Experimental and computational study of 6- Exo and 7- Endo cyclization of aryl radicals followed by Tandem SRN1 Substitution

Article abstract of DOI:10.1021/jo4001788

The reaction of N-allyl-N-(2-halobenzyl)-acetamides and derivatives was investigated in liquid ammonia under irradiation with the nucleophiles Me ₃Sn^-, Ph₂P^- and O ₂NCH₂^-. Following this procedure, novel substituted 2-acetyl-1,2,3,4-tetrahydroisoquinolines and substituted 2-acetyl-2,3,4,5-tetrahydro-1H-benzo[c]azepines were obtained in good yields. These reactions are proposed to occur through the intermediacy of aryl radicals, which by intramolecular 6-exo or 7-endo attack to a double bond cyclize to give aliphatic radicals, which react along the propagation steps of the S _RN1 chain cycle to afford the cyclic substituted compounds as main products. The reactions were modeled with DFT methods, which provide a rational understanding that relates the product distribution to the structure of the aliphatic radicals proposed as intermediates and the kinetic of their formation.

Full text of DOI:10.1021/jo4001788

Article
pubs.acs.org/joc
Experimental and Computational Study of 6-exo and 7-endo
Cyclization of Aryl Radicals Followed by Tandem SRN1 Substitution
Lucas E. Peisino and Adriana B. Pierini*
INFIQC, Departamento de Química Organ
́ ́
ica, Facultad de Ciencias Químicas, Universidad Nacional de Cordoba, Ciudad
Universitaria, 5000 Cordoba, Argentina
́
S
* Supporting Information
ABSTRACT: The reaction of N-allyl-N-(2-halobenzyl)-acet-
amides and derivatives was investigated in liquid ammonia
under irradiation with the nucleophiles Me3Sn−, Ph2P− and
−
O2NCH2 . Following this procedure, novel substituted 2-
acetyl-1,2,3,4-tetrahydroisoquinolines and substituted 2-acetyl-
2,3,4,5-tetrahydro-1H-benzo[c]azepines were obtained in good
yields. These reactions are proposed to occur through the
intermediacy of aryl radicals, which by intramolecular 6-exo or
7-endo attack to a double bond cyclize to give aliphatic radicals,
which react along the propagation steps of the SRN1 chain cycle
to afford the cyclic substituted compounds as main products.
The reactions were modeled with DFT methods, which
provide a rational understanding that relates the product distribution to the structure of the aliphatic radicals proposed as
intermediates and the kinetic of their formation.
azaheterocycles (phenanthridines,4,5 pyrroles, indoles, and
INTRODUCTION
■
pyrazoles;6 3-benzazepin-2-ones;7 2-pyrrolyl and 2-indolyl
benzoxazoles8), among others.
The radical nucleophilic substitution, or SRN1 mechanism, is a
chain process through which a nucleophilic substitution is
obtained with radicals and radical anions as intermediates.1 The
scope of this process has been considerably expanded, and
nowadays it stands as an important route to achieve the
substitution of aromatic and aliphatic compounds that do not
react by polar processes. Several nucleophiles can be used such
as carbanions and anions from compounds bearing heter-
oatoms, which react to form new C−C or C−heteroatom
bonds at good yields. Many substituents are compatible with
the reaction.1
Intramolecular addition of aryl radicals to double bonds has
also been widely studied.9,10 As shown in Scheme 2, the general
Scheme 2
The propagation steps of the mechanism (for an aromatic
substrate) are presented in Scheme 1. The process requires an
initiation step, irradiation being one of the most frequently
used.
The easy access to heterocyclic compounds under mild
reaction conditions is one of the most attractive aspects of this
process.2 For example, it has been shown to be an excellent
method for the preparation of isoquinolinones,3 fused
synthetic strategy involves the generation of intermediate
radical 1, which rearranges to the exo-cyclic radical 2 by 5-exo
(n = 1) or 6-exo (n = 2) cyclization. Radical 2 is then trapped
with hydrogen donors to yield the reduced compounds 3-r, or
with other reagents to obtain the substituted compound 3-s.
Although this general scheme is a useful protocol to obtain
carbon and heterocyclic compounds, there are only few
examples in which the cyclization step occurs along the
Scheme 1
Received: January 25, 2013
Published: April 17, 2013
© 2013 American Chemical Society
4719
dx.doi.org/10.1021/jo4001788 | J. Org. Chem. 2013, 78, 4719−4729

The Journal of Organic Chemistry
Article
propagation chain of the SRN1 reaction. Related to this, Vaillard
et al. have demonstrated that tandem 5-exo cyclization-SRN1
reactions of aryl halides containing an o-oxyallyl or aminoallyl
moiety are useful for the preparation of substituted
dihydrobenzofurans, dihydronaphthofurans and indolines (eq
4).11
Scheme 4
The slower 6-exo cyclization has been studied to a lesser
extent,12,13 with Bardagı et al. focusing on the synthetic aspects
has been informed, with 7-endo being the principal cyclic
product, accompanied by the opened reduction compound as
main reaction product (Scheme 5).18
́
of this reaction, obtaining 4-substituted chromanes and 4-
substituted benzo[ f ]chromanes (eq 5).14
Scheme 5
In these systems, the product distribution is given by the
relative rate of the exo and endo cyclizations, with the exo mode
(5-exo or 6-exo) being faster than the endo ring closure (6-endo
or 7-endo respectively, see Scheme 3).
The absolute values of the rate constants for the reactions of
aryl radicals with nucleophiles have been determined electro-
chemically for a large number of cases, with most of these
values being close to the diffusion limit. For instance, the rate
constants for the coupling of 2-, 3-, or 4-cyanophenyl; 1-
naphthyl; 3-pyridyl; and 3- and 4-quinolyl radicals with PhS−,
Scheme 3
−
(EtO)2PO−, and MeCOCH2 ions are of the order 109−1010
19
M−1 s−1 in NH3(l)
,
and the rate constant for the ring closure
reaction of o-allyloxy phenyl radical is 4.9 × 108 s−1 (in
benzene, at 50 °C).20 The fact that the ring-closure reaction is a
unimolecular process, and therefore does not depend on the
nucleophile concentration (in contrast with the coupling
reaction), led us to propose that under dilute reaction
conditions it could be possible to obtain substituted 1,2,3,4-
tetrahydroisoquinolines and 4,5-dihydro-1H-benzo[c]azepin-
2(3H)-yl ethanone by tandem cyclization-SRN1 reactions
using N-allyl-N-(2-halobenzyl)-acetamides derivates as starting
materials.
1,2,3,4-Tetrahydroisoquinoline moiety is a ubiquitous
structural core present in a number of alkaloid natural
products,21 which exhibit very good biological activities, such
as antitumor,22 antimicrobial,23 anti-inflamatory,24 anti-HIV,25
and analgesic26 activities. Benzazepine possesses a 7-membered
aza-heterocyclic ring-fused aromatic unit, a framework that is
often observed among bioactive natural products and
pharmaceuticals.27,28 For example, paullones have shown
cyclin-dependent kinase inhibitory activity and sirtuin inhib-
itory activity.28
Few reports have been published related to the aryl radical
cyclization of enamine derivates. In these studies, exo or endo
derivates have been obtained by changing the structure of the
bridge (between the aryl radical center and the double bond).
For example, the treatment of compound 4 with Bu3SnH and
1,1′-azobis(cyclohexanecarbonitrile) (ACN), has afforded a
mixture of the six- and seven-membered lactams (48% yield) at
a 3:1 ratio (Scheme 4).15 On the other hand, compound 5 gave
only the seven-membered product.15 A 7-endo cyclization by
intramolecular addition of an aryl radical to an enamide double
bond has also been informed by Rigby et al.16
́
De la Fuente and Domınguez carried out the synthesis of
pyrrolo- and pyrido[1,2-a]xanthene[1,9-de]azepines by a 7-endo
radical cyclization.17 Recently, a mechanistic study of the 7-endo
cyclization of compound 6 by treatment with Bu3SnH/AIBN
Moreover, the substituents present in the target compounds
(Me3Sn, Ph2P, O2NCH2) offer the possibility to produce
further modifications via the Stille reaction in the case of the tin
4720
dx.doi.org/10.1021/jo4001788 | J. Org. Chem. 2013, 78, 4719−4729

The Journal of Organic Chemistry
Article
compounds or via classical transformations in the case of the
nitro derivatives, while the phosphine compounds present an
important role in organic synthesis.
N-Allyl-N-(2-chlorobenzyl)-acetamide (8a) reacted with
Me3Sn− ions to furnish the cyclized-substituted compounds
14a-exo and 15a-endo at 50 and 26% yields, respectively (Table
1, entries 1,2).
RESULTS AND DISCUSSION
The photostimulated reaction of 9a gave compound 17a-
endo at high yields (65%). The main product was
uncontaminated by the 6-exo cyclization product (Table 1,
entry 7). On the other hand, the product from 7-endo
cyclization was not observed by reaction of 10a; the major
product was 18a-exo (54% yield), formed by 6-exo cyclization
with cis fused rings (Table 1, entry 10).31 Substitution products
22a and 23a (Chart 1), derived from hydrogen abstraction
from C6 and C7 (from the radical center) of the cyclohexene
ring (see Figure 2), were also formed in the reaction.
The products obtained and the lack of reaction under dark
conditions (Table 1, entries 3, 11) were taken as evidence of
the formation of aryl radicals as intermediates and the operation
of an SRN1 type reaction. Moreover, the photostimulated
reaction is inhibited by m-dinitrobenzene, a well-known
inhibitor of SRN1 reactions (1, entry 4).1
■
The nucleophilic substitution of allylamines with benzyl-
chloride (or benzylamines with allylbromide) has been
previously described as a synthetic method to obtain benzyl
allylamines.29 Here, the procedure was used to prepare o-
halobenzylallylamines. The reaction of 2-chlorobenzylchloride
with allylamine in the presence of Na2CO3 as base was carried
out to obtain N-allyl-N-(2-chlorobenzyl)-amine (7a) in isolated
yield of 72%. In order to produce the acetamide derivate, the
crude was treated with acetic anhydride, with product 8a being
isolated at 53% of the overall yield. Following the same
procedure, the corresponding N-allyl-N-(2-halobenzyl)-acet-
amides (8b, 9a, 9b, 10a and 11a) were produced at about 50%
of the isolated yield (Scheme 6).
