Radical Cyclizations in the Synthesis of 3-Methyl-cis-octahydroindol-5-ones

Article abstract of DOI:10.1002/ejoc.201700086

Three approaches to the stereoselective synthesis of 3-methyl-cis-octahydroindoles through a 5-endo-trig radical cyclization are described. First, starting from an N-vinyl-α-chloroacetamide, the cyclization was followed by lactam methylenation and hydrogenation. Second, starting from an alkyne-tethered enamide, the cyclization was promoted by Bu₃SnH, and this was followed by protonolysis of the vinylstannane and hydrogenation of the exocyclic alkene. Third, through a 2,2-dichloropropanamide cyclization onto an alkenyl bond, and hydrogenation of the resulting endocyclic double bond; this represents the most efficient sequence to form the target compounds. 1,5-Enyne cyclizations through a 5-endo-trig process are reported. Here, a remote functional group (ketal or ketone), allowed the diastereoselectivity of the octahydroindole ring formation to be reversed through steric control of the facial selectivity in the hydrogen radical delivery step.

Full text of DOI:10.1002/ejoc.201700086

A Journal of
Accepted Article
Title: Radical Cyclizations in the Synthesis of 3-Methyl-cis-
octahydroindol-5-ones
Authors: Sergi Jansana, Guilhem Coussanes, Faïza Diaba, and Josep
Bonjoch
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700086
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Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201700086
FULL PAPER
Radical Cyclizations in the Synthesis of 3-Methyl-cis-
octahydroindol-5-ones
[
a]
[a]
[a]
[a]
Sergi Jansana, Guilhem Coussanes, Faïza Diaba, and Josep Bonjoch*
Abstract: Three approaches to the stereoselective synthesis of 3-
methyl-cis-octahydroindoles through a 5-endo-trig radical cyclization
are described, starting from: a) N-vinylic α-chloroacetamide
followed by lactam methylenation and hydrogenation; b) an alkyne
tether enamide promoted by Bu SnH, followed by protonolysis of the
vinylstannane and hydrogenation of the exocyclic alkene; and c) a
,2-dichloropropanamide cyclization onto the alkenyl bond and
Scheme 1. a) Daphniphyllum alakaloids with a 3-methyloctahydroindole
embedded; b) Hanessian’s approach to a stereocontrolled access to the AC
ring.
a
3
sequence,
a stereocontrolled synthesis of a 3-methyl-cis-
2
octahydroindole was achieved. The hydrogenation of
a
hydrogenation of the resulting endocyclic double bond, which
constitutes the most efficient sequence toward the targeted
compounds. 1,5-Enyne cyclizations through a 5-endo-trig process
are reported, in which a remote functional group (ketal or ketone),
allowed the diastereoselectivity in the octahydroindole ring formation
to be overturned, through steric control in the facial hydrogen radical
delivery step.
tetrasubstituted endocyclic alkene was key in the formation of
[2,3]
the stereogenic center at C-3 (Scheme 1, bottom).
To date, no procedure has been described to
diastereoselectively obtain 3-methyloctahydroindoles with the
methyl group trans to the ring junction hydrogens (i.e. type I
compounds) starting from aminocyclohexenes or analogs, which
[4]
would allow a direct entry to this compound type (Scheme 2).
In most precedents of hydroindole synthesis using this approach,
the major diastereomer formed has the methyl substituent in a β-
disposition (the epimer of I) and cannot be used as a building
block in Daphniphyllum alkaloid synthesis. Although Hanessian
reported a process resulting in a reversed diastereoselection,
Introduction
The 3-methyl-cis-octahydroindole motif, with a stereochemical
pattern as depicted in Scheme 1, is embedded in many
Daphniphyllum alkaloids belonging to biogenetically different
.
[4g]
the dr = 2:1 precludes its synthetic application In this context,
we explored the radical cyclization of both haloacetamides and
enynes to evaluate their usefulness to stereoselectively achieve
[
1]
groups (e.g. yuzurimine- and daphniglaucine-types, top of
Scheme 1). The only stereocontrolled procedure reported so far
for to obtain octahydroindoles with the configuration found in
Daphniphyllum alkaloids (3S) was introduced by Hanessian in
3
-methyl-cis-octahydroindoles starting from functionalized 4-
aminocyclohex-3-enes (Scheme 2, bottom).
[
2]
the synthesis of the tetracyclic core ring of daphniglaucin A.
Thus, from a proline derivative and through an eight-step
reagents
A. Ph SnH, AIBN
dr α:β
O
CN
A
Me
2:3
1:6
3
N
N
B. Bu SnH, AIBN
3
[
a]
Cl
B
PhSe
C. light photoredox 0.3:1:3
CO Me
CO Me
2
2
D. Cp ZrBu ; HCl
0:1
2
2
H
[a]
E. Bu SnH, AIBN 1:3:3.4
F. FeCl3, NaBH4, air 1:1
3
C
Me
G. Bu
3
SnH, AIBN; H
2
2:1
Me
H
N
HO
R
H
N
HO
Bn
X
Bz
N
N
N
OHC
O
D
Y
E
O
yuzurimine B
daphniglaucin C
Me
H
Boc
Boc
Boc
4
steps
N
H , Pd/C
N
F
G
N
2
H
Z
H
Ts
Ts
Me
Me
I
N
CO
Me
N
O
CO Me
2
H
N
2
CO Me
2
OBn
O
O
OH
OH
this work
Bn
Boc
COCF3
Cl
N
O
N
N
H
R
3
steps
O
R
Me
CO Me
2
Me
H
CO Me
2
Boc
O
O
O
[
[
a]
b]
Laboratori de Química Orgànica, Facultat de Farmàcia, IBUB,
Universitat de Barcelona,
Scheme 2. Synthetic precedents toward cis-3-methyloctahydroindoles and the
proposed approach. [a] Three diastereomers reported, but not assigned.
Av. Joan XXIII s/n, 08028-Barcelona, Spain
E-mail: josep.bonjoch@ub.edu
http://www.ub.edu/farmaco/en/quimica/llistat_recerca/
Supporting information for this article is available on the WWW
under http://dx.doi.org/
Results and Discussion
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European Journal of Organic Chemistry
10.1002/ejoc.201700086
FULL PAPER
We first studied the feasibility of using hydroindolone 2 to
achieve the targeted type I compound, either by alkylation or
methylenation followed by hydrogenation (Scheme 3).
Compound 2 was synthesized in a three-step sequence from the
monoethylene ketal of the 1,4-cyclohexanedione by formation of
H
13.9
Me
H
9.2
Me
O
H
3
O
31.7 3a
H
3
4.0 3a
O
4
H
O
4
3
H
7
a
7a
O
O
[
5]
N
N
the imine with benzylamine, followed by chloroacetylation to
give 1. As expected, when 1 was submitted to a radical
cyclization under reductive conditions using tributyltin hydride
3
5
Bn
Bn
δ
H3 2.63 dq (8.5, 6.8 Hz)
δH3 2.59 quint (7.1 Hz)
[
6]
(
TBTH), a cis-hydroindole was obtained. The methylation at C-
occurred via the formation of enolate amide, which reacted
Figure 1. Relative configuration and conformation of lactams 3 and 5.
3
with methyl iodide to afford compound 3 with the undesired
configuration at C-3. Attempts to induce an epimerization by
treatment of 3 with LDA and subsequent reprotonation failed. As
an alternative we tried the α-methylenation of 2, which after
some unfruitful attempts was achieved using Colby´s two-step
The above approach to an octahydroindole with the
desirable stereochemistry was modified to enhance its
efficiency. Hence, a radical-mediated enyne cyclization induced
[9]
[10]
by Bu
3
SnH
was considered from alkyne 7a
(Scheme 4).
[
7]
procedure (one-pot reaction), albeit in low yield. Reduction of
the exocyclic methylene lactam under 24 bar hydrogen pressure
took place diastereoselectively, leading to lactam 5 in 77% yield,
with the desired stereochemical arrangement in the
octahydroindole ring. The minor compound 6, generated by an
isomerization of 4, was also observed (13%). After
hydrogenation under atmospheric pressure, the overall yield was
maintained, although the isomerization increased, compounds 5
The latter was prepared via imine formation from 1,4-
cyclohexanedione monoethylene ketal with propargyl amine
followed by trifluoroacetylation, which gave enamide 7 in 54%
overall yield. Initially, the radical cyclization was carried out using
3
slow addition of Bu SnH and AIBN to a refluxing benzene
solution of 7a. The radical process gave a vinylstannane (not
shown), which by treatment with TsOH was protodestannylated
to give ketal 8 in 35% overall yield together with a non-cyclized
and
6
being isolated in
a
2:1 ratio. Interestingly, the
[11]
1
,5-diene compound.
Interestingly, a different result was
tetrasubstituted alkene 6 also proved to be a precursor of the
targeted octahydroindole 5 (see Scheme 7). Lactam 5 proved to
be configurationally stable to treatment with LDA at -78 ºC (5
equiv., THF, 45 min) and quenching with water.
obtained when the cyclization was conducted with freshly
prepared tributyltin hydride (from an old sample of tributyltin
chloride and sodium cyanoborohydride in t-BuOH at reflux
[12]
temperature).
The protonolysis step was conducted as above.
In these reaction conditions, ketone 9 was isolated with an
O
Bn
O
Bn
O
[13]
Bn
overall yield similar to that observed for 8.
At that time the
N
N
N
H
H
deprotection of ketal 7a to the corresponding ketone 7b was
carried out and 7b submitted to the same reaction conditions to
promote the radical cyclization used previously from 7a, cis
azabicyclic ketone 9 being isolated in 43% yield.
