Translocation versus cyclisation in radicals derived from N-3-alkenyl trichloroacetamides

Article abstract of DOI:10.1039/c0ob01228a

Under radical reaction conditions, two different and competitive reaction pathways were observed for N-(α-methylbenzyl)trichloroacetamides with a N-3-cyclohexenyl substituent: 1,4-hydrogen translocation and radical addition to a double bond. However, for

Full text of DOI:10.1039/c0ob01228a

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PAPER
Translocation versus cyclisation in radicals derived from N-3-alkenyl
trichloroacetamides
M. Luisa Marin,*a Ramon J. Zaragoza,*b Miguel A. Miranda,a Fa¨ıza Diabac and Josep Bonjochc
Received 21st December 2010, Accepted 17th February 2011
DOI: 10.1039/c0ob01228a
Under radical reaction conditions, two different and competitive reaction pathways were observed for
N-(a-methylbenzyl)trichloroacetamides with a N-3-cyclohexenyl substituent: 1,4-hydrogen
translocation and radical addition to a double bond. However, for radicals with an acyclic alkenyl side
chain, the direct cyclisation process was exclusively observed. The dichotomy between translocation
and direct radical cyclisation in these substrates has been theoretically studied using density functional
theory (DFT) methods at the B3LYP/6-31G** computational level.
Introduction
Trichloroacetamides have been used since the 1980s as radical pre-
cursors to synthesise nitrogen-containing heterocycles, such as b-,
g-, and d-lactams, in a variety of radical processes (e.g. atom trans-
fer mediated by CuCl1 or Grubbs’ ruthenium metathesis catalysis,2
and the hydride reductive method3). Their usefulness in radical
cyclisations leading to 6-membered rings can be attributed to
the stability of the formed N-(3-alkenyl)carbamoyldichloromethyl
radicals, which reduces the occurrence of the disruptive 1,5-
hydrogen shift.4 Several years ago, we showed that N-benzyl-N-
cyclohexenyl trichloroacetamides 1 are versatile reagents for the
synthesis of 2-azabicyclo[3.3.1]nonanes 2 (Scheme 1), via radical
cyclisation.5
Scheme 2 The synthesis of 2-azabicyclo[3.3.1]nonanes (4) together with
normorphans (5) from electron-rich (3a and 3c) or electron-poor (3b and
3d) N-cyclohexenyl trichloroacetamides.
with the expected 2-azabicyclo[3.3.1]nonanes 4, the normorphans
5 were also isolated. The former are the result of 6-exo-trig radical
Scheme 1 Synthesis of 2-azabicyclo[3.3.1]nonanes.
cyclisation, whereas the latter arise from a competitive process
Attempts to extend this morphan approach to the synthesis
involving 1,4-hydrogen transfer,8 followed by 5-exo-trig cyclisation
of enantiopure compounds with a (S)-1-phenylethyl group at the
with configurational inversion at the stereogenic benzylic carbon.
nitrogen produced a surprising result when using either electron-
At this point, we decided to explore the scope of this un-
rich6 or electron-poor7 radical acceptors (Scheme 2). Together
precedented radical rearrangement occurring in the tin hydride-
promoted cyclisation of trichloroacetamides bearing a N-(1-
phenylethyl) substituent.9 To assess whether translocation is a
process particular to the synthesis of morphans or whether it
can also occur when other alkylbenzyl moieties are present,
simple open-chain trichloroacetamides (6, 7, and 9) were prepared,
and their behaviour under radical reaction conditions (using the
hydride method) was examined.
aInstituto de Tecnolog´ıa Qu´ımica-Departamento de Qu´ımica (UPV-CSIC),
Avda de los Naranjos s/n, E-46022, Valencia, Spain. E-mail: marmarin@
qim.upv.es; Fax: + 34963877809; Tel: + 34963877815
bDepartamento de Quimica Organica, Universidad de Valencia, Dr Moliner
50, 46100, Burjassot, Valencia, Spain. E-mail: ramon.j.zaragoza@uv.es
cLaboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, Institut de
Biomedicina (IBUB), Universitat de Barcelona, Av., Joan XXIII s/n,
08028-, Barcelona, Spain
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Table 1 Total (E, au) and relative energies (DE, kcal mol-1), at the
B3LYP/6-31G** level in benzene, of the stationary points for the radical
transformations of 7 leading to 11 and 11a
To obtain further insight into these radical processes leading
to mono- and bicyclic compounds, theoretical studies on their
reaction pathways were also carried out. Thus, the reductive
cyclisation of trichloroacetamides 7, 3b, 1 (R CN) and 3d
has been studied by means of DFT calculations. Based on
the theoretical data obtained, different reaction mechanisms are
proposed to explain the experimental results.