Scheme 6
Encouraged by the results obtained with the tin nucleophile,
−
the study was extended to include the Ph2P− and O2NCH2
anions, known to be good nucleophiles in SRN1 reactions.1 After
irradiation of an NH3(l) solution of Ph2P− ions with substrates
8a−10a followed by oxidation, the corresponding phospine
oxides were obtained at similar yields to the products formed
with Me3Sn− anions (Table 1, entries 5, 8, 12).
−
Within the carbanions family, it is known that O2NCH2 ,
unable to initiate the SRN1, is one of the most reactive anions in
the coupling with radicals.32 In other to achieve subtitution
with this anion, the reaction of 8a and 9b (bromine as leaving
group) were performed in the presence of acetone enolate
anion as the entrainment reagent (which enables SRN1 initiation
−
but cannot compete with O2NCH2 in the coupling to the
methylene radical formed by cyclization).1 As with Me3Sn− and
Ph2P− ions, a mixture of 6-exo and 7-endo cyclization products
was obtained with 8b, while 7-endo cyclization was the only ring
closure mode obtained with 9b (Table 1, entries 6, 9).
These reactions resulted in the formation of two new C−C
bonds, with the nitro group in the tethered chains rendering
products of interest for further synthetic transformations, which
extends the scope of the reactions.33
The mechanism proposed for these reactions is presented in
Scheme 7 for compound 8a as representative. Upon irradiation,
8a receives an electron from the nucleophile to form its radical
anion. This intermediate fragments to give radical 8•, which
cyclizes to afford radicals 14-exo• (exo-cyclization) and 15-endo•
(endo-cyclization). These radicals ultimately produce the
products 14a-exo and 15a-endo, respectively, through the
intermediary of their corresponding radical anions (Scheme
7). Under our reaction conditions, the products arising via
direct coupling of the nucleophile with the aryl radicals were
detected at a maximum yield of 10% (see Scheme 7).
When compound 7a was allowed to react with Me3Sn− ions,
low yields of cyclic substituted products (12a-exo and 13a-
endo) were obtained (ca. 30% overall yield, eq 6). In this
reaction, products from fragmentation of 7a were also
observed.
In the irradiated reaction of substrate 11a with Me3Sn− ions,
the reduced exocyclic product 20 (18% yield) and an
unresolved mixture of alkenes 21 (13% yield) were formed
(Scheme 8) (reaction time = 15 min, 44% of 11a recovered). A
longer irradiation time (60 min) was required for the complete
conversion of the substrate to products.34 In this reaction,
radical 11• would be formed. Its preferred 6-exo cyclization
mode will form a very unreactive tertiary exocyclic radical,
whose coupling reaction with the anion was disfavored.35 As
In order to protect the substrates and to avoid their possible
deprotonation under the basic reaction media,30 all further
studies were performed with the acetamides derivatives 8-11.
The results of the photostimulated reaction of compounds 8−
10 in NH3(l) with the nucleophiles under study are presented in
Table 1.
4721
dx.doi.org/10.1021/jo4001788 | J. Org. Chem. 2013, 78, 4719−4729

The Journal of Organic Chemistry
Article
a
Table 1. Photochemical Reactions of Compounds 8−10 in NH3(l) with Me3Sn−, Ph2P−, O2NCH2 Anions
−
a
Photostimulated reactions were performed with [substrate] = 1.66 × 10−3 M and [Nu−] = 1.83 × 10−3 M. Reaction times: Me3Sn− (15 min);
−
Ph2P− (60 min); O2NCH2 (240 min). Irradiation was conducted in a reactor equipped with two high pressure lamps model Philips HPI-T plus
400-W, CH3I contaminated (air- and water-refrigerated) with maximum emission at 530 nm. Yields of cyclic substituted products were determined
by GC using the internal standard method unless otherwise indicated. In all the reactions, the product from direct attack of the nucleophile to the
b
aryl radical was formed at a maximun 10% yield. Formed by hydrogen abstraction of the aryl radicals intermediates. Relative yields by GC area.
c
d
e
[substrate] = 8.3 × 10−4 M and [Nu−] = 9.2 × 10−4 M. Dark conditions. Only unreacted substrate was detected. To the solution was added 20
f
g
−
−
mol % m-dinitrobenzene; 8a was recovered in 88% yield. Yields determined by 31P NMR. [O2NCH2 ] = 5.00 × 10−3 M and [CH3C(O)CH2 ] =
h
i
3.33 × 10−3 M. Irradiation time = 4 h. Byproducts 22a (12%) and 23a (23%). Byproducts 22b and 23b, not quantified.
Chart 1
Scheme 7
shown in Scheme 8, this radical may abstract hydrogen from
the solvent or may form the alkenes mixture by hydrogen loss.
In order to rationalize our experimental results, a computa-
tional study with the DFT method (B3LYP-D and B3LYP
functionals) and the 6-31+G* basis set was carried out to
model the 6-exo and 7-endo ring closure of the aryl radicals
proposed as intermediates of our reactions. In Figure 1, the
potential energy surface (PES) for the cyclization of radical 8•
is presented accompanied by the structure and unpaired spin
density of the radical intermediates and their respective
transition state.36
To evaluate the validity of our calculations and to establish a
relationship between the nature of the bridge and the
regiochemistry of the cyclization, we also studied the cyclization
mode of a series of radicals derived from compounds of known
experimental reactivities (Chart 2).14−16,18
4722
dx.doi.org/10.1021/jo4001788 | J. Org. Chem. 2013, 78, 4719−4729

The Journal of Organic Chemistry
Article
experimental cyclization mode. With the exception of 8•,
B3LYP gave, in general, better exo:endo ratios.
Scheme 8
The difference in rate constants for the exo-endo cyclization
of 8• was estimated to be less than 1 order of magnitude
(B3LYP-D, Table 2, entry 1). As indicated by this ratio, the 6-
exo ring closure was favored over the 7-endo mode, in
agreement with the experimental outcome of the reaction.
The regiochemistry for the cyclization of 9• was also predicted
from the calculations, with the 7-endo ring closure being favored
over the 6-exo by 1.20 or 2.13 kcal/mol (B3LYP-D and B3LYP
respectively, Table 2, entry 2). A 6-exo cyclization was proposed
as preferred for radicals 11• (Table 2, entry 3), as shown in the
experiment (see Scheme 8).
The conformational PES for radical 10• was very complex
(see Supporting Information). 40% of the conformers
population corresponded to structures suitable for attacking
the double bond, and another 40% were adequate for a
hydrogen abstraction from the cyclohex-2-enyl moiety
(Supporting Information). With respect to the first reaction,
more than 99% of the conformers (according to a Maxwell−
Boltzman distribution) were suitable for 6-exo cyclization
(Supporting Information).
We also analyzed the hydrogen abstraction from C6 and C7
of the cyclohexene ring (Figure 2). For three conformers,
hydrogen abstraction from C6 was possible under an average Ea
of 3.65 kcal/mol. In contrast, for the remaining four conformers
hydrogen abstraction from C7 was possible with an average Ea
of 2.37 kcal/mol (Supporting Information). These calculations
were in agreement with the 12 and 23% product yields derived
from 6- and 7-hydrogen abstraction, respectively.
We were able to correctly predict the regiochemistry of the
cyclization reaction of radicals 24• and 25•. Thus, the
calculations agreed with the experimental outcome of the
reaction presented in eq 5 (see also Table 2), in which only the
exocyclic products are formed (at 56 and 90% yield,
respectively).14 The differences in the rate constants calculated
favored the 6-exo mode by approximately 2 orders of
magnitude.
When radical 26• is formed in toluene at reflux, the only
cyclization product is the 7-endo.16 The rate constant for this
cyclization was estimated to be higher than that of the 6-exo
mode (by approximately 3 orders of magnitude, Table 2, entry
6). Radicals 27a•−27d• and 28a•−28d• in reflux toluene
cyclize to give 7-endo radicals.15 The calculated rate constant
ratios reflected these experimental observations (Table 2,
entries 7−14).
Figure 1. Schematic energy profile for the cyclization reaction. The
aryl radical can cyclize in the exo or endo mode.
Chart 2
Interestingly, in our experimental system the 6-exo
cyclization is the preferred pathway whenever a tertiary or
primary exocyclic radical is formed. The latter is the behavior
observed in the reaction of substrate 8a•, in which the 6-exo
cyclization leading to a primary radical prevails over the 7-endo
cyclization leading to an endocyclic secondary radical. For this
type of unsubstituted bridge, the structural stabilization of the
TS in which a six-member ring is being formed may be a key
factor in determining the regiochemistry of the reaction. A
similar profile has been observed with radicals 24• and 25•.
On the other hand, the 7-endo cyclization is the regiospecific
mode when a tertiary endocyclic radical is formed. The same
behavior has been reported for radical 26•. The 7-endo
cyclization of this radical occurs through a TS in which the
unpaired spin density is stabilized by the adjacent π system as
shown in Figure 3, in which the distribution of the unparied
spin density is shown. A similar situation is observed for radical
The ΔΔE‡exo−endo values calculated for the reactions are shown
in Table 2. On the basis of the information presented in the
table, it can be concluded that the relative activation energy
(Ea) of each cyclization mode controls the preferred
regiochemistry of the cyclization. For all the cases under
study, both B3LYP-D and B3LYP predicted the preferred
4723
dx.doi.org/10.1021/jo4001788 | J. Org. Chem. 2013, 78, 4719−4729

The Journal of Organic Chemistry
Article
a
Table 2. Activation Energy Difference of 6-exo and 7-endo Cyclization Modes (kcal/mol)
b
ΔΔE‡exo−endo
B3LYP-D
estimated kexo/kendo
entry
radical
B3LYP
B3LYP-D
B3LYP
% of exo:endo cyclization experimental outcome
c
c
1
8•
−0.67
1.20
−1.51
2.13
4
24
67:33
:100
100:
100:
100:
:100
3:97
c
c
2
9•
8.0 × 10−2
1.1 × 10−2
c
c
3
11•
−2.70
−2.61
−3.08
4.65
−5.75
−2.84
−3.09
4.31
3.0 × 102
1.8 × 105
c
c
4
24•
2.5 × 102
3.9 × 102
c
c
5
25•
6.5 × 102
6.6 × 102
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
6
26•
2.2 × 10−3
2.8 × 10−1
1.2 × 10−1
1.3 × 10−1
8.8 × 10−3
4.8 × 10−2
1.1 × 10−1
1.0 × 10−1
3.8 × 10−2
3.4 × 10−3
1.3 × 10−1
8.3 × 10−2
8.9 × 10−2
2.8 × 10−3
7.5 × 10−3
5.8 × 10−4
4.0 × 10−3
1.3 × 10−3
7
27a•
27b•
27c•
27d•
28a•
28b•
28c•
28d•
0.97
1.53
8
1.60
1.88
:100
9
1.57
1.83
2:98
10
11
12
13
14
3.59
4.45
6:94
2.30
3.71
3:97
1.65
5.66
:100
:100
:100
1.75
4.17
2.57
5.04
‡
exo−E‡endo
a
b
B3LYP-D or B3LYP/6-31+G*. Implicit solvent, polarized continuum model. kexo/kendo= e−(E
)/RT, assuming equal frequency factor. R = 1.98 ×
c
d
10−3 kcal mol−1 K−1, with the temperature depending on solvent. Solvent = methanol, T = 240.5 K. Solvent = toluene, T = 383.3 K.