Cl
TBTH
LHMDS Me
H
H
AIBN
toluene
MeI
THF
71%
O
O
O
O
O
O
7
2%
1
2
3
COCF3
COCF3
i. LDA
ii. H O+
N
N
i. LHMDS, CF CO CH CF
3
2
2
3
H
(25%)
3
ii. (CH O) , K CO ,18-crown-6
i. Bu SnH, AIBN
toluene, reflux
2
n
2
3
3
H
O
Bn
O
Bn
O
Bn
N
N
N
H
H , Pd-C
EtOAc
2
H
O
O
ii. TsOH, CH Cl , rt
O
O
2
2
Me
Me
H
H
35%
7
a
8
2
4 atm
O
O
HCl 10%
THF
O
O
O
O
77%
8
3%
6
4
5
COCF3
COCF3
N
N
H
Bu SnH, AIBN
3
Scheme 3. First-generation synthesis of targeted 3-methyl cis-hydroindole.
H
toluene, reflux
4
3%
The stereochemical assignment of the compounds was
based on the coupling constants of the methine proton H-3,
which appears in 5 as a quintet (J = 7.2 Hz), whereas in lactam
O
O
7
b
9
3
it is split into a doublet of quadruplets (J = 8.5, 6.6 Hz), as
Scheme 4. Overturning the diastereoselectivity in the radical cyclization of
alkyne tether enamides 7.
[
4b]
13
reported by Ishibashi for the N-methyl analogs of 3 and 5.
C
NMR data analysis corroborated the structural elucidation,
considering the signal at C-4 (δ 31.7) in 5 is upfield with respect
to 3 (δ 34.0). This is due to a 1,3-diaxial relationship between the
methyl group and H-4ax, which is only possible with the
stereochemistry of 5. Epimeric lactams 3 and 5 are depicted in
A careful examination of the NMR data of 8 revealed the
formation of a trans-hydroindole. Notably, ketone 9 showed a
cis-ring fusion in the hydroindole ring. (For a discussion of the
elucidation of the trifluoroacetyl compounds by NMR data, see
[
8]
Figure 1 in their preferred conformation.
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European Journal of Organic Chemistry
10.1002/ejoc.201700086
FULL PAPER
below and Table 1). Thus, changing the ketal group for the
deprotected ketone altered the stereochemical course of the
radical cyclization. Overturning the diastereoselectivity was
crucial to achieve the relative configuration required for the
targeted hydroindole-type compounds. The remote stereocontrol
of the process was based on the steric hindrance induced by the
ketal group, which inhibits the transfer of the hydrogen atom
COCF3
COCF3
N
O
N
H , Pd-C
H
H
2
TFAA
9
Me
Me
18[a]
MeOH
H
H
Et N
3
(95%)
CH2Cl2
O
O
dr 2:1
(79%)
11
12
COCF3
COCF3
from the top face by the Bu
3
SnH to the radical intermediate.
N
N
O
H
H
Conversely, the reduction in the ketone substrate leading to the
H , Pd-C
2
HCl 10%
THF
Me
most stable cis-hydroindole compound 9 was sterically easy
8
H
H
(
Scheme 5). Additionally, for the comparison of NMR data, ketal
MeOH
(95%)
dr 3:2
O
O
hydrolysis in 8 was carried out to obtain ketone 10 (Scheme 6).
Although the radical cyclization gave only a moderate overall
yield of the targeted hydroindole 9, compared with that reported
(80%)
1
3
1
0
[
4g]
by Hanessian using a 5-exo-trig cyclization,
that the transformation from the 1,5-enyne 7b to 9 took place
it should be noted
Scheme 6. Transformations of hydroindoles 8 and 9. [a] See Scheme 7.
[
14]
through an unprecedented 5-endo-trig cyclization
in the
[
15,16]
nitrogen-containing heterocycles.
The cis-ring fusion in hydroindole 9 was established based
1
3
on C NMR data, which showed a shielding of 6 and 8 ppm in
the chemical shift for C3a and C7a, respectively, compared with
trans derivative 8. Moreover the strong deshielding of H-7a (δ
Bu Sn-H
3
O
H
H
H
H
O
H
SnBu3
O
7
a
4
.72) indicates a syn-coplanar disposition with respect to the
N
N
Bu Sn-H
3
O
via
acetal 8
H
carbonyl group of the trifluoroacetamide, which is only possible
in a cis-compound. Regarding the relative configuration of the
hydrogenated compound 11, the NMR spectra showed two set
of signals in a 2:1 ratio, which were assigned to a epimeric
mixture at C-3. The key configuration at C-3 was established
with the pattern of coupling constants of H-2. Thus, a triplet for
the signal at δ 3.19 (J = 11.6 Hz) is only compatible with a cis-
CF3
O
CF3
1
0
O
H
H-SnBu3
O
H
H
7
b
H
N
N
O
O
H
SnBu3
CF3
CF3
H
[
18]
9
relationship of H-2β with the methine at H-3β.
Direct
comparison with NMR data for ketal 12 was not possible since
Scheme 5. Substrate-controlled diastereoselectivity in the radical cyclization.
each compound has a different preferred conformation (Figure
2
). The conformation of ketone 11 was as expected, considering
that the amide function induces an axial disposition for the C7-
C7a bond with respect to the pyrrolidine ring to avoid the 1,3-
allylic strain. However, in ketal 12 this conformation implies a
strong 1,3-diaxial interaction between the ketal at C-5 and the
C3-C3a bond, hence the preferred endo-conformation. Finally,
to unambiguously corroborate the structural elucidation of 11, it
was also prepared by hydrolysis of ketal 12. The NMR data of
the sample of 11 obtained from 12 matched those of the major
epimer in the hydrogenation procedure from 9.
At this stage, we performed the hydrogenation of the
exocyclic methylene group at C-3 in 9. Using Pd/C as a catalyst,
the methyl derivative 11 with the desired configuration was
isolated as an epimeric mixture in a 2:1 ratio (Scheme 6). Ketal
1
2 was also available from the corresponding secondary amine,
synthesized unambiguously, as depicted in Scheme 7. To gain
additional spectroscopic data for the 3-methyloctahydroindoles,
the trans derivative 8 was also subjected to the methylene
reduction process. Its hydrogenation was very slow, requiring up
to 3 days, and led to the methyl derivative 13 alongside its
epimer in a 3:2 ratio.
H
H
O
H
H
O
H
H
H
The relative stereochemistry of bicyclic trifluoroacetamides 8
[
17]
1
13
O
and 9 (Z/E rotamers)
was elucidated from H and C NMR
N
N
CF3
O
H
spectral data (Figure 2 and Table 1). The key evidence for the
assignment of 8 was found in the coupling pattern for H-3a and
H-7a, which appears as a triplet of doublets (J = 11.2, 1.2 Hz) in
both cases. This coupling pattern is only compatible with a trans
relationship between H-3a and H-7a (both in an axial
disposition).
O
H
CF3
8
9
H
O
O
H
CH
3
7a
H
H
O
H3a
H
CH3
N
O
N
H
CF3
O
CF3
11
1
2
Figure 2. Trifluoroacetamides 8 and 9 in their preferred conformation and
stereoview of C-3 methylated compounds 11 and 12.
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European Journal of Organic Chemistry
10.1002/ejoc.201700086
FULL PAPER
Table 1. Key NMR of cis- and trans-hydroindoles 8-12
[
a]
hydroindole 15, which has a more stable configuration than that
[
21]
of its epimer at C-3.
Finally, from cis-octahydroindole 5,
[
b]
8
9
11
12
3.78
113
several derivatives were synthesized, namely lactam 16 and the
amines 17-19.
H-2
C-2
4.39
4.44
(d,15.2)
4.33
3.91
3.73
(t,11.0)
3.46
[
c]
(
d,13.8)
.22
(t, 11.6) (t, 11.1)
O
4
3.19
51.3
3.26
51.8
O
Bn
a)
Me
H
Bn
52.8
50.6
55.7
N
N
H
X
Bu SnH
AIBN
3
H-3
C-3
---
---
2.49
36.0
2.35
35.6
2.26
33.6
Me
H
143.8
144.6
toluene
O
O
O
O
H-3a
C-3a
H-4
2.54
3.27
39.8
2.66
38.1
2.35
39.4
2.10
45.0
(
t, 11.4)
3 (39%)
3 (32%) and 6 (26%)
45.7
14a X = Cl
4b X = Br
1
2.12
2.72
2.72
2.34
2.34
1.67
1.32
1.61
1.44
b)
O
Bn
(
dt,12.4)
.65
N
1
(t,13.0)
30.8
H , Pd-C
2
H
O
O
C-4
H-6
C-6
H-7
C-7
H-7a
C-7a
35.3
38.7
36.2
35.8
2
8 atm
Me
Me
Cl
Bn
O
Bn
H
O
N
N
1.89
2.30
2.45
36.5
2.38
2.22
35.5
1.55
1.45
29.4
1.84
1.61
33.4
MeOH
68%
Bu SnH
Cl
3
1
.61
O
O
AIBN
Me
33.7
5
toluene
O
O
O
H
2.98
2.30
1.86
24.9
2.66
1.94
24.7
2.70
1.93
22.8
2.84
26.7
6
0%
Na, NH
3
N
1
.65
H
5
g-scale
27.2
14c
6
Me
7
9%
H
3.18
4.72
4.44
4.00
(m)
3.37
O
O
(
td,11.2)
(td, 8.0)
57.0
(q,7.5)
58.3
(td,11.3)
60.6
65.1
59.7
1
5
1
c)
Bn
[
a] Among the H NMR data, the only coupling constants shown are those
O
Bn
[
c]
N
key in determining the configuration. [b] Values for the major Z rotamer.
N
H
H
Values of coupling constants in Hz.
LiAlH4
HClaq
THF
Me
Me
5
H
H
THF
90%
O
O
9
8%
O
In summary, although the usefulness of the process
involving the 1,5-enyne radical cyclization was compromised by
the overall yield, it allowed us to study the remote control of a
divergent stereochemical course of a radical process, which
hinged on whether a ketal or carbonyl group was embedded in
the substrate.