E
DE
0.0
13.4
12.8
-10.7
-11.9
14.5
-9.5
8.9
R-1
-1593.447221
-1593.425862
-1593.426832
-1593.464250
-1593.466231
-1593.424075
-1593.462295
-1593.432970
-1593.437124
-1593.453740
-1593.457743
TS1-si
TS1-re
R-2-si
R-2-re
TS2
Results and discussion
Synthetic studies
R-3
TS3-si
TS3-re
R-4-si
R-4-re
Preparation of the starting materials
6
and
7
from the
6.3
-4.1
-6.6
corresponding amines in the trichloroacetylation step was
improved from the previously reported procedure.10 The
unreported trichloroacetamide 9 was prepared from 7 by
ozonolysis to give aldehyde 8, followed by treatment with
isopropenyl acetate.11 The enol acetate 9 was obtained as a mixture
of Z/E isomers (4 : 6 ratio) (Scheme 3). When trichloroacetamides
6,
7
and
9
were treated with tris(trimethylsilyl)silane
(TTMSS)/AIBN, pyrrolidone 10 (80%) and piperidones 11 (53%)
and 12 (78%) were, respectively, formed. The isolated compounds
are the result of cyclisation of the 1-(carbamoyl)dichloromethyl
radical onto the double bond without any diastereoselectivity
(epimeric 1 : 1 mixtures were obtained in every case). The
1,4-translocation products were not detected for these open-chain
trichloroacetamides that contain the alkylbenzyl moiety but lack
the cyclohexene. Therefore, it seems that both structural features
are required to observe the translocation process.
Fig. 1 B3LYP/6-31G** energy profiles for the radical transformations
leading from 7 to 11 and 11a in benzene; 7, 11 and 11a are off the scale.
shown in Fig. 1 and Table 1; finally, geometries of the involved
transition states are shown in Fig. 2.
For the conversion of 7 into 11 or 11a (not observed) two
possible reaction paths (paths 1 and 2 in Scheme 4) have been inves-
tigated. In this mechanism, radical cyclisation or hydrogen translo-
cation from the initially generated 1-(carbamoyl)dichloromethyl
radical are assumed to be faster than hydrogen abstraction, as
experimentally evidenced in the morphan series.7 In path 1, the
initial intermediate R-1 undergoes an intramolecular attack of the
dichloromethyl radical onto the olefinic carbon with simultaneous
six-membered ring formation, through TS1, to give cyclic radical
R-2. Final reduction of the radical intermediate R-2 leads to the
diastereomeric mixture of methylpiperidones 11. It is worth noting
that the possibility for the radical R-1 to attack the olefin by its re-
face and si-face results in two transition states TS1-re and TS1-si,
respectively.
In the reaction path 2, R-1 suffers an intramolecular hydrogen
transfer from the benzylic position to the dichloromethyl group,
through TS2, leading to benzyl radical R-3, which is stabilised
by conjugation with the aromatic ring. Intramolecular attack of
R-3 to the olefinic carbon with simultaneous five-membered ring
formation through TS3 gives rise to R-4. Subsequent reduction
would afford the epimeric mixture of methylpyrrolidines 11a. As
mentioned above for path 1, both TS3-re and TS3-si may result
from the radical attack on both faces of the olefin, giving rise to
radicals R-4-re and R-4-si, respectively.
Scheme 3 Cyclisation of trichloroacetamides 6, 7 and 9.
The conversion of dichloromethyl radicalR-1 into the piperidine
radical R-2-re has an energy barrier of 12.8 kcal mol-1 (TS1-re),
while the energy barrier for the transformation into piperidone
radical R-2-si is 13.4 kcal mol-1 (TS1-si) (see Fig. 1 and Table 1).
Theoretical DFT studies
i) Conversion of 7 into 11 and 11a. The suggested mechanism
is depicted in Scheme 4; the energies of the relevant species are
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˚
Fig. 2 The transition states for the conversion of 7 into 11 and 11a through the mechanism postulated in Scheme 4. Bond length values are given in A.
favoured. However, this energy difference still allows competition
between both pathways in agreement with the observed exper-
imental results. Overall, the conversion of R-1 into R-2-re and
R-2-si is thermodynamically favoured by 11.9 and 10.7 kcal mol-1,
respectively.
On the other hand, the conversion of radical R-1 into the
pyrrolidine radical R-4 (path 2, Scheme 4) has an energy barrier
of 14.5 kcal mol-1 (TS2). The initial hydrogen transfer is the
rate determining step of the process (TS2), being more energetic
than the subsequent intramolecular attack of the benzyl radical
to the re-face or si-face of the olefin (TS3-re and TS3-si, 6.3
and 8.9 kcal mol-1, respectively). Hence, TS2 (path 2) is 1.7 and
1.1 kcal mol-1, respectively, above TS1-re and TS1-si (path 1).
