After work-up, the residue
was chromatographed on silica gel containing KF (10%) (hex-
ane/AcOEt, 2:1). The first eluent gave 39 (67.0 mg, 46%) as
a colorless oil: IR (CHCl3) n 1625 cmꢀ1; 1H NMR (270 MHz,
CDCl3) d 0.90 (3H, t, J¼7.3 Hz), 1.09 (3H, t, J¼7.3 Hz), 1.31
(2H, sextet, J¼7.3 Hz), 1.57e1.79 (6H, m), 2.06e2.15 (4H,
m), 2.24 (2H, t, J¼7.4 Hz), 3.39e3.47 (2H, m), 5.57e5.60
(1H, m); 13C NMR (67.8 MHz, CDCl3) d 13.4, 13.8, 21.6,
22.5, 22.8, 24.7, 28.1, 28.3, 33.3, 40.2, 127.1, 138.5, 172.4;
HRMS calcd for C13H23NO: 209.1780. Found: 209.1773. The
second eluent gave 38 (16.0 mg, 11%) as a colorless oil: IR
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
Supplementary data
Experimental procedures and compound characterization
data for compounds 12e16, 22e26, 31, 34e37, and 40e43.
Calculation for transition states B, C, E, F, HeK, H0, J0, and
MeR. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.01.016.
1
(CHCl3) n 1615 cmꢀ1; H NMR (270 MHz, CDCl3) d 1.14
(3H, t, J¼7.1 Hz), 1.22e1.94 (15H, m), 2.37 (1H, ddd,
J¼13.2, 5.9, 2.0 Hz), 2.61 (1H, td, J¼13.0, 2.5 Hz), 2.97 (1H,
dq, J¼13.8, 7.1 Hz), 3.49 (1H, td, J¼10.4, 3.5 Hz), 3.58 (1H,
dq, J¼13.8, 7.1 Hz); 13C NMR (67.8 MHz, CDCl3) d 15.0,
22.3, 25.7, 26.1, 29.4, 30.3, 30.9, 31.2, 35.5, 36.0, 41.2, 59.3,
174.6; HRMS calcd for C13H23NO: 209.1780. Found: 209.1776.
References and notes
1. For reviews on the synthesis of heterocyclic compounds and natural
products using radical cyclization, see: (a) Majumdar, K. C.;
Mukhopadhyay, P. P.; Basu, P. K. Hetrocycles 2004, 63, 1903; (b) Li,
J. J. Alkaloids: Chemical Perspectives; Pelletire, S. W., Ed.; Wiley: New
York, NY, 2001; Vol. 5, Chapter 4; (c) Renaud, P.; Sibi, M. P. Radical
in Organic Synthesis; Wiley-VCH: Weinheim, 2001; (d) Jasperse, C. P.;
Curran, D. P.; Fevis, T. L. Chem. Rev. 1991, 91, 1237.
4.10. 2-Ethyl-1-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-
3-one (44), 3-ethyl-2,3,5,6-tetrahydro-3-benzazocin-4(1H)-
one (45), and N-ethenyl-N-ethyl-3-phenylpropanamide (46)
Following the general procedure, a boiling solution of 43
(150 mg, 0.531 mmol) in toluene was treated with a solution
of Bu3SnH (232 mg, 0.794 mmol) and ACN (26.0 mg,
0.106 mmol) in toluene. After work-up, the crude material was
chromatographed on silica gel containing KF (10%) (hexane/
AcOEt,1:1).Thefirsteluentgave46(86.2 mg,80%)asacolorless
oil. 1H NMR and 13C NMR spectra of 46 showed it to contain two
rotamers: IR (CHCl3) n 1620, 1665 cmꢀ1; 1H NMR (270 MHz,
CDCl3) d 1.12 (3H, t, J¼7.1 Hz), 2.73 (2H, t, J¼7.3 Hz), 2.99
(2H, t, J¼7.3 Hz), 3.53 (2Hꢂ1/4, q, J¼7.1 Hz), 3.70 (2Hꢂ3/4,
q, J¼7.1 Hz), 4.31 (3/4H, d, J¼9.2 Hz), 4.42 (1/4H, d, J¼
9.2 Hz), 4.46 (1/4H, d, J¼15.3 Hz), 4.48 (3/4H, d, J¼15.3 Hz),
6.74 (3/4H, dd, J¼15.3, 9.2 Hz), 7.20e7.40 (5H, m), 7.45 (1/
4H, dd, J¼15.3, 9.2 Hz); 13C NMR (67.8 MHz, CDCl3) d 11.8,
12.8, 21.9, 24.3, 31.0, 33.8, 35.7, 36.7, 93.1, 93.4, 126.1, 128.3,
128.4, 130.8, 132.1, 140.9, 170.3; HRMS calcd for C13H17NO:
203.1310. Found: 203.1303. The second eluent gave 44
2. (a) Walling, C.; Cioffari, A. J. Am. Chem. Soc. 1972, 94, 6059; (b) Baldwin,
J. E. J. Chem. Soc., Chem. Commun. 1976, 734; (c) Ishibashi, H.; Ohata, K.;
Niihara, M.; Sato, T.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1 2000, 547.