1
6
17
H
H
N
N
H
H , Pd-C
HClaq
8%
H
2
Me
Me
MeOH
95%
H
9
H
O
O
We then decided to revisit the radical cyclization of
haloacetamides leading to 3-methyloctahydroindoles via
lactams, introduced by Ishibashi some years ago (73%, dr = 6:1
O
18
19
[
4b]
ratio for analogs of 3 and 5) and recently studied by Rueping
Scheme 7. Third-generation synthesis of targeted 3-methyl cis-hydroindoles.
[
4c]
using a photoredox procedure (53%, dr = 3.1). In both cases
the cyclized substrates lacked the oxygenated function at C-5
present in the current work. Starting from enamides 14a-c, the Conclusions
yield and diastereoselectivity obtained after the cyclization
depends on the degree of the substitution in the proradical
haloacetamide and the presence of the ketal group linked to the
A three-step sequence (enamide formation, radical cyclization,
and hydrogenation) either from dichloroacetamides or
propargylamines was developed to achieve cis-3-
[
19]
cycloxene ring.
The cyclization of both chloro- and
bromoacetamides 14a-b afforded a stereochemical result at C-3
similar to that obtained in a related compound by Ishibashi, the
undesired epimer 3 being formed. From bromo derivative 14b
the isomerized compound 6 was also isolated in a nearly
methyloctahydroindoles as promising building-blocks for some
Daphniphyllum-type alkaloids embodying this structural unit. The
results obtained here are interesting from the mechanistic point
of view, since unexpected reaction pathways were found in the
radical cyclization processes (Scheme 8).
[
20]
equimolecular ratio.
Working with 2,2-dichloropropamide 14c gave a synthetically
interesting result. The major product of the radical cyclization
was compound 6, prepared on a 5 g-scale and with 60% yield.
Hydrogenation under pressure of the tetrasubstituted alkene in 6
gave the building block 5 with the targeted configuration.
Reduction of 6 using sodium in ammonia led to a concomitant
reduction and N-debenzylation and the isolation of trans-
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European Journal of Organic Chemistry
10.1002/ejoc.201700086
FULL PAPER
O
4ax), 1.73 (dd, J = 14.0, 5.2 Hz, 1 H, H-4eq), 1.82-1.89 (m, 2 H, H-7),
2.35 (m, 1 H, H-3a), 2.52-2.45 (m, 2 H, H-3), 3.44 (q, J = 5.2 Hz, 1 H, H-
COCF3
Me
Cl
Bn
N
O
N
7
a), 3.93-3.88 (m, 4 H, OCH
CH Ph), 7.27-7.32 (m, 5 H, PhH) ppm. C NMR (100 MHz, CDCl
gHSQC): δ = 23.9 (C-7), 29.7 (C-6), 32.0 (C-3a), 35.7 (C-4), 37.7 (C-3),
4.0 (CH Ph), 55.0 (C-7a), 64.2 and 64.3 (OCH ), 107.9 (C-5), 127.4,
127.9, 128.6 and 136.9 (Ph), 175.5 (C-2) ppm. HRMS (ESI): m/z calcd
2
), 4.05 and 4.88 (2d, J = 15.1 Hz, 1 H each,
Cl
13
2
3
,
X
R
4
2
2
O
O
N
Y
H
+
3
for C17H22NO [M+H] 288.1594; found 288.1599.
Me
radical cyclization
radical cyclization
H
(
3RS,3aRS,7aRS)-1-Benzyl-3-Methylhexahydroindol-2,5-dione
ethylene ketal (3): To a solution of LiHMDS (1 M in THF, 1.32 mL, 2
equiv.) at -78 °C was added dropwise a solution of 2 (190 mg, 0.66 mmol,
O
Bn
COCF3
N
N
O
1
.0 equiv.) in THF (6.6 mL) over 20 min. MeI (412 µL, 10 equiv.) was
H
H
hydrogenation
then added and the reaction mixture was stirred at -78 °C for 30 min and
at room temperature for a further 30 min. The reaction was quenched
Me
H
R = H, Bn, COCF3
X = O or H,H
Y = (OCH ) or O
4
with a solution of saturated NH Cl (10 mL), and extracted with ether
O
O
(3x10 mL). The combined organic layers were dried, concentrated and
2
2
purified by chromatography (hexane/EtOAc; 95:5 to 0:100) to afford 3 as
1
a colorless oil (142 mg, 71%). H NMR (400 MHz, CDCl
3
): δ = 1.19 (d, J
Scheme 8. Overview.
=
7.0 Hz, 3 H, CH
m, 1 H, H-6ax), 1.72–1.76 (m, 2 H, H-4), 1.83-1.91 (m, 2 H, H-7), 2.03-
.10 (m, 1H, H-3a), 2.63 (dq, J = 8.5, 6.8 Hz, 1 H, H-3), 3.35 (ddd, J =
8.2, 6.2, 6.2 Hz, 1 H, H-7a), 3.88–3.94 (m, 4 H, OCH ), 4.00 and 4.92 (2d,
J = 15.0 Hz, 1 H each, CH Ph), 7.22-7.34 (m, 5 H, PhH) ppm. C NMR
(100 MHz, CDCl ): δ = 13.9 (CH ), 24.5 (C-7), 30.7 (C-6), 34.0 (C-4),
0.6 (C-3), 40.8 (C-3a), 44.2 (CH Ph), 53.4 (C-7a), 64.0 and 64.4 (OCH ),
108.0 (C-5), 127.4, 127.9, 128.6 and 137.0 (Ph), 177.3 (C-2) ppm. HRMS
3
), 1.46 (ddd, J = 14.2, 10.8, 4.0 Hz, 1 H, H-6ax), 1.58
(
2
Experimental Section
2
1
3
2
1
13
3
3
General Methods: H and C NMR spectra were recorded in CDCl
solution. Chemical shifts are reported as δ values (ppm) relative to
3
4
2
2
1
3
internal Me
solvent signal (CDCl
supported by gCOSY and gHSQC experiments. TLC was performed on
SiO (silica gel 60 F254, Merck) or on Al (aluminium oxide 60 F254
neutral, Merck). The spots were located by UV light or a 1% KMnO
aqueous solution. Chromatography refers to flash chromatography and
was carried out on SiO (Silica Flash P60, Wet & Dry, 200-500 mesh)
and when indicated on Al (aluminium oxide 90, Merck). Drying of the
organic extracts during reaction work-up was performed over anhydrous
Na SO
4
Si, and C NMR spectra are referenced to the deuterated
+
(
3
ESI): m/z calcd for C18H24NO [M+H] 302.1751; found 302.1760.
3
: 77.00 ppm). All NMR data assignments are
2
2
O
3
cis-1-Benzyl-3-methylenehexahydroindole-2,5-dione ethylene ketal
(4): To a solution of LiHMDS (1.15 mL, 1M in THF, 1.15 mmol, 2 equiv.)
was added a solution of compound 2 (165 mg, 0.57 mmol, 1 equiv.) in
THF (3 mL). The reaction mixture was allowed to warm to room
4
2
2
O
3
temperature over 20 min, and then CF
1.78 mmol, 3.1 equiv.). After an additional 24 h at room temperature,
saturated aqueous NH Cl was added, and the resulting mixture was
3 2 2 3
CO CH CF was added (238 µL,
2
4
.
4
extracted with EtOAc. The organic extracts were dried and concentrated
and the resulting crude mixture was immediately used for the next step.
To a solution of the above intermediate in benzene (10 mL) were added
4
-(N-Benzyl-2-chloroacetamido]cyclohex-3-enone ethylene ketal (1):
Benzylamine (0.23 mL, 2.1 mmol) and 1,4-cyclohexanedione
momoethylene ketal (300 mg, 1.9 mmol) were dissolved in CH Cl (6 mL)
K
2
CO
.26 equiv.), and paraformaldehyde (604 mg, 20 mmol, 35 equiv.). The
suspension was heated to reflux for 20 h. The mixture was allowed to
cool to room temperature, saturated aqueous NH Cl was added, and the
3
(246 mg, 1.78 mmol, 3.1 equiv.), 18-crown-6 (40 mg, 0.15 mmol,
2
2
0
and molecular sieves 4 Å (375 mg) were added. The reaction mixture
was stirred at room temperature for 4 h, filtered through Celite®, washed
1
4
with CH
2
Cl
2
and concentrated to give the corresponding imine: H NMR
resulting mixture was extracted with EtOAc. The organic extracts were
(
400 MHz, CDCl
3
): δ = 1.83 (dd, J = 10.0, 4.0 Hz, 2 H), 1.92 (dd, J = 10.2,
dried, concentrated, and purified by chromatography (hexane: EtOAc,
4
7
.1 Hz, 2 H), 2.55 (t, J = 4.6 Hz, 4H), 4.00 (s, 4 H), 4.55 (s, 2H), 7.20-
1
9
0:10 to 50:50) to afford 4 as a colorless oil (43 mg, 25%). H NMR (400
.30 (m, 5H) ppm. The above imine in toluene (6 mL) was added
MHz, CDCl
3
): δ = 1.49-1.57 (m, 2 H, H-6), 1.65-1.74 (m, 2 H, H-4 and H-
), 1.84-1.93 (m, 2 H, H-4 and H-7), 3.03 (dddd, J = 12.0, 6.2, 6.0, 2.0 Hz,
H, H-3a), 3.49 (q, J = 6.2 Hz, 1 H, H-7a), 3.90 (s, 4 H, OCH ), 4.18 and
.96 (2 d, J = 15.0 Hz, 1 H each, CH Ph), 5.31 and 6.04 (2 d, J = 1.9 Hz,
H each, =CH ), 7.24-7.33 (m, 5 H, PhH) ppm. C NMR (100 MHz,
): δ = 24.0 (C-7), 30.4 (C-6), 35.8 (C-4), 36.2 (C-3a), 44.6 (CH Ph),
3.3 (C-7a), 64.2 (OCH ), 107.9 (C-5), 115.1 (=CH ), 127.5, 128.0, 128.7,
and 136.6 (Ph), 144.0 (C-3), 168.5 (C-2) ppm. HRMS (ESI): m/z calcd for
dropwise to a cooled solution of acetyl chloride (0.167 mL, 2.11 mmol) in
toluene (6 mL). The resulting solution was stirred at room temperature for
7
1
4
1
2
1
3
h. After cooling at 0 ºC, a solution of Et N (0.8 mL, 5.76 mmol) in
2
toluene (6 mL) was added dropwise and stirred at room temperature for
another hour. The reaction mixture was treated with saturated aqueous
1
3
2
CDCl
3
2
2 3 2
Na CO for 1 h, extracted with Et O, washed with brine (3 x 100 mL), and
5
2
2
concentrated. Purification by chromatography (hexane/EtOAc, 1:0 to 1:1)
1
afforded enamide 1 (358 mg, 58%) as a pale yellow oil. H NMR (400
+
18 3
C H21NNaO [M+Na] 322.1414; found 322.1411.