As a consequence, the methylpyrrolidines 11a should be minor
products in the reaction mixture (ca. 3%), and may or may not be
observed.
ii) Conversion of 3b into 4b and 5b. The mechanism proposed
for the transformation of 3b into 4b and 5b (Scheme 5) is based
on a theoretical treatment analogous to that described above for
the conversion of 7 into 11 and 11a. The energies of the relevant
species are shown in Fig. 3 and Table 2. Fig. 4 shows the geometries
of the transition states involved in the proposed mechanism.
In this case, the starting point is the most stable conformer
of dichloromethyl radical R-5, bearing the acetamide moiety at
the equatorial position, that can evolve through paths 1 or 2.
Along the former path, R-5 is first converted into its conformer
R-5a by rotation of the N–CO bond through transition state
TS4. Then, R-5a changes to the inverted-chair conformation R-
Scheme 4 The suggested mechanism for the conversion of 7 into 11 and
11a.
5b, through TS5, in order to make the subsequent attack to the
double bond (by TS6) feasible. It is worth noting that inversion of
the chair conformation prior to the N–CO bond rotation, results
in a higher energetic barrier. Reduction of the intermediate R-6
leads to azabicyclononane 4b. The radical attack is only possible
These energy values indicate that the attack of radical R-1 on
the re-face of the olefin is, from a kinetic point of view, slightly
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Table 2 Total (E, au) and relative energies (DE, kcal mol-1), at the
B3LYP/6-31G** level in benzene, of the stationary points for the radical
transformations of 3b into 4b and 5b
E
DE
R-5
-1763.124648
-1763.106144
-1763.118500
-1763.103677
-1763.109453
-1763.103828
-1763.151660
-1763.102159
-1763.137806
-1763.122957
-1763.131537
-1763.111040
-1763.140392
0.00
11.6
3.9
13.2
9.5
13.1
-17.0
14.1
-8.3
1.1
TS4
R-5a
TS5
R-5b
TS6
R-6
TS7
R-7
TS8
R-7a
TS9
R-8
-4.3
8.5
-9.9
Fig. 3 B3LYP/6-31G** energy profiles for the radical transformations
of 3b leading to 4b and 5b in benzene; 3b, 4b and 5b are off the scale.
and Table 2). As TS5 and TS6 have similar energetic levels,
they are the rate limiting steps. The dichloromethyl radical R-5,
stabilised by interaction with the benzylic hydrogen, is converted
into the less stable radical R-5a (+3.9 kcal mol-1). The subsequent
conversion of R-5a into R-5b is clearly a disfavoured step from an
energetic point of view (+5.6 kcal mol-1). Remarkably, formation
of R-6 from R-5b is thermodynamically favoured. On the other
hand, the transformation of R-5 into R-8 has an energetic
barrier of 14.1 kcal mol-1 (TS7) that corresponds to the initial
hydrogen transfer. This step is more energetic than the subsequent
conformational change (TS8 = 1.1 kcal mol-1) and than the
intramolecular attack of the benzyl radical at the olefinic carbon
(TS9 = 8.5 kcal mol-1). The transformation of R-5 into R-7 is
exothermic (-8.3 kcal mol-1) due to stabilisation of the benzyl
radical formed. The conformational change from R-7 to R-7a is
again an endothermic step (+4.0 kcal mol-1); however, the radical
from the same side of the molecule, due to the conformational
restrictions of TS6, giving rise to only one diastereoisomer of 4b.
In path 2, radical R-5 undergoes an intramolecular hydrogen
transfer from the benzylic position to the dichloromethyl group
through transition state TS7. The stabilised benzyl radical inter-
mediate R-7 suffers a conformational change of the cyclohexene
ring to an inverted-chair, with simultaneous rotation of the C1–
N bond (through TS8), leading to radical R-7a. Finally, R-
7a undergoes an intramolecular radical addition at the olefinic
carbon with simultaneous five-membered ring-formation (through
TS9), giving rise to R-8. Eventually, reduction of this radical
affords normorphan 5b.
Thus, dichloromethyl radical R-5 is converted into R-6 through
three transition states TS4, TS5 and TS6 with relative energy
values of 11.6, 13.2 and 13.1 kcal mol-1, respectively (see Fig. 3
˚
Fig. 4 Transition structures corresponding to the conversion of 3b into 4b and 5b. Bond length values are given in A.
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Table 3 Total (E, au) and relative energies (DE, kcal mol-1), at the
B3LYP/6-31G** level in benzene, of the most relevant transition states
for the radical transformations of 3d and 1 into 4d/5d and 2/2a
E
DE
0.0
13.8
13.2
14.5
0.0
13.0
10.9
16.1
R-9
-1763.117817
-1763.095888
-1763.096831
-1763.094658
-1723.802658
-1723.781910
-1763.785349
-1763.777087
TS10
TS11
TS12
T9a
TS10a
TS11a
TS12a
path 1 and TS7 for path 2, that of the former is 0.9 kcal mol-1
lower. This small difference allows competition between the two
pathways, with the formation of azabicyclononane 4b being
slightly favoured over that of normorphane 5b, in agreement with
the experimentally observed results.
iii) Conversion of 3d and 1 into 4d/5d and 2/2a. From the
above theoretical calculations, the rate limiting steps for the
conversion of 3b into 4b/5b are TS5/TS6 and TS7, respectively.