compound 9 is 7-endo regiospecific (53−65% yields). The
products distribution depended strongly on the bridge between
the radical center and the double bond. Moreover, we
demonstrated that the regiochemistry of the radical ring
closure could be controlled by changing the substitution at
the double bond (see Table 1). In addition, this regiochemistry
was determined by the stabilization of the transition states for
each cyclization (exo or endo) mode. Mainly two factors seem
to affect the relative stability of the transition states of our
experimental type system (nonresonance stabilization of the
cyclization TS): the conformation effect (Baldwin’s rule) and
the stability of the radical being formed. Exo-cyclization to
Figure 2. Conformers of radical 10• suitable for hydrogen abstraction
reaction.
primary, secondary or tertiary radicals is preferred over endo-
cyclization to secondary radicals. In the first case, the
conformation factors compensate the lower stability of a
primary radical and the reaction is partially selective. In the
second two cases, conformation and radical stability factors are
responsible for a regiospecific exo-cyclization. On the other
hand, the stability of a tertiary-endocyclic radical overcomes
conformational factors, and its formation is always the preferred
one.
Computational calculations were used to predict the product
distribution, which may be employed to predict the
regiochemical outcome of similar type of reactions.
EXPERIMENTAL SECTION
■
Figure 3. 7-endo cyclization TS. The spin density is delocalized over
Computational Procedure. All the calculations were performed
using the Gaussian09 program, the B3LYP and B3LYP-D37 DFT
the π system.
functional and the 6-31+G* basis set. For the hydrogen abstraction
reaction, the 6-31++G** basis set was used. Calculations were
27, for which the 7-endo cyclization is the regiospecific mode.
This pathway leads to an endocyclic secondary radical stabilized
by the π system of the adjacent substituent as shown in Figure
3.
performed with full geometry optimization, including in all cases the
effect of the solvent through the Tomasi’s polarized continuum model
(PCM)38 as implemented in Gaussian09. The effect was evaluated
using methanol as model polar solvent.5 The transition states (TS)
and intermediates were localized by a scan of the distinguished
reaction coordinate. After refinement, the characterization of stationary
points was done by Hessian matrix calculations, with all positive
eigenvalues for a minimum and only one negative eigenvalue for the
TSs. The energy reported for all species includes zero-point
corrections.
CONCLUSIONS
■
In this work the synthesis of 11 novel heterocycles substituted
by Me3Sn, Ph2P and O2NCH2 groups has been achieved. In the
reaction of compounds 8 the exo-cyclization prevails (50%
yield), accompanied by the product from 7-endo cyclization
(25% yield). Regiospecific 6-exo cyclization was obtained with
compound 10 (39−54% yield), while the cyclization of
General Methods. The internal standard method was used for
quantitative GC analysis with authentic samples, and the following
column was employed: (30 m × 0.32 mm ID DF = 0.25 column). The
4724
dx.doi.org/10.1021/jo4001788 | J. Org. Chem. 2013, 78, 4719−4729

The Journal of Organic Chemistry
Article
phosphorus containing products products were quantified by 31P
NMR. All NMR spectra were obtained on a 400 MHz spectrometer
(1H NMR (400 MHz), 13C NMR (100 MHz), 31P NMR, 119Sn NMR,
COSY, HSQC, HMBC and NOE) using CCl3-d as a solvent unless
otherwise indicated. The coupling constants (J) are given in hertz.
GC−MS analyses were carried out on a GC apparatus coupled with a
mass selective detector and a DB-5 (30 m × 0.25 mm ID) capillary
column. High-resolution mass spectra were recorded on a TOF
analyzer, using an ESI source in a positive mode, with nitrogen as the
nebulizing and drying gas and sodium formiate (10 mM) as the
internal calibrant.
Materials. Trimethyl tin chloride, triphenylphosphine, nitro-
methane, potassium t-butoxide and t-butanol were obtained from
commercial sources. Acetone and nitromethane were double distilled
and stored under nitrogen over 4 Å molecular sieves. To prepare the
substrates, commercially available 2-chlorobenzyl chloride, 2-bromo-
benzyl bromide, 2-iodobenzyl chloride, allyl bromide, allyl amine, 2-
methylallyl bromide and 3-dimethylallyl bromide were used. In
addition, 2-chlorobenzyl amine and 2-bromobenzyl amine were
prepared from 2-chlorobenzyl chloride and 2-bromobenzyl bromide,
respectively, by substitution reaction with an excess of 38%
ammonium hydroxide solution.39 The compound 3-bromocyclohex-
ene was prepared as previously reported.29 Silica gel (0.063−0.200
mm) was used in column chromatography and on 2 mm plates (silica
gel 60 PF254) in radial thin-layer chromatography purification. All
solvents were of analytical grade and used as received from the
supplier.
3H); 3.87 (br d, 1H, J = 4.9 Hz, overlapping); 4.03 (br d, 1H, J = 6.0
Hz, overlapping); 4.70 (s, 2H); 5.18 (m, 2H, overlapping); 5.78 (m,
1H, overlapping); 7.07−7.38 (clpx. m, 3H, overlapping); 7.53 (d, 1H, J
= 7.9 Hz). Minor isomer δH: 2.08 (s, 3H); 3.87 (br d, 1H, J = 4.9 Hz,
overlapping); 4.03 (br d, 1H, J = 6.0 Hz, overlapping); 4.52 (s, 2H);
5.18 (m, 2H, overlapping); 5.78 (m, 1H, overlapping); 7.07−7.38
(clpx. m, 3H, overlapping); 7.58 (d, 1H, J = 7.9 Hz). 13C NMR (100
MHz, CDCl3) major isomer δC: 21.3; 48.3 (overlapping); 50.5; 117.0;
122.7; 127.7; 128.7; 129.1; 132.2; 132.8; 135.6; 171.3. Minor isomer
δC: 21.5; 48.3 (overlapping); 51.6; 117.8; 123.6; 126.9; 127.9; 129.0;
132.7; 133.2; 136.5; 171.2. m/z (%): 56 (40), 77 (8), 89 (24), 90 (29),
91 (14), 117 (3), 130 (2), 146 (8), 169 (20), 170 (11), 184 (36), 186
(34), 188 (100), 226 (3), 228 (2). ESI-HRMS m/z [M + H]+ calcd for
C12H15BrNO 268.0337, found 268.0341.
N-(2-Chlorobenzyl)-N-(2-methylallyl)acetamide (9a). This
reaction was carried out using a procedure similar to that described
for 8a, but the substrate utilized was 2-methylallyl bromide (7 mmol)
and the amine 2-chlorobenzylamine (7 mmol). Compound 9a (48%
yield) was separated as a pale yellow oil by column chromatography
using petroleum ether−ethyl ether, 30:70. 1H NMR (400 MHz,
CDCl3) mixture of interconverting rotational isomers with respect to
the N-formyl bond, major isomer δH: 1.72 (s, 3H, overlapping); 2.17
(s, 3H); 3.75 (s, 2H); 4.71 (s, 2H); 4.83 (br s, 1H); 4.95 (br m, J = 1.3
Hz); 7.10−7.42 (cplx. m, 4H, overlapping). Minor isomer δH: 1.72 (s,
3H, overlapping); 2.11 (s, 3H); 3.99 (s, 2H); 4.54 (s, 2H); 4.75 (br s,
1H); 4.96 (br s, 1H); 7.10−7.42 (cplx. m, 4H, overlapping). 13C NMR
(100 MHz, CDCl3) major isomer δC: 20.10(overlapping); 21.2; 46.0;
53.6; 111.2; 127.0; 128.5; 129.1; 129.5; 133.6; 134.9; 139.6; 171.5.
Minor isomer δC: 20.1 (overlapping); 21.4; 48.7; 50.7; 112.4; 126.6;
127.3; 128.7; 129.9; 132.9; 134.0; 140.3; 171.3. m/z (%): 70 (68), 89
(12), 99 (12), 125 (47), 127 (17), 140 (55), 154 (9), 182 (6), 202
(100), 237 (7). ESI-HRMS m/z [M + H]+ calcd for C13H17ClNO
238.0999, found 238.1002.
N-Allyl-N-(2-chlorobenzyl)-amine (7a)40 and N-Allyl-N-(2-
chlorobenzyl)-acetamide (8a). Sodium carbonate (1 g), allyl
amine (40 mmol) and water (1 mL) were added to a round-bottomed
flask equipped with a reflux condenser and magnetic stirring. The
mixture was first heated to 80 °C, and 2-chlorobenzyl chloride (10
mmol) was added. Then, heating was carried out for a further three
hours before the mixture was left to cool at rt. The aqueous phase was
extracted with dichloromethane (3 × 50 mL), and the organic phase
was dried over magnesium sulfate and evaporated under a vacuum.
The crude was separated into two parts. From one, 7a (72% yield)
was isolated as a pale yellow oil by column chromatography using
petroleum ether−ethyl ether, 50:50. The other part was poured into a
two-necked round-bottomed flask equipped with magnetic stirring and
a reflux condenser, and acetic anhydride was then added in excess (4
mL). The mixture was boiled for 2 h before water was added in excess
(2 mL), and the new mixture was boiled for an additional 2 h. The
aqueous phase was extracted with dichloromethane (3 × 50 mL), and
the organic layer was dried (magnesium sulfate) and evaporated.
Compound 8a (53% yield) was separated as a pale yellow oil by
column chromatography using petroleum ether−ethyl ether, 40:60.