MHz, CDCl
3
): δ = 1.79 (t, J = 6.5 Hz, 2 H), 2.26 (m, 4 H), 3.97 (s, 4 H),
4
.14 (s, 2 H), 4.64 (br s, 2 H), 5.35 (br s, 1 H), 7.27-7.32 (m, 5 H) ppm.
1
3
C NMR (100 MHz, CDCl
3
): δ = 26.9, 31.0, 35.2, 41.7, 49.9, 64.6, 106.8,
(3RS,3aSR,7aSR)-1-Benzyl-3-Methylhexahydroindol-2,5-dione
ethylene ketal (5): Compound 4 (43 mg, 0.14 mmol, 1.0 equiv.) was
dissolved in EtOAc (15 mL), and Pd/C (18 mg, 40% w/w) was added.
The resulting suspension was stirred at room temperature under 20 atm
1
26.7, 127.5, 128.4, 128.8, 137.0, 137.5, 166.0 ppm. HRMS (ESI): m/z
+
3
calcd for C17H21ClNO [M+H] 322.1204; found 322.1210.
2
of H . After 24 h, the reaction mixture was filtered twice through Celite®
cis-1-Benzylhexahydroindole-2,5-dione ethylene ketal (2): Enamide 1
6.32 g, 19.6 mmol) was dissolved in toluene (280 mL) and the solution
was brought to reflux. A solution of Bu SnH (6.34 mL, 23.6 mmol) and
and concentrated to afford 5 together with minor amounts of 6 in an 8:1
(
1
ratio, as a colorless oil (38 mg, 87% overall yield). H NMR (400 MHz,
3
CDCl
3 3
): δ = 1.14 (d, J = 7.2 Hz, 3H, CH ), 1.25 (m, 1H, H-6ax), 1.32 (t, J
AIBN (1.61 g, 9.8 mmol) in toluene (10 mL) was added to the reaction
mixture via syringe pump over 4 h. After cooling, the mixture was
=
12.8 Hz, 1 H, H-4ax), 1.45 (dq, J = 13.2, 3.2 Hz, 1 H, H-6eq), 1.58 (ddd,
J = 13.6, 5.6, 2.8 Hz, 1 H, H-4eq), 1.80 (tt, J = 14.0, 4.2 Hz, 1H, H-7ax),
2.02 (dq J = 13.2, 3.0 Hz, 1 H, H-7eq), 2.47 (dddd J = 12.6, 7.0, 6.0, 5.0
Hz, 1 H, H-3a), 2.59 (quintuplet, J = 7.2 Hz, 1 H, H-3), 3.41 (td, J = 4.3,
concentrated and purified by chromatography (hexane/EtOAc; 75:25 to
1
0
:100) to afford 2 as a colorless oil (4.06 g, 72%). H NMR (400 MHz,
3
CDCl ): δ = 1.41-1.45 (m, 2 H, H-6), 1.57 (dd, J = 13.8, 8.4 Hz, 1 H, H-
2
2
.6 Hz, 1 H, H-7a), 3.90-3.94 (m, 4 H, OCH ), 4.07 and 4.88 (2 d, J =
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700086
FULL PAPER
1
3
1
5.1 Hz, 1 H each, CH
2
Ph), 7.20-7.36 (m, 5 H, PhH) ppm. C NMR (100
), 23.1 (C-7), 29.0 (C-6), 31.7 (C-4), 36.8 (C-
Ph), 53.5 (C-7a), 64.2 and 64.4 (OCH ), 108.2
C-5), 127.3, 127.8, 128.6, and 137.0 (Ph), 178.2 (C-2) ppm. HRMS
Purification by chromatography (hexane/EtOAc, 20:1 to 3:1) afforded 4-
MHz, CDCl
3
): δ = 9.2 (CH
3
(N-trifluoroacetyl-N-allyl)aminocycloxen-3-enone (18 mg, 12%) and then
1
3
a), 42.0 (C-3), 44.0 (CH
2
2
9 (66 mg, 43%) as a brown oil. H NMR (400 MHz, CDCl
3
, 5:2 mixture of
(
(
Z/E rotamers) Rotamer Z: δ =1.80-1.92 (m, 1 H, H-7), 2.14-2.46 (m, 3 H,
H-6 and H-7), 2.72 (m, 2H, H-4), 3.27 (m, 1H, H-3a), 4.33 and 4.44 (2 dd,
J = 15.2, 0.8 Hz, 1 H each, H-2), 4.72 (td, J = 8.0, 4.8 Hz, 1H, H-7a), 5.10
+
3
ESI): m/z calcd for C18H24NO [M+H] : 302.1751 found: 302.1760. For
analytical data of 6, see below. When the hydrogenation of 4 was carried
out at atmospheric pressure, compounds 5 and 6 were isolated in a 2:1
ratio and 90% overall yield.
and 5.23 (2 q, J = 2.4 Hz, 1H each, =CH
2
). Rotamer E: δ =1.80-1.92 (m,
1 H, H-7), 2.14-2.46 (m, 3 H, H-6 and H-7), 2.75 (m, 2 H, H-4), 3.35 (m,
1
1
H, H-3a), 4.08 and 4.44 (2 d, J = 16.0 Hz, 1 H each, H-2), 4.60 (dt J =
0.8, 6.2 Hz, 1 H, H-7a), 5.14 and 5.29 (2 q, J = 2.0 Hz, 1 H each, =CH
2
)
[
4-(N-Trifluoroacetyl-N-propargyl)amino]-3-cyclohexenone ethylene
1
3
ppm. C NMR (100 MHz, CDCl
8.7 (C-4), 39.8 (C-3a), 50.6 (C-2), 57.0 (C-7a), 109.4 (=CH
C-F = 286 Hz, CF ), 144.6 (C-3), 155.7 (q, JC-O = 35.0 Hz, CO), 208.3 (C-
). Rotamer E: δ = 28.0 (C-7), 37.4 (C-6), 38.1 (C-4), 43.8 (C-3a), 50.4
), 117.5 (CF ), 142.0 (C-3), 155.4 (CO),
3
): Rotamer Z: δ = 24.9 (C-7), 36.5 (C-6),
ketal (7a): Following the general procedure, cyclohexanedione
3
2
), 116.1 (q,
monoethylene ketal (2.37 g, 15.15 mmol, 1.0 equiv.) and benzylamine
[
22]
J
3
were dissolved in CH
2
Cl
2
(2 mL). The resulting imine was treated with
N in
5
trifluoroacetic anhydride (2.6 mL, 18.18 mmol, 1.2 equiv.) and Et
3
(
C-2), 56.8 (C-7a), 109.8 (=CH
2
3
toluene (166 mL). Chromatography (hexane/ EtOAc, 90:10 to 0:100)
+
1
2
2
13 3 2
06.9 (C-5) ppm. HRMS (ESI): m/z calcd for C11H F NO [M+H]
afforded 7 (2.33 g, 54%) as a pale yellow solid: m.p. 87-92 °C. H NMR
48.0893; found 248.0888.
(
400 MHz, CDCl
H), 3.98-4.01 (m, 4 H), 4.26 (s, 2 H), 5.74 (s, 1 H) ppm. C NMR (100
MHz, CDCl ): δ = 26.5, 30.9, 35.3, 37.5, 64.6, 73.0, 106.4, 127.3, 134.8
ppm. HRMS (ESI): m/z calcd for C13
90.0989.
3
): δ = 1.87 (t, J = 6.8 Hz, 2 H), 2.30 (s, 1 H), 2.40 (m, 4
1
3
3
trans-3-Methylene-1-trifluoroacetyloctahydroindol-5-one (10): Ketal 8
(18 mg, 0.06 mmol, 1.0 equiv.) was dissolved in a THF: HCl (10%)
mixture (4:1, 1.5 mL) and stirred at room temperature. After 18 h, the
+
15 3 3
H F NO [M+H] 290.0999; found
2
reaction was quenched with
extracted with CH Cl The resulting organic layer was dried,
concentrated, and purified by chromatography (hexane/EtOAc, 9:1) to
2 3
a saturated solution of Na CO and
2
2
.
[
4-(N-trifluoroacetyl-N-propargyl)amino]-3-cyclohexenone (7b): Ketal
a (95 mg, 0.33 mmol, 1.0 equiv.) was dissolved in a THF: HCl (10%)
mixture (4:1, 2.5 mL) and stirred at room temperature. After 24 h, the
reaction was quenched with saturated solution of Na CO and
extracted with CH Cl The resulting organic layer was dried,
concentrated, and purified by chromatography (hexane/EtOAc, 9:1 to
7
1
afford 10 (12 mg, 80%) as a clear oil. H NMR (400 MHz, CDCl
.77 (qd, J = 12.3, 5.3 Hz, 1 H, H-7ax), 2.36 (m, 1 H, H-4ax), 2.44 (m, 1
H, H-6), 2.61 (m, 2 H, H-6 and H-3a), 2.80 (dq, J = 15.0, 3.2 Hz, 1 H, H-
eq), 3.27 (m, 1 H, H-7eq), 3.60 (td, J = 11.6, 2.8 Hz, 1 H, H-7a), 4.34 (d,
J = 14.0 Hz, 1 H, H-2), 4.47 (d, J = 14.0 Hz, 1 H, H-2), 4.90 and 5.09 (2 d,
3
): δ =
1
a
2
3
2
2
.