Hence, to simplify the theoretical study for the conversion of 3d
into 4d/5d and 1 into 2/2a only those transition states have been
considered (for clarity, compound 3d has been depicted as its
enantiomer, see Scheme 6). The energies of the relevant species
are shown in Table 3. Fig. 5 shows the geometries of the involved
transition states.
Scheme 6 A simplified mechanism for the conversion of 3d and 1 into
4d/5d and 2/2a.
Here, R-9 is the initially formed radical in the transformation
of 3d into 4d or 5d. Transition states TS10 and TS11 correspond
to the energetic barriers for the conformational change for chair
inversion and intramolecular radical attack to the olefinic carbon,
respectively, along path 1. Likewise, TS12 is the barrier for the
translocation of the benzylic hydrogen to the dichloromethyl
moiety leading to 5d along path 2. The equivalent species for the
transformation of trichloroacetamide 1 into the azabicyclononane
2 or normorphane 2a (not experimentally observed) are R-9a,
TS10a, TS11a and TS12a.
Scheme 5 The suggested mechanism for the conversion of 3b into 4b and
5b.
attack on the double bond giving rise to the bicyclic radical R-8 is
exothermic (-5.6 kcal mol-1).
Overall, both proposed pathways are exothermic by
-17.0 kcal mol-1 and -9.9 kcal mol-1, respectively. When the
energetic barriers of both pathways are compared, TS5/TS6 for
The energetic barriers for the conversion of 3d into 4d/5d
are similar to the ones calculated above for the epimer 3b (see
Table 3). Again, TS10 and TS11 (path 1) have very similar values
(13.8 kcal mol-1 and 13.2 kcal mol-1, respectively) while TS12
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Fig. 5 Transition structures corresponding to the conversion of 3d and 1 into 4d/5d and 2/2a. Bond length values are given in A.
(path 2) is higher in energy (14.5 kcal mol-1). When the energetic
barriers for the two pathways are compared, TS10 for path 1 and
TS12 for path 2, that of the former is 0.7 kcal mol-1 lower. This
difference is slightly smaller than that observed for the isomer 3b
(0.9 kcal mol-1) and supports the experimentally observed trend
of increased translocation product 5d.
chain alkenyl moiety, the obtained products result only from the
cyclisation of the 1-(carbamoyl)dichloromethyl radical onto the
double bond. The 1,4-translocation products are not detected.
Therefore, it seems that the two structural features are required
for the translocation to occur, namely the alkyl benzyl moiety and
the cyclohexene ring.
Finally, the theoretical calculations are significantly different
for trichloroacetamide 1, which contains a benzyl instead of a 1-
phenylethyl group. The energies of the implied transition states in
path 1 for conversion of 1 into 2 (TS10a and TS11a) are lower
(13.0 kcal mol-1 and 10.9 kcal mol-1, respectively) than in the
case of TS10 and TS11. On the other hand, TS12a (the energetic
barrier for the conversion of 1 into 2a through path 2 is now
16.1 kcal mol-1, much higher than TS12 (14.5 kcal mol-1). This
is reasonable, in view of the lower stability of secondary versus
tertiary benzylic radicals. As a conclusion, the energy barrier
for the conversion of 1 into 2 through path 1 is clearly lower
by 3.1 kcal mol-1 than for the conversion of 1 into 2a through
path 2. These calculations are in complete agreement with the
experimental results, and explain why normorphane 2a was not
observed.
Theoretical DFT calculations have been performed to explain
the formation of products resulting from cyclisation of the 1-
(carbamoyl)dichloromethyl radical onto the double bond (path
1) and/or the products arising from translocation of the benzylic
hydrogen to the dichloromethyl moiety followed by a cyclisation
(path 2). The relative energy barriers for the involved processes are
in good agreement with the experimental results.
Experimental Section
General
All reactions were carried out under an argon atmosphere with dry,
freshly distilled solvents under anhydrous conditions. Analytical
thin-layer chromatography was performed on SiO2 (Merck silica
gel 60 F254), and the spots were located with 1% aqueous KMnO4
or 2% ethanolic anisaldehyde. Chromatography refers to flash
chromatography and was carried out on SiO2 (SDS silica gel 60
ACC, 35-75 mm, 230-240 mesh ASTM). The drying of organic
extracts during work-up of the reactions was performed over
anhydrous MgSO4, except where stated otherwise. NMR spectra
were recorded in CDCl3 on a Varian Gemini 300 or Varian
Summary and conclusions
The radical cyclisation of N-cyclohexenyl trichloroacetamides
using AIBN/TTMSS gives rise to 2-azabicyclo[3.3.1]nonanes
with good overall yields. However, when N-cyclohexenyl-N-(1-
phenylethyl) trichloroacetamides are submitted to similar condi-
tions, normorphane derivatives are also isolated. The former are
the result of the expected 6-exo-trig radical cyclisation, whereas
the latter come from a competitive process involving a 1,4-
hydrogen transfer, followed by a 5-exo-trig cyclisation. When the
same experimental conditions were applied to trichloroacetamides
bearing an N-(1-phenylethyl) substituent and a simple open-
1
VNMRS 400. Chemical shifts of H and 13C NMR spectra are
reported in ppm downfield (d) from Me4Si.