This product was characterized by standard spectroscopic techniques
N-(2-Bromobenzyl)-N-(2-ethylallyl)acetamide (9b). This re-
action was performed by a procedure similar to that described for 9a,
but the substrate used was 2-bromobenzylamine. Compound 9b (50%
yield) was purified as a yellow oil by column chromatography using
1
petroleum ether−ethyl ether, 20:80. H NMR (400 MHz, CDCl3)
mixture of interconverting rotational isomers with respect to the N-
formyl bond, major isomer δH: 1.72 (s, 3H, overlapping); 2.17 (s, 3H);
3.70 (s, 2H); 4.70 (s, 2H); 4.83 (br s, 1H); 4.97 (br s, 1H); 7.07−7.38
(cplx. m, 3H, overlapping); 7.53 (dd, 1H, J = 7.8, 0.6 Hz). Minor
isomer δH: 1.72 (s, 3H, overlapping); 2.10 (s, 3H); 3.99 (s, 2H); 4.49
(s, 2H); 4.75 (br s, 1H); 4.91 (br s, 1H); 7.07−7.38 (cplx. m, 3H,
overlapping); 7.59 (dd, 1H, J = 8.0, 0.7 Hz). 13C NMR (100 MHz,
CDCl3) major isomer δC: 20.1 (overlapping); 21.2; 48.5; 53.5; 111.2;
123.7; 127.7; 128.7; 129.0 (overlapping); 132.8; 136.5; 139.5; 171.5.
Minor isomer δC: 20.1 (overlapping); 21.4; 50.8; 51.5; 112.5; 122.7;
126.7; 127.9; 129.0 (overlapping); 133.2; 135.5; 140.3; 171.3. m/z
(%): 55 (13), 70 (59), 89 (15), 90 (19), 96 (7), 112 (9), 146 (7), 169
(27), 171 (19), 184 (33), 186 (30), 202 (100), 226 (6), 228 (4), 281
(1.25), 283 (1.00). ESI-HRMS m/z [M + H]+ calcd for C13H17BrNO
282.0494, found 282.0499.
1
as follows. H NMR (400 MHz, CDCl3) mixture of interconverting
rotational isomers with respect to the N-formyl bond, major isomer
δH: 2.19 (s, 3H); 3.87 (br d, 1H, J = 4.9 Hz, overlapping); 4.02 (br d,
1H, J = 6.0 Hz, overlapping); 4.72 (s, 2H); 5.17 (m, 2H, overlapping);
5.78 (m, 1H, overlapping); 7.09−7.47 (clpx. m, 4H, overlapping).
Minor isomer δH: 2.10 (s, 3H); 3.87 (br d, 1H, J = 4.9 Hz,
overlapping); 4.02 (br d, 1H, J = 6.0 Hz, overlapping); 4.56 (s, 2H);
5.17 (m, 2H, overlapping); 5.78 (m, 1H, overlapping); 7.09−7.47
(clpx. m, 4H, overlapping). 13C NMR (100 MHz, CDCl3) major
isomer δC: 21.1; 45.8; 50.6; 117.0; 127.0; 128.5; 129.2; 129.5; 132.3;
134.0; 134.9; 171.3. Minor isomer δC: 21.5; 48.2; 49.1; 117.8; 126.8;
127.3; 128.8; 129.9; 132.7; 134.8; 133.6; 171.2. m/z (%): 56 (38), 70
(6), 82 (13), 89 (18), 125 (41), 127 (13), 140 (71), 142 (21), 188
(100). ESI-HRMS m/z [M + H]+ calcd for C12H15ClNO 224.0842,
found 224.0853.
N-Allyl-N-(2-bromobenzyl)-acetamide (8b). This reaction was
carried out using a procedure similar to that described for 8a, but the
substrate utilized was 2-bromobenzyl bromide (10 mmol). Compound
8b (55% yield) was separated as a pale yellow oil by column
chromatography using petroleum ether−methylene chloride, 50:50.
1H NMR (400 MHz, CDCl3) mixture of interconverting rotational
isomers with respect to the N-formyl bond, major isomer δH: 2.19 (s,
N-(2-Chlorobenzyl)-N-(cyclohex-2-en-1-yl)acetamide (10a).
This reaction was carried out using a procedure similar to that
described for 9a, but with 3-bromocyclohexene as subtrate.
Compound 10a (51% yield) was separated as a viscous amber oil by
column chromatography using petroleum ether−ethyl ether, 65:35. 1H
NMR (400 MHz, CDCl3) mixture of interconverting rotational
isomers with respect to the N-formyl bond, major isomer δH: 1.37 (m,
1H); 1.72 (m, 2H); 1.95 (s, 3H); 1.96 (m, 1H); 2.01 (m, 2H); 4.47
(m, 1H); 4.53 (m, 1H); 5.40 (m, 1H); 5.43 (m, 1H, overlapping); 5.88
(m, 1H, overlapping); 7.10−7.41 (cplx. m, 4H, overlapping). Minor
isomer δH: 1.52 (m, 1H); 1.80 (m, 2H); 1.89 (m, 1H); 1.94 (m, 2H);
2.29 (s, 3H); 4.49 (m, 1H); 4.62 (d, 1H, J = 16.8 Hz); 4.51 (m, 1H);
5.43 (m, 1H, overlapping); 5.88 (m, 1H, overlapping); 7.10−7.41
(cplx. m, 4H, overlapping). 13C NMR (100 MHz, CDCl3) major
isomer δC: 21.3; 22.2; 24.5; 27.6; 46.2; 51.3; 126.9; 127.0; 127.4;
127.6; 128.2; 132.5; 136.0; 136.2; 172.0. Minor isomer δC: 21.5; 22.0;
24.3; 28.7; 43.8; 56.1; 126.7; 127.3; 129.2; 129.6; 132.1; 132.2; 132.4;
4725
dx.doi.org/10.1021/jo4001788 | J. Org. Chem. 2013, 78, 4719−4729

The Journal of Organic Chemistry
Article
171.1. m/z (%): 53 (5), 77 (11), 79 (20), 96 (100), 125 (39), 127
(12), 138 (70), 140 (27), 148 (12), 193 (5), 228 (20). ESI-HRMS m/
z [M + H]+ calcd for C15H19ClNO 264.1155, found 264.1163.
N-(2-Chlorobenzyl)-N-(3-dimethylallyl)acetamide (11a). This
reaction was carried out using a procedure similar to that described for
9a, but the substrate utilized was 3-dimethylallyl bromide. Compound
11a (48% yield) was separated as pale yellow oil by column
Hz); 7.05−7.25 (cplx. m, 4H, overlapping). 13C NMR (100 MHz,
CDCl3) major isomer δC: −9.3; 16.2; 37.1; 44.5; 51.5; 126.6; 126.7;
126.8; 126.9; 132.5; 140.1; 170.0. Minor isomer δC: −9.3; 16.7; 21.9;
36.3; 46.4; 48.3; 126.0; 126.3; 127.1; 131.6; 141.5; 169.8. m/z (%): 63
(1), 77 (3), 91 (10), 115 (22),116 (8), 117 (23), 118 (4), 128 (5),129
(11), 130 (10), 131 (7), 144 (32), 146 (100), 147 (12), 165 (12), 188
(62), 338 (isotopic cluster, 23). ESI-HRMS m/z [M + H]+ calcd for
C15H24NOSn 354.0880, found 354.0889.
1
chromatography using petroleum ether−ethyl ether, 75:25. H NMR
(400 MHz, CDCl3) δH: mixture of interconverting rotational isomers
with respect to the N-formyl bond, major isomer δH: 1.70 (dd, 6H, J =
4.6, 1.1 Hz); 2.20 (s, 3H); 4.01 (d, 2H, J = 7.1 Hz); 4.70 (s, 2H); 5.11
(m, 1H); 7.12−7.42 (cplx. m, 4H, overlapping). Minor isomer δH: 1.54
(br d, 6H, J = 8.2 Hz); 2.07 (s, 3H); 3.83 (d, 2H, J = 6.7 Hz); 4.53 (s,
2H); 5.18 (m, 1H); 7.12−7.42 (cplx. m, 4H, overlapping). 13C NMR
(100 MHz, CDCl3) major isomer δC: 17.8; 21.57; 25.67; 45.6; 46.4;
119.4; 126.92; 128.3; 129.4; 129.8; 133.5; 134.5; 136.8; 171.1. Minor
isomer δC: 17.7; 21.55; 25.71; 43.0; 48.8; 119.3; 126.88; 127.2; 128.6;
129.0; 132.8; 135.0; 136.3; 170.9. m/z (%): 70 (67), 89 (15), 112 (7),
125 (51), 127 (16), 140 (52), 142 (18), 182 (8), 202 (100), 222 (3),
224 (1), 237 (2). ESI-HRMS m/z [M + H]+ calcd for C14H19ClNO
252.1155, found 252.1169.
1-(4-(Trimethylstannyl)-4,5-dihydro-1H-benzo[c]azepin-
2(3H)-yl)ethanone (15a-endo). Colorless liquid. Isolated (30 mg,
19% yield) by radial thin-layer chromatography eluted with petroleum
1
ether−ethyl ether, 50:50. H NMR (400 MHz, CDCl3), mixture of
interconverting rotational isomers with respect to the N-formyl bond,
major isomer δH: 0.04 (s, 9H); 1.67 (cplx. m, 1H, overlapping); 2.11
(s, 3H); 2.99−3.32 (br m, 2H, overlapping); 4.39 (br s, 1H); 4.50 (s,
2H, overlapping); 4.79 (br s, 1H); 7.04−7.42 (cplx. m, 4H,
overlapping). Minor isomer δH: 0.06 (s, 9H); 1.62 (cplx. m, 1H,
overlapping); 2.02 (s, 3H); 2.99−3.32 (br m, 2H, overlapping); 3.67
(br t, 1H, J = 10.8 Hz); 4.50 (s, 2H, overlapping); 4.00 (dd, 1H, J =
14.6 Hz, 3.1 Hz); 7.04−7.42 (cplx. m, 4H, overlapping). 13C NMR
(100 MHz, CDCl3) major isomer δC: −10.6; 21.9; 26.3; 39.8; 50.7;
54.0; 126.3; 128.0; 128.5; 130.0; 137.7; 142.9; 169.6. Minor isomer δC:
−10.9; 21.6; 27.9; 39.0; 53.0; 56.4; 126.5; 127.5; 128.8; 130.1; 137.1;
142.2; 168.5. m/z (%): 60 (6), 72 (6), 91 (15), 105 (3), 115 (26), 116
(13), 117 (21), 118 (8), 128 (14), 129 (34), 130 (17), 131 (12), 144
(17), 146 (100), 147 (16), 165 (14), 188 (72), 206 (8), 207 (6), 208
(10), 338 (isotopic cluster, 21). ESI-HRMS m/z [M + H]+ calcd for
C15H24NOSn 354.0880, found 354.0891.