4
1
3
:1) to afford ketone 7b (66 mg, yellow oil, 83%). H NMR (400 MHz,
CDCl ): δ 2.34 (t, J = 2.4 Hz, 1 H, C≡CH), 2.67 (br s, 4 H, H-6 and H-7),
.05 (d, J = 3.6 Hz, 2 H, H-4), 4.35 (br s, 2 H, CH N), 5.96 (t, J = 3.6 Hz,
): δ 27.5 (C-7), 37.4 (CH N),
7.8 (C-6), 38.5 (C-4), 73.8 (CH≡C), 76.6 (C≡CH), 116.2 (q, JC-F = 286
), 127.2 (CH-CN), 135.1 (CN), 156.0 (q, JC-O = 36 Hz, CO), 206.2
1
3
J = 1.2 Hz, 1 H each, =CH
), 38.8 (C-6), 41.4 (C-4), 46.9 (C-3a), 52.9 (C-2), 63.8 (C-7a), 106.0
=CH ), 116.1 (q, JC-F = 286 Hz, CF ), 142.6 (C-3), 155.5 (q, JC-O = 36 Hz,
CO), 207.2 (C-5) ppm. HRMS (ESI): m/z calcd for C11
48.0893 found: 248.0902.
2 3
) ppm. C NMR (100 MHz, CDCl ): δ 28.0 (C-
3
7
3
1
3
2
1
3
(
2
3
H, CHCN) ppm. C NMR (100 MHz, CDCl
3
2
+
13 3 2
H F NO [M+H] :
2
Hz, CF
C-5) ppm. HRMS (ESI): m/z calcd for C11
found: 246.0731.
3
+
(
11 3 2
H F NO [M+H] : 246.0736
(3RS,3aSR,7aSR)-1-Trifluoroacetyl-3-Methyloctahydroindol-5-one
11): Ketone 9 (31 mg) in MeOH (2 mL) was hydrogenated overnight,
using Pd-C (15 mg). Octahydroindole 11 (as a 2:1 epimeric mixture) was
(
trans-3-Methylene-1-trifluoroacetyloctahydroindol-5-one
ethylene
1
obtained in 95% yield: H NMR (400 MHz, CDCl
H, CH ), 1.94 (m, 1 H, H-7), 2.22 (m, 1 H, H-6), 2.34 (m, 2 H, H-4), 2.38
m, 1 H, H-6), 2.49 (m, 1 H, H-3), 2.61 – 2.71 (m, 2 H, H-7 and H-3a),
.19 (t, J = 11.6 Hz, 1 H, H-2), 3.91 (td, J = 11.6, 1.6 Hz, 1 H, H-2), 4.44
3
): δ = 1.06 (d, J = 6.8 Hz,
ketal (8): Alkyne 7 (240 mg, 0.83 mmol, 1.0 equiv.) was dissolved in
benzene (12 mL) and heated up to reflux. TBTH (268 µL, 1.00 mmol, 1.2
equiv.) and AIBN (68 mg, 0.41 mmol, 0.5 equiv.) were added with a
syringe pump over 1.5 h. The reaction was maintained at reflux for 1.5 h.
The mixture was cooled to room temperature and concentrated. Then,
solid p-toluenesulfonic monohydrate (190 mg, 1.00 mmol, 1.2 equiv.) was
3
3
(
3
1
3
(
(
q, J = 7.5 Hz, 1 H, H-7a) ppm. C NMR (100 MHz, CDCl
CH ), 24.7 (C-7), 35.5 (C-6), 36.0 (C-3), 36.2 (C-4), 38.1 (C-3a), 51.3 (C-
), 58.3 (C-7a), 116.1 (q, JC-F = 286 Hz, CF ), 155.5 (q, JC-O = 36 Hz, CO),
3
): δ = 12.0
3
2
2
3
3
added in CH
mixture was neutralized and washed with Na
concentrated. Purification by chromatography (hexane/EtOAc, 95:5 to
2
Cl
2
(25 mL) and the solution stirred for 3 h. The reaction
11.2 (C-5) ppm. Minor Signals 15.8, 25.1, 28.6, 36.0, 36.9, 38.6,
2
CO dried, and
3
,
9.7,43.4, 52.9, 57.5, 65.7, 205.4 ppm. HRMS (ESI): m/z calcd for
+
1
C
11
H
15
F
3
NO
2
[M+H] : 250.1049 found: 250.1049. A pure sample of
5
0:50) afforded 8 (60 mg, 35%) as a white solid: m.p. 51-56 °C. H NMR
400 MHz, CDCl ): δ = 1.60-1.70 (m, 3 H, H-6ax, H-4ax and H-7), 1.89
dt, J = 10.4, 3.2 Hz, 1 H, H-6eq), 2.12 (dt, J = 12.4, 2.8 Hz, 1 H, H-4eq),
ketone 11 as a yellow oil was obtained by hydrolysis of ketal 12 using
THF-10% HCl (4:1). The NMR data matched those of the major epimer
obtained in the above hydrogenation procedure.
(
(
3
2
1
1
.54 (t, J = 11.6, 1.2 Hz, 1 H, H-3a), 2.98 (m, 1 H, H-7), 3.18 (td J = 11.0,
.2 Hz, 1 H, H-7a), 3.97-3.99 (m, 4 H, OCH ), 4.22 and 4.39 (2 br d, J =
3.8 Hz, 1 H each, H-2), 4.84 and 4.97 (2d, J = 1.2 Hz, 1 H each, =CH
2
2
)
(3RS,3aSR,7aSR)-1-Trifluoroacetyl-3-Methyloctahydroindol-5-one
ethylene ketal (12): To a cooled solution (0 ºC) of 50 mg (0.25 mmol) of
1
3
ppm. C NMR (100 MHz, CDCl
5.7 (C-3a), 52.8 (C-2), 64.3 (OCH
=CH ), 108.5 (C-5), 116.1 (q, JC-F = 286 Hz, CF
3
): δ = 27.2 (C-7), 33.7 (C-6), 35.3 (C-4),
), 64.7 (OCH ), 65.1 (C-7a), 104.3
), 143.8 (C-3) ppm;
4
2
2
amine 17 (see below) in CH
mmol) and triethylamine (106 µL, 0.76 mmol). After
temperature the solution was quenched by a solution of NaHCO
3
2
Cl
2
(2 mL) were added TFAA (70 µL, 0.50
at room
and
(
2
3
4 h
+
masked (CO). HRMS (ESI): m/z calcd for C13
H
17
F
3
NO
3
[M+H] 292.1155;
found 292.1157.
extracted with EtOAc. The organic extracts were washed with 1 N HCl,
dried, concentrated, and purified by chromatography (hexane/EtOAc,
1
2
0:1) to give trifluoroacetamide 12 as a yellow oil (58 mg, 79%): H NMR
cis-3-Methylene-1-trifluoroacetyloctahydroindol-5-one (9): To
a
(
3 3
400 MHz, CDCl ): δ = 0.99 (d, J = 6.4 Hz, 3 H, CH ), 1.32 (t, J = 13.0 Hz,
solution of alkyne 7b (153 mg, 0.72 mmol, 1.0 equiv.) in toluene (9 mL) at
reflux temperature, TBTH (232 µL, 0.86 mmol, 1.2 equiv.) and AIBN (59
mg, 0.36 mmol, 0.5 equiv.) were added with a syringe pump over 1.5 h.
The reaction mixture was maintained at reflux for 1.5 h, cooled to room
temperature and concentrated. To the vinylstannane intermediate, solid
p-toluenesulfonic monohydrate (164 mg, 0.86 mmol, 1.2 equiv.) was
1
1
2
H, H-4ax), 1.45 (dd, J = 13.2, 3.9 Hz, 1 H, H-6eq), 1.55 (m, 1 H, H-6ax),
.67 (ddd, J = 13.7, 5.7, 2.4 Hz, 1 H, H-4eq), 1.88 –1.99 (m, 1 H, H-7ax),
.33 (m, 1 H, H-3a), 2.39 (m, 1 H, H-3), 2.70 (dq, J = 15.1, 4.0 Hz, 1 H,
H-7eq), 3.26 (t, J = 11.1 Hz, 1 H, H-2), 3.78 (td, J = 9, 1.2 Hz, 1 H, H-2),
1
3
3
.94-3.98 (m, 4 H, OCH
CDCl ): δ = 11.5 (CH ), 22.8 (C-7), 29.4 (C-6), 30.8 (C-4), 35.6 (C-3),
9.4 (C-3a), 51.8 (C-2), 59.7 (C-7a), 64.2 and 64.4 (OCH ), 108.5 (C-5),
16.0 (q, JC-F = 286 Hz, CF ), 143.8 (C-3), 157.0 (q, JC-O = 35.0 Hz, CO)
2
), 4.00 (m, 1 H, H-7a) ppm. C NMR (100 MHz,
added in CH
2
Cl
2
(19 mL) and the solution stirred for 3 h. The reaction
CO solution, dried, and concentrated.
3
3
3
1
2
mixture was washed with Na
2
3
3
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700086
FULL PAPER
+
ppm. HRMS (ESI): m/z calcd for C13
H
19
F
3
NO
3
[M+H] : 294.1312 found:
From 14a: Following the general procedure for the cyclization of 1,
haloamide 14a (140 mg, 0.42 mmol, 1.0 equiv) was dissolved in toluene
2
94.1313.
(
3
6 mL) and heated to reflux. Bu SnH (135 µL, 0.50 mmol, 1.2 equiv) and
AIBN (14 mg, 0.08 mmol, 0.2 equiv) were added over 4 h with a syringe
pump. Purification by chromatography (hexane/EtOAc, 95:5 to 50:50)
afforded 3 as a colorless oil (49 mg, 39%). For analytical data when 3
was obtained from 2, see above.