N-[(S)-1-phenylethyl]-N-(2-propenyl)-2,2,2-trichloroacetamide 6
To a solution of N-[(S)-1-phenylethyl]allylamine12 (470 mg,
2.92 mmol) in CH2Cl2 (15 mL) was added triethylamine (0.81 mL,
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5.84 mmol) and the solution was cooled to 0 ◦C. Trichloroacetyl
chloride (0.49 mL, 4.38 mmol) in CH2Cl2 (1.5 mL) was added and
the resulting mixture was heated under reflux for 24 h. The reaction
mixture was concentrated, and the resulting residue was dissolved
in CH2Cl2, washed with 1 N aqueous HCl, and saturated aqueous
Na2CO3. The organic layer was dried, concentrated, and purified
by chromatography (10% EtOAc–hexane) to give 6 (643 mg, 72%)
as a yellow oil: IR (NaCl) 1668 (CO); 1H NMR (300 MHz, 50 ◦C)
1.74 (d, J = 7 Hz, 3 H), 3.51 and 4.12 (2 br s, 2 H), 5.04–5.14 (m,
2 H), 5.74–5.90 (m, 2 H), 7.20–7.40 (m, 5 H); 13C NMR (75 MHz,
DEPT) 17.7 (CH3), 48.6 (C-1), 56.8 (CH), 93.4 (CCl3), 117.1 (C-3),
126.5, 127.5, 128.4 (C-o, C-m, C-p), 132.5 (C-2), 138.8 (C-ipso),
159.9 (CO). Anal. calcd for C13H14Cl3NO: C, 50.92; H, 4.60; N,
4.57. Found: C, 50.77; H, 4.65; N, 4.45.
EtOAc–hexane) gave enol acetate 9 (80 mg, 68%) as a yellow oil
and as an E : Z isomeric mixture (6 : 4 according to 1H-NMR): IR
(NaCl) 1760, 1674; H NMR (400 MHz) 1.74 (br s, 3H, CH3),
1
2.05, 2.10 (2 s, 3H, CH3CO), 3.40–3.55 and 3.85–4.00 (2 m, 1.2H,
E isomer, CH2N), 3.60–3.75 and 4.00–4.10 (2 m, 0.8H, Z isomer,
CH2N), 5.00 (m, 0.4H, Z isomer, CH ), 5.40–5.50 (m, 0.6H, E
isomer, CH ), 5.80–6.00 (m, 1H, CH), 7.01 (dt, J = 6.3, 1.2 Hz,
0.4H, Z isomer, OCH ), 7.08 (dm, J = 12.9 Hz, 0.6H, E isomer,
OCH ), 7.20–7.40 (m, 5H, ArH); 13C NMR (100 MHz, DEPT)
17.4, 17.9 (CH3), 20.6 (CH3CO), 41.1 (CH2N, Z isomer), 44.0
(CH2N, E isomer), 56.9 (CH), 108.4 (CH , Z isomer), 108.8
(CH , E isomer), 126.9, 127.7, 127.8, 128.6 (C-o, C-m, C-p),
135.1 ( CHO), 138.6, 139.0 ( CHO), 160.1 (CO), 167.1, 167.5
(CO). Anal. calcd for C15H16Cl3NO3: C, 49.41; H, 4.42; N, 3.84.
Found: C, 49,24; H, 4.48; N, 3.69.
N-(2-butenyl)-N-[(S)-1-phenylethyl]-2,2,2-trichloroacetamide 7
Similarly,
from
N-(2-butenyl)-N-[(S)-1-phenylethyl]amine13
(4R)- and (4S)-4-methyl-1-[(S)-1-phenylethyl]pyrrolidin-2-one 10
(284 mg, 1.63 mmol) and after chromatography (hexane/EtOAc,
9 : 1) trichloroacetamide 7 (489 mg, 94%) was isolated as a
yellow oil. All spectroscopic data were in accordance with those
previously reported.10 IR (NaCl): 1670; 1H NMR (300 MHz) 1.60
(d, J = 7 Hz, 3H, CH3), 2.22 (m, 2H, CH2), 2.74 and 3.25 (2 m,
1H each, CH2), 4.82 (m, 2H, CH2), 5.48 (m, 1H, CH), 5.73 (m,
1H, CH), 7.20–7.40 (m, 5H); 13C NMR (75 MHz, DEPT) 17.9
(CH3), 32.3 (C-2), 46.4 (C-1), 56.8 (CH), 94.2 (CCl3), 117.0 (C-4),
127.0, 127.7, 128.6 (C-o, C-m, C-p), 135.2 (C-3), 139.0 (C-ipso),
160.2 (CO). HRMS (ESI-TOF): calcd for C14H17Cl3NO 320.0370
(M+ + 1). Found 320.0374.