Reactions of 8a, 9a, 10a and 11a with Me3Sn− Ions in NH3(l)
.
First, 300 mL of NH3(l) were condensed, previously dried with Na
metal under nitrogen in a three-necked, 500 mL round-bottomed flask
equipped with a coldfinger condenser charged with ethanol, a nitrogen
inlet, and a magnetic stirrer. Me3SnCl (0.55 mmol) was then added,
and Na metal (1.325 mmol) in small pieces was introduced, waiting
for total bleaching between each new addition. A lemon yellow
solution of Me3Sn− ions was obtained. The substrates (0.50 mmol)
were dissolved in 1 mL of dried ethyl ether and added to the solution.
The reaction mixture was irradiated for 15 min and then quenched by
adding ammonium nitrate in excess. The ammonia was allowed to
evaporate, and water (50 mL) was added. The aqueous phase was
extracted with dichloromethane (3 × 50 mL), the organic phase was
dried (magnesium sulfate), and the solvent was evaporated in a
vacuum. The products were purified as indicated.
1-(4-((Diphenylphosphoryl)methyl)-3,4-dihydroisoquinolin-
2(1H)-yl)ethanone (14b-exo). White solid. mp 217−220 °C.
Isolated (60 mg, 33% yield) by radial thin-layer chromatography
1
eluted with dichloromethane-methanol, 95:5. H NMR (400 MHz,
CDCl3) δH: 2.27 (s, 3H); 2.40 (ddc, 1H, J = 15.5 Hz, 7.3 Hz, 1.2 Hz);
2.61 (dd, 1H, J = 15.5, 11.2 Hz); 3.28 (td, 1H, J = 11.3, 2.5 Hz); 3.50
(br dd, 1H, J = 13.2, 3.3 Hz); 4.33 (d, 1H, J = 17.8 Hz); 4.48 (dd, 1H,
J = 13.2, 2.9 Hz); 5.11 (d, 1H, J = 17.8 Hz); 6.91 (br d, 1H, 7.1 Hz);
7.09−7.19 (br cplx. m, 3H); 7.36−7.94 (cplx. m, 10H). 13C NMR
(100 MHz, CDCl3) δC: 21.9; 33.5 (d, C−PJ = 68.0 Hz); 34.0 (d, 2.3
Hz); 44.2; 47.2; 126.9; 127.0; 127.2; 127.4; 128.9 (d, C−PJ = 11.9 Hz);
129.0 (d, C−PJ = 11.9 Hz); 130.2 (d, C−PJ = 9.6 Hz); 131.0 (d, C−PJ =
9.7 Hz); 131.8 (d, C−PJ = 96.6 Hz); 132.0 (d, C−PJ = 9.04 Hz); 132.1
(d, C−PJ = 9.04 Hz); 132.6; 133.8 (d, C−PJ = 99.2 Hz); 137.8 (d, C−PJ =
13.3 Hz); 171.5. 31P NMR (CDCl3) δP: 30.51. m/z (%): 77 (25), 91
(4), 107 (5), 115 (5), 123 (6), 150 (11), 152 (14), 165 (40), 166 (23),
183 (18), 184 (3), 199 (18), 201 (11), 208 (6), 213 (22), 228 (9), 241
(14), 271 (11), 288 (20), 289 (17), 291 (100), 292 (28), 305 (15),
306 (45), 330 (1), 346 (97), 347 (24), 348 (21), 388 (1). ESI-HRMS
m/z [M + H]+ calcd for C24H25NO2P 390.1623, found 390.1633.
1-(4-(2-Nitroethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-
ethanone (14c-exo). Amber liquid. Isolated (25 mg, 21% yield) by
radial thin-layer chromatography eluted with ethyl ether−methanol,
98:2. 1H NMR (400 MHz, CDCl3) mixture of interconverting
rotational isomers with respect to the N-formyl bond, major isomer
δH: 2.09 (cplx. m, 1H); 2.22 (s, 3H); 2.26 (cplx. m, 1H, overlapping);
2.96 (br m, 1H, overlapping); 3.03 (dd, 1H, J = 13.6, 3.5 Hz); 4.52 (m,
1H, overlapping); 4.58 (m, 1H, overlapping); 4.65 (m, 1H,
overlapping); 4.72 (br m, 1H, overlapping); 4.75 (m, 1H, over-
lapping); 7.09−7.30 (cplx. m, 4H, overlapping). Minor isomer δH: 2.18
(cplx. m, 1H, overlapping); 2.21 (s, 3H); 2.37 (cplx. m, 1H,
overlapping); 3.01 (br m, 1H, overlapping); 3.58 (dd, 1H, J = 13.1,
3.3 Hz); 3.85 (dd, 1H, J = 13.1, 2.9 Hz); 4.42 (m, 1H, overlapping);
4.43 (m, 2H, overlapping); 5.05 (d, 1H, J = 18.02 Hz); 7.09−7.30
(cplx. m, 4H, overlapping). 13C NMR (100 MHz, CDCl3) major
isomer δC: 21.8 (overlapping); 31.9; 35.7; 41.3; 48.1; 73.5; 126.3;
127.28; 127.30; 129.1; 131.8; 137.0; 170.1. Minor isomer δC: 21.8
(overlapping); 31.3; 36.3; 44.4; 48.0; 73.3; 126.8; 127.4; 127.7; 128.3;
132.6; 134.9; 170.3. m/z (%): 77 (12), 91 (19), 103 (9), 104 (5), 115
(27), 116 (13), 117 (10), 128 (13), 129 (22), 130 (100), 131 (49),
132 (16), 144 (7), 158 (6), 172 (10), 173 (36), 174 (6), 201 (3), 205
Inhibited Photostimulated Reaction with Me3Sn−. The
procedure was similar to that for the previous reactions, except that
m-dinitrobenzene (20 mol %) was added to the solution of the
nucleophile prior to substrate addition.
Reactions of 8a, 9a and 10a with Ph2P− Ions in NH3(l). These
reactions were performed in a fashion similar to those with Me3Sn−
ions, but 0.55 mmol of Ph3P was added instead followed by Na metal
(1.325 mmol) in small pieces. The addition of Na metal continued
until no more solid was present and the blue color from solvated
electrons in excess remained for 20 min before becoming orange-
brown. Then, t-BuOH (0.55 mmol) was added to this solution to
neutralize the amide ions formed. After irradiation and quenching (and
previous to drying), the dichloromethane phase was treated with 20%
H2O2 (50 mL) and then with water (50 mL). The products were
purified as indicated.
−
Reactions of 8b and 9b with O2NCH2 Ions in NH3(l). These
reactions were performed by a procedure similar to that described for
the other two nucleophiles, but 1.5 mmol of nitromethane, 1 mmol of
acetone and 2.75 mmol of KOBu- t were added, waiting 15 min for the
formation of the nucleophile and the entrainment reagent to occur. A
slightly colored solution was obtained. The reactions were irradiated
for 240 min.
1-(4-((Trimethylstannyl)methyl)-3,4-dihydroisoquinolin-
2(1H)-yl)ethanone (14a-exo). Colorless liquid. Isolated (46 mg,
29% yield) by radial thin-layer chromatography eluted with petroleum
1
ether−ethyl ether, 50:50. H NMR (400 MHz, CDCl3), mixture of
interconverting rotational isomers with respect to the N-formyl bond,
major isomer δH: 0.05 (s, 9H); 1.21 (cplx. m, 2H, overlapping); 2.18
(s, 3H); 3.21 (br m, 1H, overlapping); 3.42 (dd, 1H, J = 12.7 Hz, 6.2
Hz); 3.67 (m, 1H, overlapping); 4.64 (d, 1H, J = 17.1 Hz); 4.81 (d,
1H, J = 17.1 Hz); 7.05−7.25 (cplx. m, 4H, overlapping). Minor isomer
δH: 0.06 (s, 9H); 1.21 (cplx. m, 2H, overlapping); 2.20 (s, 3H); 3.18
(br m, 1H, overlapping); 3.64 (cplx, 1H, overlapping); 3.75 (dd, 1H, J
= 12.8 Hz, 3.4 Hz); 4.58 (d, 1H, J = 16.0 Hz); 4.67 (d, 1H, J = 16.0
4726
dx.doi.org/10.1021/jo4001788 | J. Org. Chem. 2013, 78, 4719−4729

The Journal of Organic Chemistry
Article
(1), 214 (4), 231 (3). ESI-HRMS m/z [M + H]+ calcd for
C13H17N2O3 249.1239, found 249.1247.
Minor isomer δP: 35.26. m/z (%): 201 (10), 202 (13), 203 (22), 217
(63), 291 (73), 292 (12), 345 (5), 362 (100), 363 (22), 404 (63). ESI-
HRMS m/z [M + H]+ calcd for C25H27NO2P 404.1779, found
404.1794.
1-(4-(Nitromethyl)-4,5-dihydro-1H-benzo[c]azepin-2(3H)-yl)-
ethanone (15c-endo). Amber liquid. Isolated (15 mg, 13% yield) by
radial thin-layer chromatography eluted with dichloromethane. 1H
NMR (400 MHz, CDCl3) mixture of interconverting rotational
isomers with respect to the N-formyl bond, major isomer δH: 2.15 (s,
3H); 2.85 (br m, 1H); 2.98 (dd, 1H, J = 14.9, 7.2 Hz); 3.18 (br d, 1H,
J = 14.9 Hz); 3.59 (br m, 1H); 4.06 (dd, 1H, J = 13.3, 9.4 Hz); 4.30
(m, 1H, overlapping); 4.40 (dd, 1H, J = 13.3, 4.9 Hz); 4.49 (d, 1H, J =
15.7 Hz); 4.57 (d, 1H, J = 15.7 Hz); 7.10−7.41 (cplx. m, 4H,
overlapping). Minor isomer δH: 2.08 (s, 3H); 2.80 (br m, 1H); 2.91
(dd, 1H, J = 14.5, 7.4 Hz); 3.13 (br m, 1H, overlapping); 3.65 (br m,
1H, overlapping); 3.80 (dd, 1H, J = 15.0, 3.4 Hz); 4.14 (dd, 1H, J =
13.8, 8.5 Hz, overlapping); 4.28 (dd, 1H, J = 13.4, 5.6 Hz,
overlapping); 4.57 (m, 1H, overlapping); 4.65 (m, 1H, overlapping);
7.10−7.41 (cplx. m, 4H, overlapping). 13C NMR (100 MHz, CDCl3)
major isomer δC: 21.6; 35.7; 37.2; 50.2; 54.3; 76.8; 127.4; 128.3; 128.5;
131.7; 136.8; 136.9; 170.6. Minor isomer δC: 21.4; 36.7; 37.1; 50.7;
52.6; 76.5; 127.6; 128.1; 129.9; 129.9; 136.8 (overlapping); 137.0;
169.5. m/z (%): 63 (17), 65 (18), 73 (25), 77 (29), 78 (23), 91 (88),
102 (10), 103 (16), 104 (17), 105 (11), 115 (78), 116 (60), 117 (32),
118 (27), 129 (66), 130 (61), 131 (100), 132 (14), 142 (65), 143
(34), 144 (31), 157 (17), 158 (25), 160 (20), 171 (12), 172 (8), 189
(4), 201 (20), 202 (4), 214 (21), 231 (12), 232 (3). ESI-HRMS m/z
[M + H]+ calcd for C13H17N2O3 249.1239, found 249.1234.