(
3RS,3aRS,7aRS)-1-Trifluoro-3-Methyloctahydroindol-5-one ethylene
ketal (13): To a stirred solution of alkene 8 (30 mg, 0.13 mmol) in MeOH
2 mL) was added Pd/C (45 mg) at room temperature. The reaction
(
mixture was stirred under a hydrogen atmosphere for 72 h, filtered
through Celite®, concentrated and purified by chromatography
(
Hexane/EtOAc, 90:10) to afford 13 (mixture of epimers, dr 3:2) as a
From 14b: From the bromo derivative 14b (175 mg, 0.46 mmol) and
using the same reaction conditions, lactam 3 (45 mg, 32%) and lactam 6
(36 mg, 26%) were obtained in 58% overall yield.
1
yellow oil (29 mg, 95%). H NMR (400 MHz, CDCl
Hz, 3 H, CH ), 1.44 (m, 1 H, H-4), 1.59 – 1.64 (m, 2 H, H-4 and H-6),
.81 – 1.88 (m, 2 H, H-6 and H-7ax), 2.10 (m, 1 H, H-3a), 2.26 (qdd, J =
3
): δ = 0.90 (d, J = 7.2
3
1
7
3
2
.2, 6.0, 4.0, 1.2 Hz, 1 H, H-3), 2.84 (dq, J = 12.0, 4.0 Hz, 1 H, H-7eq),
.37 (td, J = 11.4, 3.2 Hz, 1 H, H-7a), 3.46 (dd, J = 11.0, 1.5 Hz, 1 H, H-
From 14c. 1-Benzyl-3-methyl-4,6,7,7a-tetrahydro-1H-indol-2,5-dione
ethylene ketal (6): Following the general procedure for the cyclization of
1
3
), 3.73 (dd, J = 11.0, 5.8 Hz, 1 H, H-2), 3.96 (s, 4 H, (OCH
): δ = 13.1 (CH ), 26.7 (C-7), 33.4 (C-6), 33.6 (C-3),
5.8 (C-4), 45.0 (C-3a), 55.7 (C-2), 60.6 (C-7a), 64.6 and (OCH ), 64.6
), 109.1 (C-5), 116.1 (q, JC-F = 288 Hz, CF ), 156.9 (q, JC-O = 36.0
Hz, CO). NMR data for the minor epimer at C-3: H NMR (400 MHz,
CDCl ): δ = 1.01 (d, J = 6.4 Hz, 3 H, CH ), 1.44 (m, 2 H, H-4 and H-7),
.54 (m, 1 H, H-3a), 1.59–1.64 (m, 1 H, H-6), 1.81–1.88 (m, 2 H, H-3 and
H-6), 1.98 (dt, J = 12.3, 2.8 Hz, 1 H, H-4), 2.84 (m, 1 H, H-7), 3.17 (t, J =
2
). C NMR
1
, dichloroamide 14c (12.5 g, 33.8 mmol, 1.0 equiv) was dissolved in
(
100 MHz, CDCl
3
3
toluene (480 mL) and heated to reflux. Bu SnH (20 mL, 74.3 mmol, 2.2
3
3
2
equiv) and AIBN (1.66 g, 10.1 mmol, 0.3 equiv) were added with a
(
OCH
2
3
syringe pump over 4 h. Chromatography (hexane/EtOAc, 9:1 to 0:1)
1
1
afforded 6 as a white oil (6.03 g, 60%). H NMR (400 MHz, CDCl
3
): δ =
3
3
1
.19 (tdd, J = 13.8, 11.2, 4.0, 1 H, H-7ax), 1.64 (td, J = 13.8, 3.5 Hz, 1 H,
H-6ax), 1.78 (dq, J = 13.8, 3.4 Hz, 1 H, H-6eq), 1.84 (t, J = 1.6 Hz, 3 H,
CH ), 2.14 (dddd, J = 11.6, 6.8, 3.6, 3.2 Hz, 1 H, H-7eq), 2.38 (dd, J =
4.2, 1.2 Hz, 1 H, H-4ax), 2.84 (dd, J = 14.0, 2.8 Hz, 1 H, H-4eq), 3.57
dd, J = 11.4, 5.0 Hz, 1 H, H-7a), 3.85-4.00 (m, 4 H, OCH ), 4.23 and
Ph), 7.22-7.32 (m, 5 H, PhH) ppm.
): δ = 8.5 (CH ), 27.9 (C-7), 32.1 (C-6), 36.0
Ph), 59.1 (C-7a), 64.5 and 64.7 (OCH ), 64.5 and 64.7
), 109.7 (C-5), 127.2 (C-3), 127.3, 127.9, 128.6, 137.9 (Ph), 149.4
1
3
1
0.7 Hz, 1 H, H-2), 3.24 (m, 1 H, H-7a), 3.91 (m, 1 H, H-2), 3.96 (s, 4 H,
1
1
3
2 3 3
OCH ) ppm. C NMR (100 MHz, CDCl ): δ = 14.1 (CH ), 26.6 (C-7),
(
2
3
6
3.4 (C-6), 36.5 (C-3), 36.8 (C-4), 48.7 (C-3a), 55.4 (C-2), 65.3 (C-7a),
4.3 (OCH ), 64.4 (OCH ), 108.6 (C-5), 120.4 (CF ), 156.5 (CO).
4
.98 (2d, J = 15.2 Hz, 1 H each, CH
2
1
3
2
2
3
C NMR (100 MHz, CDCl
C-4), 44.0 (CH
3
3
(
2
2
4
-[(N-Benzyl-N-2-chloropropanoyl)amino]-3-cyclohexenone ethylene
(OCH
2
+
ketal (14a): The same imine used above for enamide 1 was prepared on
a1.92 mmol scale and treated with 2-chloropropionyl chloride (205 µL,
3
(C-3a), 172.1 (C-2) ppm. HRMS (ESI): m/z calcd for C18H22NO [M+H]
300.1594; found 300.1591.
2
.11 mmol, 1.1 equiv.) and TEA in dry toluene (12 mL). Purification by
chromatography (hexane/EtOAc, 100:0 to 50:50) afforded 4 (288 mg,
Hydrogenation of 6. Synthesis of Lactam 5: To a solution of alkene 6
538 mg, 1.80 mmol, 1.0 equiv.) in MeOH (15 mL) was added Pd/C (215
mg, 40% w/w). The resulting suspension was stirred at room temperature
under 27 atm of H for 2 days. The reaction mixture was filtered through
1
4
1
4%) as a yellow solid: m.p. 75-79°C. H NMR (400 MHz, CDCl
3
): δ =
(
.67 (d, J = 6.6 Hz, 3 H), 1.80 (dd, J = 11.0, 4.4 Hz, 2 H), 2.17-2.34 (m, 4
H), 3.97 (s, 4 H), 4.56 (masked, 1 H), 4.74 (br s, 2 H), 5.37 (br s, 1 H),
2
1
3
7
3
.24-7.30 (m, 5 H) ppm. C NMR (100 MHz, CDCl
3
): δ = 21.7, 27.2, 31.0,
Celite® and concentrated. Chromatography (hexane/EtOAc, 85:15)
5.2, 50.0, 50.4, 64.5, 106.7, 126.4, 127.4, 128.4, 128.7, 137.2, 169.2
afforded 5 (346 mg, 64%). For NMR data of lactam 5, see above.
+
3
ppm. HRMS (ESI): m/z calcd for C18H23ClNO [M+H] 336.1361; found
3
36.1361.
(
(
3RS,3aRS,7aSR)-3-Methylhexahydroindol-2,5-dione ethylene ketal
15): NH was condensed in a flask at -78 °C (50 mL) and Na (excess)
3
4
-[(N-Benzyl-N-2-bromopropanoyl)amino]-3-cyclohexenone ethylene
was added to afford a dark blue solution. A solution of 6 (74 mg, 0.25
ketal (14b): The same imine used above for enamide 1 was prepared on
a 1.93 mmol scale and treated with 2-bromopropionyl chloride (221 µL,
mmol, 1.0 equiv.) in THF (12.5mL) was added dropwise. After 20 min,
the reaction mixture was quenched with a saturated solution of NH
The reaction mixture was gradually warmed to room temperature until the
bubbling stopped. It was then extracted with CH Cl and the resulting
organic layer was washed with brine, dried, and concentrated to afford 15
4
Cl.
2
.13 mmol, 1.1 equiv.) and TEA in dry toluene (6 mL). Chromatography
(
1
hexane/EtOAc, 95:5 to 75:25) afforded 5 as a brown oil (343 mg, 47%).
2
2
H NMR (400 MHz, CDCl
3
): δ = 1.25 (d, J = 7.1 Hz, 3 H), 2.16 – 2.27 (m,
4
H), 2.35 – 2.43 (m, 2 H), 3.97 (br s, 4 H), 4.52 (br s, 1 H), 4.75 (br s, 2
1
(
41 mg, 79%) as a colorless solid: m.p. 178-182 °C. H NMR (400 MHz,
CDCl ): δ = 1.15 (d, J = 6.8 Hz, 3 H, CH ), 1.52 – 1.59 (m, 2 H, H-4ax
and H-7ax), 1.64 (td, J = 13.2, 4.0 Hz, 1 H, H-6ax), 1.73 (m, 1 H, H-3a),
.87 (ddd, J = 13.2, 4.4, 3.6 Hz, 1 H, H-6eq), 1.93 (dtd, J = 12.0, 2.8, 0.8
Hz, 1 H, H-4eq), 2.00 (dq, J = 12.0, 3.6 Hz, 1 H, H-7eq), 2.08 (dq, J =
1
3
H), 5.41 (br s, 1 H), 7.25 – 7.32 (m, 5 H) ppm. C NMR (100 MHz,
CDCl ): δ = 14.2, 22.2, 31.0, 35.1, 39.5, 50.0, 64.5, 106.7, 126.4, 127.4,
28.4, 128.7, 137.2, 169.3 ppm; (C-4 not observed). HRMS (ESI): m/z
3
3
3
1
1
+
3
calcd for C18H23BrNO [M+H] 380.0856; found 380.0861.