A suspension of 6 (201 mg, 0.66 mmol) and AIBN (115 mg,
0.70 mmol) in benzene (6 mL) was heated to reflux. Then, TTMSS
(0.71 mL, 2.30 mmol) was added dropwise and the reaction
mixture was stirred at this temperature for 2 h and concentrated.
Purification of the residue by chromatography (CH2Cl2) gave 10
(106 mg, 80%) as a yellow oil and as an epimeric mixture (1 : 1 ratio
by 1H-RMN) All spectroscopic data were in accordance with those
previously reported.14 IR (NaCl) 1670; 1H NMR (300 MHz) 0.97
and 1.10 (2d, J = 7 Hz, 3H, CH3), 1.50 (d, J = 7 Hz, 3H, CH3), 2.00
(dd, J = 16.5, 6.3 Hz, 0.5 H), 2.05 (dd, J = 16.5, 7.2 Hz, 0.5H) 2.20–
2.40 (m, 1H), 2.50–2.60 (m,1.5H), 2.85 (dd, J = 9.4 and 6.4 Hz,
0.5H), 3.10 (dd, J = 9.4 and 7.6 Hz, 0.5H), 3.40 (dd, J = 9.3 and
7.5 Hz, 0.5H), 5.50 (q, J = 7 Hz, CH), 7.25–7.40 (m, 5H); 13C
NMR (75 MHz, DEPT) 16.6 (CH3), 20.0 (CH3), 26.8, 27.1 (C-4),
40.3 (C-3), 49.2 (CH), 49.9, 50.3 (C-5), 127.5, 127.9, 128.9 (C-o,
C-m, C-p), 140.8 (C-ipso), 174.4 (CO). HRMS (ESI-TOF): calcd
for C13H18NO 204.1383 (M+ + 1). Found 204.1388.
N-(3-oxopropyl)-N-[(S)-1-phenylethyl]-2,2,2-trichloroacetamide 8
A stirred solution of 7 (1.88 g, 5.87 mmol) in CH2Cl2 (19.4 mL)
at -78 ◦C was charged with a constant stream of ozone. After
15 min, the solution was purged with Ar until it was clear and
then Me2S (11.6 mL, 158 mmol) was added. The reaction mixture
was left at rt for 48 h. It was diluted with CH2Cl2 (50 mL), washed
with brine, dried and concentrated. Purification of the residue by
chromatography (20% EtOAc–hexane) gave aldehyde 8 (1.37 g,
73%) as a clear oil: IR (NaCl): 1670, 1724; 1H NMR (400 MHz)
1.74 (d, J = 6.9 Hz, 3H, CH3), 2.50–2.76 (m, 2H, CH2), 3.24–
3.40 (m, 1H, NCH), 3.48–3.64 (m, 1H, NCH), 5.82–5.94 (q, J =
(4R)- and (4S)-1-[(S)-1-phenylethyl]-4-methylpiperidin-2-one 11
Similarly, trichloroacetamide 7 (290 mg, 0.91 mmol) in benzene
(8.7 mL) was treated with AIBN (164 mg, 1.00 mmol) and TTMSS
(0.98 mL, 3.17 mmol), and the crude material was purified by
chromatography (EtOAc) to give 6 (105 mg, 53%) as a yellow oil
6.9 Hz, 1H, CH), 7.30–7.50 (m, 5H, ArH), 9.63 (s, 1H, CHO); 13
C
NMR (100 MHz, DEPT) 17,3 (CH3), 39.9 (CH2), 42.3 (NCH2),
56.8 (CH), 126.8, 128.0 and 128.7 (C-o, C-m, C-p), 138.3 (C-ipso),
160.4 (CO), 199.5 (CO). Anal. calcd for C13H14Cl3NO2: C, 48,40;
H, 4,37; N, 4,34. Found: C, 48,27; H, 4,34; N, 4,27.