1-(4-Methyl-4-(nitromethyl)-4,5-dihydro-1H-benzo[c]-
azepin-2(3H)-yl)ethanone (17c-endo). White wax. Isolated (45
mg, 35% yield) by radial thin-layer chromatography eluted with
dichloromethane. 1H NMR (400 MHz, CDCl3) mixture of
interconverting rotational isomers with respect to the N-formyl
bond, major isomer δH: 1.10 (br s, 3H); 2.16 (s, 3H); 2.94 (br d, 1H, J
= 15.4 Hz, overlapping); 3.11 (d, 1H, J = 14.6 Hz, overlapping); 3.15−
4.00 (2H, overlapping); 4.16 (cplx. m, 1H, overlapping); 4.35 (d, 1H, J
= 11.8 Hz, overlapping); 4.47 (d, 1H, J = 15.4 Hz, overlapping); 4.56
(d, 1H, J = 15.4 Hz, overlapping); 7.10−7.40 (clpx. m, 4H,
overlapping). Minor isomer δH: 1.08 (s, 3H); 2.15 (s, 3H); 2.94 (br
d, 1H, J = 15.4 Hz, overlapping); 3.11 (d, 1H, J = 14.6 Hz,
overlapping); 3.15−4.00 (2H, overlapping); 4.16 (cplx. m, 1H,
overlapping); 4.35 (d, 1H, J = 11.8 Hz, overlapping); 4.47 (d, 1H, J
= 15.4 Hz, overlapping); 4.56 (d, 1H, J = 15.4 Hz, overlapping); 7.10−
7.40 (clpx. m, 4H, overlapping). 13C NMR (100 MHz, CDCl3) major
isomer δC: 21.7; 22.26 (overlapping); 38.7; 43.7 (overlapping); 54.1;
56.2 (overlapping); 81.7 (overlapping); 127.3; 128.1; 128.5; 132.4;
136.6; 136.8 (overlapping); 170.4. Minor isomer δC: 21.5; 22.26
(overlapping); 38.6; 43.7 (overlapping); 50.6; 56.2 (overlapping); 81.7
(overlapping); 127.7; 128.0; 129.7; 130.3; 135.6; 136.8 (overlapping);
170.0. m/z (%): 73 (35), 77 (20), 91 (48), 105 (25), 117 (65), 129
(86), 130 (58), 145 (100), 157 (44), 174 (30), 185 (21), 203 (8), 215
(30), 228 (25), 245 (14), 246 (4). ESI-HRMS m/z [M + H]+ calcd for
C14H19N2O3 263.1396, found 263.1404.
1-(4-Methyl-4-(trimethylstannyl)-4,5-dihydro-1H-benzo[c]-
azepin-2(3H)-yl)ethanone (17a-endo). Colorless liquid. Isolated
(94 mg, 52% yield) by radial thin-layer chromatography eluted with
1
petroleum ether−ethyl ether, 80:20. H NMR (400 MHz, CDCl3)
1-(1-(Trimethylstannyl)-1,2,3,4,4a,10b-hexahydrophenan-
thridin-5(6H)-yl)ethanone (18a-exo). Colorless liquid. Isolated (76
mg, 39% yield) by radial thin-layer chromatography eluted with
mixture of interconverting rotational isomers with respect to the N-
formyl bond, major isomer δH: −0.22 (br s, 9H); 1.11 (s, 3H); 2.13 (s,
3H); 2.40−5.30 (cplx. m, 4H, overlapping); 4.43 (d, 1H, J = 15.4 Hz);
4.50 (d, 1H, J = 15.4 Hz); 7.00−7.40 (cplx. m, 4H, overlapping).
Minor isomer δH: −0.09 (br s, 9H); 1.07 (s, 3H); 2.03 (s, 3H); 2.40−
5.30 (cplx. m, 6H, overlapping); 7.00−7.40 (cplx. m, 4H, overlapping).
13C NMR (100 MHz, CDCl3) major isomer δC: −10.7; 21.8; 25.1
1
petroleum ether−ethyl ether, 80:20. H NMR (400 MHz, CDCl3)
mixture of interconverting rotational isomers with respect to the N-
formyl bond, major isomer δH: 0.23 (s, 9H); 1.24−1.77 (cplx. m, 6H,
overlapping); 2.20 (s, 3H); 2.58 (br c, 1H, J = 2.0 Hz); 3.29 (br t, 1H,
J = 15.7 Hz); 4.03 (dt, 1H, J = 11.7, 4.4 Hz); 4.38 (d, 1H, J = 18.1
Hz); 4.99 (d, 1H, J = 18.1 Hz); 7.08−7.32 (cplx. m, 3H); 7.46 (d, 1H,
J = 7.7 Hz). Minor isomer δH: 0.22 (s, 9H); 1.24−1.77 (cplx. m, 6H,
overlapping); 2.17 (s, 3H); 2.49 (br m, 1H); 3.15 (br t, 1H, J = 16.2
Hz); 4.55 (d, 1H; J = 16.2 Hz); 4.63 (d, 1H, J = 16.2 Hz); 4.90 (dt,
1H; J = 12.2, 4.27 Hz); 7.08−7.32 (cplx. m, 3H); 7.50 (d, 1H, J = 7.8
Hz). 13C NMR (100 MHz, CDCl3) major isomer δC: −9.1; 21.9; 23.1;
25.3; 26.2; 27.5 (overlapping); 40.7; 42.9; 54.7; 125.7; 126.3; 126.8;
126.9; 133.3; 135.5; 169.4. Minor isomer δC: −9.2; 22.4; 23.6; 25.2;
26.0; 27.5 (overlapping); 39.9; 46.0; 49.2; 126.0; 126.1; 126.2; 127.2;
132.7; 137.3; 169.4. m/z (%): 91 (4), 115 (5), 127 (2), 128 (6), 129
(4), 130 (5), 141 (8), 163 (6), 165 (isotopic cluster, 10), 184 (12),
186 (100), 187 (15), 228 (74), 229 (13), 378 (isotopic cluster, 5).
ESI-HRMS m/z [M + H]+ calcd for C18H28NOSn 394.1193, found
394.1194.
(overlapping); 31.5 (overlapping); 48.7; 54.1 (overlapping); 60.1
(overlapping); 126.6; 128.2; 128.4; 130.6; 137.7; 141.0; 169.6. Minor
isomer δC: −11.0; 21.5; 25.1 (overlapping); 31.5 (overlapping); 46.6;
54.1 (overlapping); 60.1 (overlapping); 126.8; 127.6; 129.5; 129.9;
137.5; 139.9; 168.7. 119Sn NMR (CDCl3) δSn: 6.34. m/z (%): 91 (11),
115 (10), 129 (23), 131 (17), 143 (27), 144 (16), 160 (100), 165
(isotopic cluster, 15), 202 (74), 352 (40), 354 (5), 355 isotopic
cluster, (7). ESI-HRMS m/z [M + H]+ calcd for C16H26NOSn
368.1036, found 368.1045.
1-(4-(Diphenylphosphoryl)-4-methyl-4,5-dihydro-1H-benzo-
[c]azepin-2(3H)-yl)ethanone (17b-endo). White wax. Isolated (90
mg, 45% yield) by radial thin-layer chromatography eluted with
dichloromethane−methanol, 98:2. 1H NMR (400 MHz, CDCl3)
mixture of interconverting rotational isomers with respect to the N-
formyl bond, major isomer δH: 0.93 (dd, 3H, J = 15.7, 3.7 Hz,
overlapping); 2.10 (s, 3H); 3.04 (td, 1H, J = 11.2, 1.8 Hz); 3.36 (dd,
1H, J = 13.4, 2.6 Hz); 3.51 (br d, 1H, overlapping); 4.34 (d, 1H, J =
15.6 Hz); 4.50 (d, 1H, J = 15.6 Hz); 3.98 (dd, 1H, J = 13.1, 4.5 Hz);
7.00−7.22 (cplx. m, 4H, overlapping); 7.46−7.66 (cplx. m, 6H,
overlapping); 7.95−8.10 (cplx. m, 4H, overlapping). Minor isomer δH:
0.93 (dd, 3H, J = 15.7, 3.7 Hz, overlapping); 1.98 (s, 3H); 2.92 (td,
1H, J = 12.4, 1.3 Hz); 3.56 (br d, 1H, overlapping); 3.77 (d, 1H, J =
14.1 Hz); 3.83 (dd, 1H, J = 14.3, 3.1 Hz); 4.04 (dd, 1H, J = 14.3, 4.8
Hz); 5.19 (d, 1H, J = 14.1 Hz); 7.00−7.22 (cplx. m, 4H, overlapping);
7.46−7.66 (cplx. m, 6H, overlapping); 7.95−8.10 (cplx. m, 4H,
overlapping). 13C NMR (100 MHz, CDCl3) major isomer δC: 16.7;
21.6; 40.2 (d, C−PJ = 66.3 Hz); 40.5; 54.2; 52.7; (d, C−PJ = 8.5 Hz);
126.7; 128.0; 128.1; 128.5−129.0 (cplx. m, overlapping); 131.8−132.7
(cplx. m, overlapping); 132.0; 136.8; 137.5 (d, C−PJ = 13.9 Hz); 170.1.
Minor isomer δC: 16.4; 21.3; 40.2; 40.7 (d, C−PJ = 66.1 Hz); 50.5; 56.4;
(d, C−PJ = 7.5 Hz); 127.2; 127.5; 128.5−129.0 (cplx. m, overlapping);
129.7; 131.8−132.7 (cplx. m, overlapping); 130.5; 136.9; 136.3 (d,
C−PJ = 14.4 Hz); 169.8. 31P NMR (CDCl3) major isomer δP: 36.92.