1
2.0, 6.8 Hz, 1 H, H-3), 3.03 (ddd, J = 13.2, 9.6, 3.2 Hz, 1 H, H-7a), 3.94
1
3
4
-[(N-Benzyl-N-2,2-dichloropropanoyl)amino]-3-cyclohexenone
– 3.99 (m, 4 H, (OCH
2
), 5.93 (br s, 1 H, NH) ppm. C NMR (100 MHz,
), 27.7 (C-7), 33.7 (C-6), 36.9 (C-4), 42.5 (C-3),
48.9 (C-3a), 57.4 (C-7a), 64.4 and (OCH ), 108.4 (C-5), 180.8 (C-2) ppm.
HRMS (ESI): m/z calcd for C11 [M+H] : 212.1281 found: 212.1288.
ethylene ketal (14c): The same imine used above for enamide 1 was
prepared on a 22.2 mmol scale and treated with TEA in toluene (130 mL),
and 2,2-dichloropropionyl chloride (3.40 mL, 31.10 mmol, 1.4 equiv.) was
3 3
CDCl ): δ = 12.4 (CH
2
+
H
18NO
3
added slowly in toluene (70 mL). Chromatography (CH
to 95:5) afforded 14c (5.53 g, 68%) as a yellow solid: m.p. 73-76 °C.
NMR (400 MHz, CDCl ): δ = 1.82 (br s, 2 H), 2.10-2.32 (m, 2 H), 2.35 (s,
H), 2.38-2.52 (m, 2 H), 3.95 (s, 4 H), 4.25 and 5.00 (2 br s, 1 H each),
2 2
Cl /EtOAc 100:0
1
H
(
3RS,3aSR,7aSR)-1-Benzyl-3-methylhexahydro-2H-indole-2,5(3H)-
3
dione (16): Ketal 5 (100 mg, 0.33 mmol, 1.0 equiv.) was dissolved in a
THF:HCl (10%) mixture (1:5, 6 mL) and stirred at room temperature.
After an overnight stirring, the resulting solution was extracted with
3
5
2
1
1
3
.53 (br s, 1 H), 7.24-7.31 (m, 5 H) ppm. C NMR (100 MHz, CDCl
6.8 (CH ), 31.0, 35.0, 37.2, 50.3, 64.4, 80.6, 106.8, 127.5, 128.3, 128.7,
36.7, 165.1 ppm, (C-3 and C-4 not observed). HRMS (ESI): m/z calcd
3
): δ =
3
CH
mg, 98%). H NMR (400 MHz, CDCl
.01 (m, 1 H, H-7), 2.08 (m, 1 H, H-7), 2.13 (m, 1 H, H-6), 2.19 (m, 1 H,
H-6), 2.28 (m, 2 H, H-4), 2.75 (m, 2 H, H-3a, H-3), 3.69 (q, J = 5.2 Hz, 1
2
Cl , dried, and concentrated to afford ketone 16 as a yellow oil (84
2
1
3
3
): δ = 1.17 (d, J = 6.0 Hz, 3 H, CH ),
+
2 3
for C18H22Cl NO [M+H] 370.0971; found 370.0974.
2
1
3
Cyclization of enamides 14
H, H-7a), 4.06 and 4.99 (2d, J = 15.0 Hz, 1 H each, CH
NMR (100 MHz, CDCl ): δ =10.6 (CH ), 25.0 (C-7), 35.1 (C-6), 35.6 (C-
a), 37.7 (C-4), , 40.3 (C-3), 44.3 (CH Ph), 53.3 (C-7a), 127.7, 127.9,
2
Ph) ppm.
C
3
3
3
2
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700086
FULL PAPER
1
28.7, and 136.4 (Ph), 176.8 (C-2), 210.5 (C-5) ppm. HRMS (ESI): m/z
Keywords: Radical reactions • Nitrogen heterocycles • Lactams
+
2
calcd for C16H20NO [M+H] 258.1489; found 258.1490.
•
Cyclization • Hydrogenation
(
3RS,3aSR,7aSR)-1-Benzyl-3-methyloctahydroindol-5-one ethylene
[
1]
a) J. Kobayashi, H. Morita, “The Daphniphyllum Alkaloids” in The
ketal (17): LiAlH (26 mg, 2.0 equiv.) was suspended in dry THF (2 mL).
4
Alkaloids, Vol 60 (Eds.: G.A. Cordell), Academic Press, New York,
A solution of 5 (100 mg, 0.33 mmol, 1.0 equiv.) in THF (6 mL) was added
2
003, pp 165-205; b) J. Kobayashi, T. Kubota, Nat. Prod. Rep. 2009,
6, 936-962. c) A. K. Chattopadhyay, S. Hanessian, Chem. Rev. 2017,
dropwise. The resulting suspension was heated to reflux for 4 h. It was
2
cooled to room temperature and the remaining LiAlH
4
was quenched with
DOI: 10.1021/acs.chemrev.6b00412.
a 15 % solution of NaOH. The resulting suspension was filtered through
®
[2]
S. Hanessian, S. Dorich, H. Menz, Org. Lett. 2013, 15, 4134-4137.
For other syntheses of penta-, tetra- and tricyclic core structures of
Daphniphyllum alkaloids with the 3a-methyloctahydroindole scaffold,
see respectively: a) S. E. Denmark, R. Y. Baiazitov, S. T. Nguyen,
Tetrahedron 2009, 65, 6535-6548. b) J. Boudreault, F. Lévesque, G.
Bélanger, J. Org. Chem. 2016, 81, 9247-9268. c) I. Coldham, A. J.
Burrell, H. D. S. Guerrand, N. Oram, Org. Lett. 2011, 13, 1267-1269.
a) From tethered phenylseleno alkenes: D. L. J. Clive, A. Y.
Mohammed, Heterocycles 1989, 28, 1157-1167; b) Radical cyclization
from 2-chloropropanamides: T. Sato, N. Nakamura, K. Ikeda, M. Okada,
H. Ishibashi, M. Ikeda, J. Chem. Soc. Perkin Trans 1, 1992, 2399-2407;
c) Recently, Rueping has reported this cyclization type by a visible light
photoredox process: E. Fava, M. Nakajima, M. B. Tabak, M. Rueping,
Green Chem. 2016, 18, 4531-4535; d) Zr-promoted reductive coupling
of dienes: M. Mori, N. Uesaka, M. Shibasaki, J. Org. Chem. 1992, 57,
Celite and washed several times with CH
washed with brine, dried, and concentrated. Chromatography
CH Cl /MeOH, 100:0 to 98:2) afforded 17 (85 mg, 90%) as a brown oil.
H NMR (400 MHz, CDCl ): δ = 0.84 (d, J = 6.8 Hz, 3 H, CH ), 1.44–1.53
m, 2 H, H-4eq and H-6eq), 1.66 (t, J = 12.8 Hz, 1 H, H-4ax), 1.77 (br dt,
J = 14.0, 3.6 Hz, 1 H, H-7eq), 1.84-1.92 (m, 1 H, H-7ax), 1.98 (td, J =
2 2
Cl . The resulting filtrate was
[
3]
(
1
2
2
3
3
(
1
2
1
3
3.6, 4.4, 1 H, H-6ax), 2.11 (dddd, J = 12.8, 6.4. 6.4, 3.2 Hz, 1 H, H-3a),
.26–2.35 (m, 1 H, H-3), 2.47 (t, J = 9.6 Hz, 1 H, H-2), 2.65 (t, J = 9.6 Hz,
[
4]
2
H, H-2), 2.79 (q, J = 3.2 Hz, 1 H, H-7a), 3.23 (d, J = 14 Hz, 1 H, CH Ph),
1
3
.95-4.00 (m, 5 H, OCH
): δ = 13.6 (CH
), 34.2 (C-3), 41.8 (C-3a), 58.0 (CH
2
and CH
2
Ph), 7.17–7.32 (m, 5 H, PhH) ppm.
), 24.1 (C-7), 29.0 (C-6), 31.6 (C-
Ph), 59.1 (C-2), 62.7 (C-7a), 64.0
2
), 110.1 (C-5), 126.5, 128.1, 128.2, and 140.7 (Ph) ppm.
C
NMR (100 MHz, CDCl
3
3
4
2
and 64.3 (OCH
+
2
HRMS (ESI): m/z calcd for C18H26NO [M+H] 288.1958; found 288.1959.
3
519-3521; N. Uesaka, M. Mori, K. Okamura, T. Date, J. Org. Chem.
994, 59, 4542-4547; e) Bu SnH-promoted acrylamides tethered
(
3RS,7SR,7aSR)-3-Methyloctahydroindol-5-one ethylene ketal (18):
1
3
Amine 17 (73 mg, 0.25 mmol, 1.0 equiv.) was dissolved in MeOH (2.5
alkenes: A. F. Parsons, D. A. J. Williams, Tetrahedron 1998, 54, 13405-
3420; f) For iron-catalyzed redox radical cyclization of 1,6-dienes, see:
T. Taniguchi, N. Goto, A. Nishibata, H. Ishibashi, Org. Lett. 2010, 12,
mL) and Pd/C (15 mg, 20% w/w) was added. The resulting suspension
1
was stirred under 1 atm of H
reaction mixture was filtered through Celite , concentrated, and purified
by chromatography (CH Cl /MeOH, 99:1 to 90:10) to afford 18 (50 mg,
nearly quantitative) as a brown oil. H NMR (400 MHz, CDCl
2
at room temperature. After 24 h, the
®
1
7
12-115; g) S. Dorich, J. R. Del Valle, S. Hanessian, Synlett 2014, 25,
2
2
99–804. h) For cyclization of cyclohexene-tethered 2-enynamides
1
3
): δ = 0.93
2
using FeX , see: M.-C. P. Yeh, Y.-S. Shiue, H.-H. Lin, T.-Y. Yu, T.-C.