3. Ishibashi, H.; Kato, I.; Takeda, Y.; Kogure, M.; Tamura, O. Chem.
Commun. 2000, 1527.
4. Taniguchi, T.; Ishita, A.; Uchiyama, M.; Tamura, O.; Muraoka, O.;
Tanabe, G.; Ishibasi, H. J. Org. Chem. 2005, 70, 1922.
5. For a portion of this work, see: Taniguchi, T.; Tamura, O.; Uchiyama, M.;
Muraoka, O.; Tanabe, G.; Ishibashi, H. Synlett 2005, 1179.
6. Esker, J. L.; Newcomb, M. J. Org. Chem. 1993, 58, 4933.
7. Yang, T.; Lin, C.; Fu, H.; Jiang, Y.; Zhao, Y. Bioorg. Chem. 2005, 33, 386.
8. Lessard, J.; Cote, R.; Mackiewicz, P.; Furstoss, R.; Waegell, B. J. Org.
Chem. 1973, 43, 3750.
9. Booth, H.; Griffiths, V. J. Chem. Soc., Perkin Trans. 2 1975, 111.
10. For a review on acyl radical, see: (a) Chatgilialoglu, C.; Crich, D.;
Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991. Leading references
on acyl radical cyclizations, see: (b) Wong, L. S.-M.; Sherburn, M. S.
Org. Lett. 2003, 5, 3603; (c) Yoshikai, K.; Hayama, T.; Nishimura, K.;
Yamada, K.; Tomioka, K. J. Org. Chem. 2005, 70, 681.
(6.0 mg, 6%) as a colorless oil: IR (CHCl3) n 1670, 1630 cmꢀ1
1H NMR (270 MHz, CDCl3) d 1.11, 1.13 (total 3H, t,
;
11. For recent studies on the regioselectivity in radical cyclizations, see: (a)
´
Pinter, B.; De Proft, F.; Van Speybroeck, V.; Hemelsoet, K.; Waroquier,

T. Taniguchi et al. / Tetrahedron 64 (2008) 2634e2641
2641
´
M.; Chamorro, E.; Veszpremi, T.; Geerlings, P. J. Org. Chem. 2007, 72,
Zhang, L. Org. Lett. 2002, 4, 3329. See also Refs. 1c and 5 and references
therein.
348; (b) Guan, X.; Phillips, D. L.; Yang, D. J. Org. Chem. 2006, 71,
1984; (c) Leach, A. G.; Wang, R.; Wohlhieter, G. E.; Khan, S. I.; Jung,
M. E.; Houk, K. N. J. Am. Chem. Soc. 2003, 125, 4271; (d) Milet, A.;
Arnaud, R. J. Org. Chem. 2001, 66, 6074. See also Ref. 1c.
16. For recent and limited examples of 7-exo-selective radical cyclization,
see: (a) Inoue, M.; Yamashita, S.; Ishihara, Y.; Hirama, M. Org. Lett.
2006, 8, 5805; (b) Grant, S. W.; Zhu, K.; Zhang, Y.; Castle, S. L. Org.
Lett. 2006, 8, 1867; (c) Bogliotti, N.; Dalko, P. I.; Cossy, J. J. Org.
Chem. 2006, 71, 9528. See also Ref. 1c.
12. Forreviewsonradicalcascades, see:(a)McCarroll, A. J.;Walton,J. C.Angew.
Chem., Int. Ed. 2001, 40, 2224; (b) J. Chem. Soc., Perkin Trans. 1 2001, 3215.
´
13. (a) Aube, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113, 8965; (b)
17. For recent and limited examples of 8-endo-selective radical cyclization,
see: (a) Liu, L.; Chen, Q.; Wu, Y.-D.; Li, C. J. Org. Chem. 2005, 70,
1539; (b) Bacque, E.; Pautrat, F.; Zard, S. Z. Org. Lett. 2003, 5, 325.
See also Ref. 1c.
Hunter, R.; Richards, P. Synlett 2003, 271.
14. For a review on cylindricines and related alkaloids, see: Weinreb, S. M.
Chem. Rev. 2006, 106, 2531.
15. For recent studies on cyclizations of 6-pentenyl radical, see: (a) Jezek,
E.; Schall, A.; Kreitmeier, P.; Reiser, O. Synlett 2005, 915; (b) Padwa,
A.; Rashatasakhon, P.; Ozdemir, A. D.; Willis, J. J. Org. Chem. 2004,
70, 519; (c) Fang, X.; Xia, H.; Yu, H.; Dong, X.; Chen, M.; Wang, Q.;
Tao, F.; Li, C. J. Org. Chem. 2002, 67, 8481; (d) Koreeda, M.; Wang, Y.;
18. For the preparation of silica gel column containing KF, see: Horrowven,
D. C.; Guy, I. L. Chem. Commun. 2004, 1968.
19. Grillot, A.-L.; Hart, D. J. Tetrahedron 1995, 51, 11377.
20. Masamune, S.; Hayase, Y.; Schilling, W.; Chan, W. K.; Bates, G. S. J. Am.
Chem. Soc. 1977, 99, 6756.