1-(1-(Diphenylphosphoryl)-1,2,3,4,4a,10b-hexahydrophe-
nanthridin-5(6H)-yl)ethanone (18b-exo). White wax. Isolated (50
mg, 25% yield) by radial thin-layer chromatography eluted with
1
dichloromethane−acetone−methanol, 89:10:1. H NMR (400 MHz,
CDCl3) δH: 1.51 (cplx. m, 1H); 1.52 (cplx. m, 1H); 1.56 (cplx. m,
1H); 1.667 (cplx. m, 1H); 1.668 (cplx. m, 1H); 2.21 (cplx. m, 1H);
2.27 (s, 3H); 3.36 (br s, 2H); 4.22 (d, 1H, J = 18.2 Hz); 5.12 (d, 1H, J
= 18.2 Hz); 5.30 (cplx m, 1H); 7.09−7.34 (cplx. m, 4H); 7.52 (br d;
6H, J = 15.1 Hz); 7.92 (br m, 4H). 13C NMR (100 MHz, CDCl3) δC:
19.9; 21.9; 21.1; 26.2; 34.9 (d, C−PJ = 70.9 Hz); 37.2; 40.1; 51.1; 124.4;
126.7; 127.0; 127.2; 128.9 (d, C−PJ = 11.4 Hz); 129.1 (d, C−PJ = 11.1
Hz); 130.5 (d, C−PJ = 8.1 Hz); 130.8 (d, C−PJ = 8.5 Hz); 131.8; 131.9;
132.4 (d, C−PJ = 73.0 Hz); 133.0; 133.1 (d, C−PJ = 14.5 Hz); 133.9;
170.0. 31P NMR (CDCl3) δP: 36.40. m/z (%): 201 (89), 202 (8), 203
(22), 219 (14), 371 (83), 372 (16), 388 (100), 389 (19), 430 (22).
ESI-HRMS m/z [M + H]+ calcd for C27H29NO2P 430.1936, found
430.1958.
1-(4-Isopropyl-3,4-dihydroisoquinolin-2(1H)-yl)ethanone
(20). Colorless liquid. Isolated by radial thin-layer chromatography
4727
dx.doi.org/10.1021/jo4001788 | J. Org. Chem. 2013, 78, 4719−4729

The Journal of Organic Chemistry
Article
eluted with dichloromethane. Quantified by GC using the internal
standard method. 1H NMR (400 MHz, CDCl3) mixture of
interconverting rotational isomers with respect to the N-formyl
bond, major isomer δH: 0.91 (d, 3H, J = 6.7 Hz); 0.99 (d, 3H, J = 6.7
Hz); 1.82−1.89 (cplx. m, 1H, overlapping); 2.21 (s, 3H); 2.55 (cplx.
m, 1H, overlapping); 3.42 (dd, 1H, J = 12.8, 3.5 Hz); 3.93 (dd, 1H, J =
12.8, 3.5 Hz); 4.55 (d, 1H, J = 17.7 Hz); 4.75 (d, 1H, J = 17.7 Hz);
7.08−7.24 (cplx. m, 4H, overlapping). Minor isomer δH: 0.93 (d, 3H, J
= 6.8 Hz); 0.95 (d, 3H, J = 6.8 Hz); 1.82−1.89 (cplx. m, 1H,
overlapping); 2.18 (s, 3H); 2.55 (cplx. m, 1H, overlapping); 3.10 (dd,
1H, J = 13.1, 3.7 Hz); 4.53 (d, 1H, J = 15.9 Hz); 4.58 (dd, 1H, J =
12.8, 3.7 Hz); 4.67 (d, 1H, J = 15.9 Hz); 7.08−7.24 (cplx. m, 4H,
overlapping). 13C NMR (from HSQC and HMBC spectra, CDCl3)
major isomer δC: 20.4; 21.3 (overlapping); 21.8; 29.7; 44.9; 45.6; 46.3;
126.0; 126.7; 126.9; 128.8; 132.7; 137.4; 170.0 (overlapping). Minor
isomer δC: 19.9; 21.3 (overlapping); 22.0; 30.7; 40.8; 45.3; 47.9; 126.2;
126.3; 126.4; 129.4; 132.0; 138.5; 170.0 (overlapping). m/z (%): 77
(21), 91 (29), 103 (18), 104 (11), 115 (34), 116 (19), 117 (28), 130
(72), 131 (97), 132 (100), 143 (12), 160 (17), 174 (30), 175 (22),
202 (6), 217 (62). ESI-HRMS m/z [M + H]+ calcd for C14H20NO
218.1545, found 218.1540.
95:5. 1H NMR (400 MHz, CDCl3) δH: 1.39 (s, 3H); 1.70 (br m, 2H);
2.08 (cplx. br m, 2H); 3.74 (br t, 1H, J = 10.8 Hz); 3.91 (d, 1H, J =
16.5 Hz); 4.36 (br s, 1H); 4.44 (d, 1H, J = 16.5 Hz); 5.37 (d, 1H, J =
9.7 Hz); 5.63 (br d, 1H, J = 9.7 Hz); 7.17−7.37 (cplx. m, 5H); 7.41−
8.12 (cplx. m, 10H). 13C NMR (100 MHz, CDCl3) δC: 22.70
C−P
(overlapping); 24.5 (d, C−PJ = 11.4 Hz); 34.5 (d,
J = 73.7 Hz);
55.1, 56.9 (d, C−PJ = 3.5 Hz); 126.4; 127.4; 127.6; 128.4 (d, C−PJ = 11.5
C−P
Hz); 128.71; 128.72 (d,
J = 10.8 Hz); 129.9 (d, C−PJ = 9.1 Hz);
130.3 (d, C−PJ = 9.2 Hz); 130.5 (d,
J = 8.8 Hz); 132.8 (d, C−PJ =
C−P
93.2 Hz); 133.7 (d, C−PJ = 90.8 Hz); 136.9. m/z (%): 183 (13), 184
(1), 185 (9), 201 (23), 202 (2), 203 (100), 281 (18), 282 (2), 388 (2).
ESI-HRMS m/z [M + H]+ calcd for C27H29NO2P 430.1936, found
430.1934.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C, COSY, HSQC and HMBC NMR spectra for all
compounds obtained. Optimized geometries of relevant
species. This material is available free of charge via the Internet
at http://pubs.acs.org/.
N-Benzyl-N-(6-(trimethylstannyl)cyclohex-2-en-1-yl)-
acetamide (22a). Colorless liquid. Isolated (12 mg, 6% yield) by
radial thin-layer chromatography eluted with petroleum ether−ethyl
ether, 90:10. 1H NMR (400 MHz, CDCl3) mixture of interconverting
rotational isomers with respect to the N-formyl bond, major isomer
δH: 0.09 (s, 9H); 1.583 (dd, 1H, J = 8.0 Hz, 3.0 Hz, overlapping);
1.586 (cplx. m, 1H, overlapping); 1.73 (cplx. m, 1H, overlapping);
1.90 (cplx. m, 1H, overlapping); 1.97 (cplx. m, 1H, overlapping); 1.95
(s, 3H); 4.49 (d, 1H, J = 17.7 Hz); 4.58 (d, 1H, J = 17.7 Hz); 5.40
(cplx. m, 1H, J = 2.8 Hz); 5.52 (dc, 1H, J = 10.2, 2.2 Hz, overlapping);
5.86 (br d, 1H, J = 9.9 Hz); 7.14−7.38 (cplx. m, 5H, overlapping).
Minor isomer δH: 0.01 (s, 9H); 1.74 (m, 1H, overlapping); 1.83−2.05
(cplx. m, 4H, overlapping); 2.21 (s, 3H); 4.38 (d, 1H, J = 15.0 Hz);
4.46 (m, 1H, overlapping); 4.71 (d, 1H, J = 15.0 Hz); 5.44 (m, 1H),
overlapping; 5.86 (m, 1H, overlapping); 7.14−7.38 (cplx. m, 5H,
overlapping). 13C NMR (100 MHz, CDCl3) major isomer δC: −10.2;
22.8; 24.8; 25.8; 26.9; 48.7; 53.9; 125.9; 127.0; 128.4; 128.7; 132.4;
138.9; 171.7. Minor isomer δC: −10.5; 22.6; 25.4; 25.6; 27.5; 46.9;
59.0; 126.8; 128.2; 128.3; 129.4; 131.7 ; 139.4; 170.9. m/z (%): 77
(47), 79 (100), 91 (37), 106 (60), 149 (37), 165 (isotopic cluster, 9),
186 (3), 228 (3), 298 (isotopic cluster, 11), 312 (5), 378 (isotopic
cluster, 5). ESI-HRMS m/z [M + Na]+ calcd for C18H27NOSnNa
416.1012, found 416.1029.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: adriana@fcq.unc.edu.ar. Phone: +54 (0)351 4334170/
4334173. Fax: +54 (0)351 4333030/4334174.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by the Consejo Nacional de
́
Investigaciones Cientıficas y Tec
́
nicas (CONICET), the
́
́ ́
n Cientıfica y Tecnica
Agencia Nacional de Promocio
(ANPCyT), the Secretaria de Ciencia y Tecnologıa (Uni-
versidad Nacional de Cordoba) and the Agencia Cordoba
́
́
́
Ciencia, Argentina. L.E.P gratefully acknowledges the receipt of
a fellowship from CONICET.
REFERENCES
■
(1) Rossi, R. A.; Pierini, A. B.; Penen
́
ory, A. B. Chem. Rev. 2003, 103,
̃
̃
71−167.