(
d, J = 7.2 Hz, 3 H, CH ), 1.35 (t, J = 13.0 Hz, 1 H, H-4ax), 1.48–1.54 (m,
3
Hu, J.-J. Hong, Org. Lett. 2016, 18, 2407-2410.
2
1
2
H, H-4eq and H-6eq), 1.73–1.81 (m, 2 H, H-7), 1.89 (tt, J = 14.0, 4.0 Hz,
H, H-6ax), 2.06 (dq, J = 12.6, 5.2 Hz, 1 H, H-3a), 2.16 (br s, 1 H, NH),
.32-2.44 (m, 1 H, H-3), 2.62 (t, J = 10.4 Hz, 1 H, H-2), 3.14 (t, J = 10.4
[
[
5]
6]
For synthesis of enamides by acylation of imines with haloacetyl
chlorides, see: a) J. Cassayre, B. Quiclet-Sire, J.-B. Saunier, S. Z. Zard,
Tetrahedron 1998, 54, 1029-1040; b) A. J. Clark, D. P. Curran, D. J.
Fox, F. Ghelfi, C. S. Guy, B. Hay, N. James, J. M. Phillips, F. Roncaglia,
P. B. Sellars, P. Wilson, H. Zhang, J. Org. Chem. 2016, 81, 5547-5565.
For radical cyclyzation of analog haloacetamides leading to 3-
unsubstituted hydroindoles, see: a) O. Tamura, H. Matsukida, A. Toyao,
Y. Takeda, H. Ishibashi, J. Org. Chem. 2002, 67, 5537-5545; b) D. P.
Curran, D. B. Guthrie, S. J. Geib, J. Am. Chem. Soc. 2008, 130, 8437-
8445; c) D. B. Guthrie, K. Damodaran, D. P. Curran, P. Wilson, A. J.
Clark, J. Org. Chem. 2009, 74, 4262-4266.
2
Hz, 1 H, H-2), 3.28 (q, J = 4.0 Hz, 1 H, H-7a), 3.93–3.97 (m, 4 H, OCH )
1
3
ppm. C NMR (100 MHz, CDCl
3
): δ = 13.1 (CH
0.4 (C-4), 37.9 (C-3), 41.1 (C-3a), 51.5 (C-2), 56.8 (C-7a), 64.2 and
4.3 (OCH ), 109.4 (C-5) ppm. HRMS (ESI): m/z calcd for C11
3
), 25.7 (C-7), 28.6 (C-6),
3
6
2
H20NO
2
+
[
M+H] 198.1489; found 198.1487.
(
3RS,3aSR,7aSR)-3-Methyloctahydro-5H-indol-5-one (19): Ketal 18
40 mg, 0.20 mmol, 1.0 equiv.) was dissolved in HCl (10%) (1 mL) and
stirred at room temperature. After an overnight stirring, the resulting
solution was extracted with CH Cl , quenched with a saturated solution of
Na CO and extracted with CHCl :iPrOH (4:1). The resulting organic
layer was dried and concentrated to afford 19 (31 mg, near quantitative)
(
[7]
[8]
[9]
M. V. Riofski, J. P. John, M. M. Zheng, J. Kirshner, D. A. Colby, J. Org.
Chem. 2011, 76, 3676-3683.
2
2
2
3
3
For stereochemical elucidation of cis-trans octahydroindoles, see: D.
Solé, J. Bosch, J. Bonjoch Tetrahedron 1996, 52, 4013-4028.
G. Stork, R. Mook, J. Am. Chem. Soc. 1987, 109, 2829-2831.
1
as an amorphous orange solid. H NMR (400 MHz, CDCl
3
): δ = 0.94 (d, J
=
6.4 Hz, 3 H, CH
3
), 1.95 (dddd, J = 12.8, 6.4, 6.4, 3.2 Hz, 1 H, H-7eq),
[10] For radical cyclizations initiated by intermolecular radical addition to
alkynes, see: U. Wille, Chem. Rev. 2013, 113, 813-853.
[11] The non-cyclized allyl derivative depicted below was also isolated in
30% yield.
2
.04 (m, 1 H, H-7), 2.09 (td, J = 6.0, 6.0, 1.6 Hz, 1 H, H-6), 2.12 - 2.16 (m,
H, H-4), 2.18 (br s, 1H, NH), 2.33 – 2.39 (m, 3 H, H-4, H-3, H-3a), 2.57
2.63 (m, 1 H, H-6), 2.68 (t, J = 9.2 Hz, 1 H, H-2), 3.19 (dd, J = 10.0, 9.2
1
–
1
3
Hz, 1 H, H-2), 3.52 (br s, 1 H, H-7a).
C NMR (100 MHz, CDCl
3
): δ =
COCF3
N
1
5
3.3 (CH
1.8 (C-2), 56.9 (C-7a), 213.6 (C-5). HRMS (ESI): m/z calcd for C
3
), 28.6 (C-7), 35.9 (C-6), 37.9 (C-4), 38.2 (C-3), 42.1 (C-3a),
9
H16NO
+
[
M+H] 154.1226; found 154.1224.
O
O
[
12] (a) G. Stork; P. M. Sher; H.-L- Chen, J. Am. Chem. Soc. 1986, 108,
6384-6385. (b) A. Srikrishna; R. Viswajanani, C. V. Yelamaggad,
Tetrahedron 1997, 53, 10479-10488.
Acknowledgements
[
[
3
13] We also observed that when using long-stored Bu SnH, a mixture of
Financial support for this research was provided by the Projects
CTQ2013-41338-P and CTQ2016-75350-P from the Ministry of
Economy and Competitiveness of Spain/ FEDER funds and the
FP7 Marie Curie Actions of the European Commission via the
ITN ECHONET Network (MCITN-2012–316379).
cis- and trans-hydroindoles 8 and 9 was isolated.
14] a) 1,5-enynes allows the 5-membered ring formation via gold-catalyzed
-endo-dig cycloisomerizations: R. Dorel, A. M. Echavarren, Chem.
5
Rev. 2015, 115, 9083-9072. b) For regioselective 6-endo-dig
cyclizations of N-propargyl enamine derivatives using gold- and
rhodium-catalyzed reactions, see: G. Abbiati, A. Arcadi, G. Bianchi, S.
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European Journal of Organic Chemistry
10.1002/ejoc.201700086
FULL PAPER
Di Giuseppe, F. Marinelli, E. Rossi, J. Org. Chem. 2003, 68, 6959-6866.
c) H. Kim, C. Lee, J. Am. Chem. Soc. 2006, 128, 6336-6337.
[
15] For cyclization of tethered alkyne enamides in a 5-exo process, see: a)
B. Alcaide, I. M. Rodríguez-Campos, J. Rodríguez-López, A.
Rodríguez-Vicente, J. Org. Chem. 2004, 64, 5377-5387; b) reference
4
g.
[
[
16] For tethered alkyne imines, see: J. A. Pigza, J.-S. Han, A. Chandra, D.
Mutnick, M. Pink, J. N. Johnston, J. Org. Chem. 2013, 78, 822-843.
17] For
a discussion about NMR data of Z/E rotamers in nitrogen-
containing rings with an exocyclic amide of carbamate function, see: a)
N. Valls, V. M. Segarra, J. Bonjoch, Magn. Reson. Chem. 1991, 29,
9
85-992; b) N. Valls, M. López-Canet, M. Vallribera, J. Bonjoch, Chem.
Eur. J. 2001, 7, 3446-3460.
1
[
[
18] For the analysis of coupling constants in
H NMR in substituted
cyclopentanes, see: G. M. Constantino, G. V. J. da Silva, Tetrahedron
988, 54, 11363-11374.
1
19] Rueping has observed that when starting from 4,4-disubstituted
aminocyclohexenes leading to 5,5-disubstituted octahydroindoles, the
process took place with lower yields than with other types of substrates
in the same reaction conditions. See reference 4c.
[
[
20] For the influence of the halogen atom in the 5-endo radical cyclization
of haloacetamides leading to octahydroindoles, see reference 6b.
21] M. Kojima, T. Tomioka, Chem. Pharm. Bull. 1976, 24, 1613-1620. For
3
-methyl trans-octahydroindol-2-ones, see also: W. J. Nodes, D. R.
Nutt, A. M. Chippindale, A. J. A. Cobb, J. Am. Chem. Soc. 2009, 131,
6016-16017.
1
1
[
22]
3
H NMR (400 MHz, CDCl ): δ = 1.84 (tt, J = 6.8, 1.2 Hz, 2 H), 1.90 (tt, J
=
7.2, 0.8 Hz, 2 H), 2.29 (t, J = 2.4 Hz, 1 H), 2.48 (m, 4 H), 4.00 (s, 4 H),
.26 (d, J = 2.4 Hz, 2 H).
4
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European Journal of Organic Chemistry
Bn
10.1002/ejoc.201700086
O
O
R
O
X
R
R
e
l
Bn
N
O
N
N
N
O
N
H
H
H
Cl
Me
Me
FULL PAPER
H
H
R =TFA
O
O
O
O
hydrogenation
radical cyclization
FULL PAPER
Radical Cyclizations
Sergi Jansana, Guilhem Coussanes,
Faïza Diaba, Josep Bonjoch*
Page No. – Page No.
Radical cyclizations in the Synthesis
of 3-Methyl-cis-octahydroindol-5-
ones
Stereoselective syntheses of 3-methyl-cis-octahydroindoles through a 5-endo-trig
radical cyclization followed by an hydrogenation step were achieved from either an
alkyne tether enamide or
a
N-alkenyl-2,2-dichloropropanamide. 1,5-Enyne
cyclizations via a 5-endo-trig process are reported, in which a remote functional
group (ketone or ketal) allowed the diastereoselectivity in the octahydroindole ring
formation to be overturned.
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