1
and as an epimeric mixture (1 : 1 ratio by H-RMN): IR (NaCl)
1634; 1H NMR (400 MHz) 0.95, 0.97 (2 d, J = 2.4 Hz, 3H, CH3),
1.24 (dtd, J = 13.6, 10.4, 5.6 Hz, 0.5 H, H-5ax), 1.49 and 1.50 (2
d, J = 6.9 Hz, 3H, CH3), 1.75 (dm, J = 13.2 Hz, 0.5H, H-5eq),
1.80–2.00 (m, 1H, H-4), 2.06 (dd, J = 17.2, 3.6 Hz, 0.5H, H-3),
2.08 (dd, J = 17.2, 4.4 Hz, 0.5H, H-3), 2.56 (td, J = 5.2, 2 Hz, 0.5H,
H-3), 2.61 (td, J = 5.3, 2 Hz, 0.5H, H-3), 2.66 (ddd, J = 12.5, 10.5,
4.6 Hz, 0.5H, H-6ax), 2.86 (ddd, J = 12.1, 4.8, 3.4 Hz, 0.5H, H-6eq),
3.07–3.16 (m, 1H, H-6), 6.14 (q, J = 7 Hz, 1H, CH), 7.20–7.40 (m,
5H, ArH); 13C NMR (100 MHz, DEPT) 15.0, 15.3 (CH3), 20.8,
21.1 (CH3), 27.3, 27.8 (C-4), 30.7, 30.8 (C-5), 40.2, 40.4, 40.5, 40.6
(C-3 and C-6), 49.3, 49.4 (CH), 126.9, 127.0, 127.3, 128.2 (C-o,
C-m, C-p), 140.0, 140.5 (C-ipso), 169.1, 169.2 (C-2). Anal. calcd
for C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 77.21; H, 8.84;
N, 6.40.
N-(3-acetoxyprop-2-enyl)-N-[(S)-1-phenylethyl]-2,2,2-
trichloroacetamide 9
To a solution of p-toluenesulfonic acid monohydrate (6 mg,
0.032 mmol) in isopropenyl acetate (1.5 mL) warmed at reflux
temperature was added a solution of aldehyde 8 (103 mg,
0.32 mmol) in isopropenyl acetate (3 mL) and the mixture was
stirred for 24 h. To the cooled reaction mixture was added Et2O
(10 mL) and the solution was washed with 5% aqueous NaHCO3
and H2O. The aqueous extracts were extracted with EtOAc,
and the combined organic layers were dried, and concentrated.
Purification of the residue by chromatography (FlorisilTM, 5%
3186 | Org. Biomol. Chem., 2011, 9, 3180–3187
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(4R)- and (4S)-4-acetoxymethyl-1-[(S)-1-
phenylethyl]pyrrolidin-2-one 12
Lett., 2006, 47, 1145; (c) F. I. McGonagle, L. Brown, A. Cooke and A.
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Heterocycles, 1999, 50, 731; (c) J. Quirante, C. Escolano, F. Diaba and
J. Bonjoch, J. Chem. Soc., Perkin Trans. 1, 1999, 1157.
Following the above procedure for the cyclization of 6 to 10, from
trichloroacetamide 9 (282 mg, 0.77 mmol) with a 3 h reaction time,
pyrrolidone 12a (78 mg) and its epimer 12b (79 mg) were obtained
after chromatography (EtOAc) as yellow oils (78% overall yield).
1
12a: IR (NaCl) 1741, 1684; H NMR (400 MHz) 1.52 (d, J =
6.8 Hz, 3H, CH3), 2.05 (s, 3H, CH3CO), 2.26 (dd, J = 20.4, 10 Hz,
1H, H-3), 2.58 (dd, J = 19.8, 8.4 Hz, 1H, H-3), 2.56–2.62 (m, 1H,
H-4), 3.09 (d, J = 6 Hz, 2H, H-5), 4.02 (dd, J = 11.4, 6.8 Hz, 1H,
CHO), 4.08 (dd, J = 11.2, 5.6 Hz, 1H, CHO), 5.50 (q, J = 7.2 Hz,
1H, CH), 7.20–7.40 (m, 5H, ArH); 13C NMR (100 MHz, DEPT)
16.0 (CH3), 20.7 (CH3CO), 30.4 (C-4), 34.4 (C-3), 44.8 (C-5), 48.9
(CH), 65.9 (CH2O), 127.0, 127.5 and 128.5 (C-o, C-m, C-p), 139.8
(C-ipso), 170.8 (CO), 172.7 (CO). Anal. calcd for C15H19NO3·1/10
H2O: C, 68.47; H, 7.35; N, 5.32. Found: C, 68.30; H, 7.55; N, 5.37.
6 J. Quirante, M. Torra, F. Diaba, C. Escolano and J. Bonjoch,
Tetrahedron: Asymmetry, 1999, 10, 2399.
7 J. Quirante, F. Diaba, X. Vila, J. Bonjoch, E. Lago and E. Molins, C.
R. Acad. Sci. Paris, 2001, 4, 513.
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Org. Lett., 2000, 2, 2591; (c) J. Cassayre and S. Z. Zard, J. Organomet.
Chem., 2001, 624, 316.
9 For radical cyclizations involving N-(a-methylbenzyl) substituted com-
pounds, see: (a) B. Cardillo, R. Galeazzi, G. Mobbili, M. Orena and M.