N-Benzyl-N-(5-(trimethylstannyl)cyclohex-2-en-1-yl)-
acetamide (23a). Colorless liquid. Isolated (18 mg, 9% yield) by
radial thin-layer chromatography eluted with petroleum ether−ethyl
ether, 90:10. 1H NMR (400 MHz, CDCl3) mixture of interconverting
rotational isomers with respect to the N-formyl bond, major isomer
δH: 0.04 (s, 9H); 1.41 (br m, 1H); 1.91 (ddd, 1H, J = 13.6, 6.4, 3.6
Hz); 1.99 (s, 3H); 2.02 (m, 1H, overlapping); 2.03 (m, 1H,
overlapping); 2.31 (m, 1H, overlapping); 4.56 (d, 1H, J = 18.0 Hz);
4.62 (d, 1H, J = 18.0 Hz); 5.24 (br m, 1H); 5.48 (br d, 1H, J = 10.3
Hz, overlapping); 5.99 (cplx. m, 1H); 7.15−7.39 (clpx. m, 5H,
overlapping). Minor isomer δH: 0.03 (s, 9H); 1.52 (m, 1H); 1.983 (m,
2H, overlapping); 1.987 (m, 2H, overlapping); 2.24 (s, 3H); 4.34 (br
m, 1H); 4.43 (d, 1H, J = 15.7 Hz); 4.71 (d, 1H, J = 15.7 Hz); 5.48 (br
d, 1H, J = 10.3 Hz, overlapping); 5.89 (m, 1H); 7.15−7.39 (clpx. m,
5H, overlapping). 13C NMR (100 MHz, CDCl3) major isomer δC:
−10.9; 17.9; 22.5; 28.7; 32.3; 48.8; 49.9; 125.6; 126.8; 128.3; 128.7;
133.9; 139.0; 171.8. Minor isomer δC: −10.6; 18.6; 22.2; 28.4; 33.2;
46.5; 54.7; 126.5; 126.9; 127.0; 127.1; 133.2; 139.5; 170.9. m/z (%):
77 (30), 79 (56), 81 (36), 91 (100), 96 (66), 106 (40), 120 (12), 138
(36), 148 (43), 165 (isotopic cluster, 33), 186 (35), 228 (54), 255
(11), 298 (isotopic cluster, 16), 312 (isotopic cluster, 17), 378
(isotopic cluster, 16). ESI-HRMS m/z [M + H]+ calcd for
C18H28NOSn 394.1193, found 394.1190.
(2) Bardagí, J. I.; Vaillard, V. A.; Rossi, R. A. In Encyclopedia of
Radicals in Chemistry, Biology and Materials; Chatgilialoglu, C., Studer,
A., Eds.; John Wiley & Sons, Ltd: Chichester, UK, 2012; Chapter: The
SRN1 Reaction, pp 1505−1519.
(3) Guastavino, J. F.; Barolo, S. M.; Rossi, R. A. Eur. J. Org. Chem.
2006, 3898−3902.
(4) Buden
8742.
(5) Buden
́
, M. E.; Rossi, R. A. Tetrahedron Lett. 2007, 48, 8739−
́
, M. E.; Dorn, V. B.; Gamba, M.; Pierini, A. B.; Rossi, R. A.
J. Org. Chem. 2010, 75, 2206−2218.
(6) Vaillard, V. A.; Buden, M. E.; Martín, S. E.; Rossi, R. A.
Tetrahedron Lett. 2009, 50, 3829−3832.
(7) Guastavino, J. F.; Buden, M. E.; García, C. S.; Rossi, R. A.
ARKIVOC 2011, 2011, 389−405.
(8) (a) Vaillard, V. A.; Guastavino, J. F.; Buden
́
́
́
, M. E.; Bardagí, J. I.;
Barolo, S. M.; Rossi, R. A. J. Org. Chem. 2012, 77, 1507−1519.
(b) Vaillard, V. A.; Rossi, R. A.; Arguello, J. E. Org. Biomol. Chem.
̈
2012, 10, 9255−9261.
(9) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P. Tetrahedron
2005, 61, 10603−10642.
(10) (a) Beckwith, A. L. J.; Gara, W. B. J. Chem. Soc., Perkin Trans. 2
1975, 593−600. (b) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073−
3100. (c) Beckwith, A. L. J.; Gerba, S. Aus. J. Chem. 1992, 289−308.
(11) Vaillard, S. E.; Postigo, A.; Rossi, R. A. J. Org. Chem. 2002, 67,
8500−8506.
N-Benzyl-N-(6-(diphenylphosphoryl)cyclohex-2-en-1-yl)-
acetamide (22b). White wax. Isolated (10 mg, 5% yield) by radial
thin-layer chromatography eluted with dichloromethane−methanol,
4728
dx.doi.org/10.1021/jo4001788 | J. Org. Chem. 2013, 78, 4719−4729

The Journal of Organic Chemistry
Article
(12) Beckwith, A. L. J.; Palacios, S. M. J. Phys. Org. Chem. 1991, 4,
404−412.
(38) (a) Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55,
117. (b) Miertus, S.; Tomasi, J. Chem. Phys. 1982, 65, 239−245.
(c) Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J. Chem. Phys. Lett.
1996, 255, 327−335.
(13) Annunziata, A.; Galli, C.; Marinelli, M.; Pau, T. Eur. J. Org.
Chem. 2001, 1323−1329.
(39) Kato, I.; Higashimoto, M.; Tamura, O.; Ishibashi, H. J. Org.
Chem. 2003, 68, 7983−7989.
(14) Bardagí, J. I.; Vaillard, S. E.; Rossi, R. A. ARKIVOC 2007, iv,
73−83.
(40) Shapiro, S. L.; Parrino, V. A.; Freedman, L. J. Am. Chem. Soc.
1959, 81, 3728−3736.
(15) Taniguchi, T.; Ishita, A.; Uchiyama, M.; Tamura, O.; Muraoka,
O.; Tanabe, G.; Ishibashi, H. J. Org. Chem. 2005, 70, 1922−1925.
(16) Rigby, J. H.; Qabar, M. N. J. Org. Chem. 1993, 58, 4473−4475.
(17) de la Fuente, M. C.; Domínguez, D. J. Org. Chem. 2007, 72,
8804−8810.
(18) Kamimura, A.; Ishihara, Y.; So, M.; Hayashi, T. Tetrahedron Lett.
2009, 50, 1727−1730.
(19) (a) Amatore, C.; Oturan, M. A.; Pinson, J.; Saveant, J.-M.;
́
Thieb
C.; Pinson, J.; Savea
103, 6930−6937. (c) Amatore, C.; Oturan, M. A.; Pinson, J.; Savea
J.-M.; Thieb
́
ault, A. J. Am. Chem. Soc. 1985, 107, 3451−3459. (b) Amatore,
nt, J.-M.; Thiebault, A. J. Am. Chem. Soc. 1981,
nt,
́
́
́
́
ault, A. J. Am. Chem. Soc. 1984, 106, 6318−6321.
(20) Abeywickrema, A. N.; Beckwith, A. L. J. J. Chem. Soc., Chem.
Commun. 1986, 464−465.
(21) Bentley, K. W. Nat. Prod. Rep. 2006, 23, 444−463.
(22) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669−1730.
(23) Stermitz, F. R.; Lorenz, P.; Tawara, J. N.; Zenewicz, L. A.; Lewis,
K. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 1433−1437.
(24) Cortijo, J.; Villagrasa, V.; Pons, R.; Berto, L.; Marti-Cabrera, M.;
Martinez-Losa, M.; Domenech, T.; Beleta, J.; Morcillo, E. J. Br. J.
Pharmacol. 1999, 127, 1641−1651.
(25) Kashiwada, Y.; Aoshima, A.; Ikeshiro, Y.; Chen, Y.-P.; Furukawa,
H.; Itoigawa, M.; Fujioka, T.; Mihashi, K.; Cosentino, L. M.; Morris-
Natschke, S. L.; Lee, K.-H. Bioorg. Med. Chem. 2005, 13, 443−448.
(26) Goodman, A. J.; Le Bourdonnec, B.; Dolle, R. E. ChemMedChem
2007, 2, 1552−1570.
(27) (a) Hoyt, S. B.; London, C.; Gorin, D.; Wyvratt, M. J.; Fisher,
M. H.; Abbadie, C.; Felix, J. P.; Garcia, M. L.; Li, X.; Lyons, K. A.;
McGowan, E.; MacIntyre, D. E.; Martin, W. J.; Priest, B. T.; Ritter, A.;
Smith, M. M.; Warren, V. A.; Williams, B. S.; Kaczorowski, G. J.;
Parsons, W. H. Bioorg. Med. Chem. Lett. 2007, 17, 4630−4634.
(b) Chang, J. H.; Kang, H.-U.; Jung, I.-H.; Cho, C.-G. Org. Lett. 2010,
12, 2016−2018.
(28) (a) Enders, D.; Lenzen, A.; Raabe, G. Angew. Chem., Int. Ed.
2005, 44, 3766−3769. (b) Cedron
́
, J. C.; Estev
́
ez-Braun, A.; Ravelo, A.
ez-Hernandez, N.;
G.; Gutierrez, D.; Flores, N.; Bucio, M. A.; Per
́
́
́
Joseph-Nathan, P. Org. Lett. 2009, 11, 1491−1494. (c) Soto, S.; Vaz,
E.; Dell’Aversana, C.; Alvarez, R.; Altucci, L.; de Lera, A. R. Org.
Biomol. Chem. 2012, 10, 2101−2112.
(29) Vogel’s Textbook of Practical Organic Chemistry, 5th ed.;
Longman Scientific & Technical: Harlow, England, 1991.
(30) A pKa value of 23.5 for trimethylstannane has been reported:
Petrov, E. S.; Terekhova, M. I.; Mirskov, R. G.; Voronkov, M. G.;
Shatenstein, A. I. Dokl. Akad. Nauk SSSR 1975, 221, 111; Chem. Abstr.
1975, 8, 155040.
(31) Determined by NOE experiments; see Supporting Information.
(32) Arguello, J. E.; Penen
65, 7175−7182.
́
ory, A. B.; Rossi, R. A. J. Org. Chem. 2000,
̈
̃
̃
(33) (a) Kornblum, N. Aldrichimica Acta 1990, 23, 71−78.
(b) Kornblum, N. Angew. Chem., Int. Ed. Engl. 1975, 14, 734−745.
(34) A longer irradiation time allowed the occurrence of more
initiation events. Compound 20 formed in 42% yield and alkenes 21 in
27% yield. This reaction is proposed to occur without propagation
steps.
(35) (a) Santiago, A. N.; Rossi, R. A. J. Chem. Soc., Chem. Commun.
1990, 206−208. (b) Pierini, A. B.; Gallego, M. H.; Andrada, K. F. C. J.
Org. Chem. 2007, 72, 3089−3092.
(36) Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J.; Thoma, G.;
̈
Kuliche, K. J.; Trach, F. In Organic Reactions; Paquette, L. A., Ed.; John
Wiley & Sons, Inc.: New York, 1996; Vol. 48, Chapter 2.
(37) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785−
789. (b) Becke, A. D. Phys. Rev. A 1988, 38, 3098−3100. (c) Grimme,
S. J. Comput. Chem. 2006, 27, 1787−1799.
4729
dx.doi.org/10.1021/jo4001788 | J. Org. Chem. 2013, 78, 4719−4729