Rossetti, Heterocycles, 1994, 38, 2663; (b) H. Ishibashi, C. Kameoka,
K. Kodama and M. Ikeda, Tetrahedron, 1996, 52, 489; (c) H. Ishibashi,
Y. Fuke, T. Yamashita and M. Ikeda, Tetrahedron: Asymmetry, 1996,
7, 2531; (d) H. Ishibashi, K. Kodama, C. Kameoka, H. Kawanami and
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K. Kodama, H. Kawanami, M. Humada and M. Okeda, Tetrahedron,
1997, 53, 9611; (f) M. Ikeda, S. Ohtani, T. Sato and H. Ishibashi,
Synthesis, 1998, 1803.
1
12b: IR (NaCl): 1740, 1683; H NMR (400 MHz) 1.53 (d, J =
7.2 Hz, 3H, CH3), 1.97 (s, 3H, COCH3), 2.23 (ddd, J = 19.6, 10,
4.2 Hz, 1H, H-3), 2.53–2.67 (m, 2H, H-3, H-4), 2.74 (dd, J = 10,
4.8 Hz, 1H, H-5), 3.45 (dd, J = 10, 7.6 Hz, 1H, H-5), 3.87 (dd,
J = 10.8, 6.8 Hz, 1 H, CHO), 3.94 (dd, J = 10.6, 6 Hz, 1H, CHO),
5.50 (q, J = 7.2 Hz, 1H, CH), 7.20–7.40 (m, 5H, ArH); 13C NMR
(100 MHz, DEPT) 16.0 (CH3), 20.6 (CH3CO), 30.1 (C-4), 34.5
(C-3), 44.9 (C-5), 49.0 (CH), 65.8 (CH2O), 127.0, 127.6 and 128.5
(C-o, C-m, C-p), 139.8 (C-ipso), 170.7 (CO), 172.8 (CO). Anal.
calcd for C15H19NO3·1/2 H2O: C, 66.64; H, 7.46; N, 5.18. Found:
C, 66.64; H, 7.37; N, 5.18.
10 A. J. Clark, F. De Campo, R. J. Deeth, R. P. Filik, S. Gatard, N. A.
Hunt, D. Laste´coue`res, G. H. Thomas, J.-B. Verlhac and H. Wongtap,
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11 R. I. Duclos Jr. and A. Makriyannis, J. Org. Chem., 1992, 57, 6156.
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Tetrahedron, 1991, 47, 2263; (b) B. Cardillo, R. Galeazzi, G. Mobbili, M.
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Tetrahedron, 2004, 60, 10809.
Computational methods
All calculations were carried out with the Gaussian 03 suite of
programs.15 Density functional theory16 calculations (DFT) have
carried out using the B3LYP17 exchange–correlation functionals,
together with the standard 6-31G** basis set.18 The stationary
points were characterized by frequency calculations in order
to verify that minima and transition structures have zero and
one imaginary frequency, respectively. The inclusion of solvent
effects has been considered by using a relatively simple self-
consistent reaction field (SCRF)method19 based on the polarizable
continuum model (PCM) of Tomasi’s group.20 We have used
benzene as the solvent. Gaussian treats H atoms as part of a
fragment (OH, CH, SH etc.) when creating cavities in the PCM
model. In some cases (e.g. heavy atom-H bond is elongated), cavity
building fails. For this reason, we have used the cavity model that
also assigns spheres to hydrogens (radii = uff).
13 P. Karoyan and G. Chassaing, Tetrahedron: Asymmetry, 1997, 8,
2025.
14 For alternative radical procedures leading to 10 and their analytical
data, see: (a) M. Ikeda, H. Teranishi, K. Nozaki and H. Ishibashi, J.
Chem. Soc., Perkin Trans. 1, 1998, 1691; (b) B. Cardillo, R. Galeazzi,
G. Mobbili, M. Orena and M. Rossetti, Heterocycles, 1994, 38, 2663.
15 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, J. A. Montgomery Jr., T. Vreven, K. N. Kudin, J. C.
Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci,
M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M.
Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox,
H. P. Hratchian, J. B. Cross, C. Adamo, J. Jaramillo, R. Gomperts,
R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J.
W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J.
J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C.
Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B.
Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski,
B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R.
L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A.
Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen,
M. W. Wong, C. Gonzalez and J. A. Pople, Gaussian 03, Revision C. 02,
Gaussian, Inc., Wallingford CT, 2004.
Acknowledgements
This research was supported by the Ministry of Education and
Science (Spain)-FEDER through projects CTQ2007-61338/BQU,
CTQ2009-11027/BQU and CTQ2009-13699 and Universidad
Politecnica de Valencia (2005-PPI-06-05).
16 (a) R. G. Parr and W. Yang, Density Functional Theory of Atoms and
Molecules, Oxford University Press, New York, 1989; (b) T. Ziegler,
Chem. Rev., 1991, 91, 651.
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18 W. J. Hehre, L. Radom, P. V. R. Schleyer and J. A. Pople, Ab initio
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The Royal Society of Chemistry 2011
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