Chlorine atom transfer radical 6-exo cyclizations of carbamoyldichloroacetate-tethered alkenes, enol acetates and α,β-unsaturated nitriles leading to morphans

Article abstract of DOI:10.1002/ejoc.201301590

The Cu^I-mediated atom transfer radical cyclization of amino-tethered dichloromalonamides and electron-rich, electron-poor, and nonactivated double bonds is a useful methodology for the synthesis of 2-azabicyclo[3.3.1]nonanes. A study of the rea

Full text of DOI:10.1002/ejoc.201301590

FULL PAPER
DOI: 10.1002/ejoc.201301590
Chlorine Atom Transfer Radical 6-exo Cyclizations of
Carbamoyldichloroacetate-Tethered Alkenes, Enol Acetates and
α,β-Unsaturated Nitriles Leading to Morphans
Faïza Diaba,*[a] Agustín Martínez-Laporta,[a] and Josep Bonjoch*[a]
Keywords: Synthetic methods / Radicals / Cyclization / Nitrogen heterocycles / Lactams
The CuI-mediated atom transfer radical cyclization of amino-
tethered dichloromalonamides and electron-rich, electron-
poor, and nonactivated double bonds is a useful methodology
for the synthesis of 2-azabicyclo[3.3.1]nonanes. A study of
the reaction conditions and the scope of the process is re-
ported. Cyclopropane ring formation was observed from the
resulting 1,3-dichlorides in some morphan substrates using
either CuI, Pd, or Zn.
of trichloro- or dichloroacetamides.[9] We report herein the
first 6-exo-trig radical cyclization of α,α-dichloroamido es-
ters (Scheme 1). The purpose of this work is to examine the
scope and limitations of this radical methodology in the
search for nitrogen-containing building blocks that might
be useful in alkaloid synthesis. The process was studied with
three types of radical acceptors: α,β-unsaturated nitriles,
alkenes, and enol acetate moieties, each with different elec-
tron density. The stereochemical course of the reactions as
well as the chemical behavior of the resulting azabicyclic
compounds is also reported.
Introduction
The morphan nucleus (2-azabicyclo[3.3.1]nonane ring) is
found in many alkaloids[1] belonging to highly diverse bio-
genetic families (Figure 1). In earlier work, we developed a
synthetic entry to morphan derivatives based on the re-
ductive cyclization of trichloroacetamides, using tributyltin
hydride as well as tris(trimethylsilyl)silane.[2] Recently,
based on the well-known ability of copper(I) complexes to
catalyze atom transfer radical cyclization (ATRC) reactions
of olefins with polyhalogenated compounds,[3] we reported
a new synthetic route to polyfunctionalized morphan com-
pounds.[4] The procedure was based on the use of a CuI
complex with TPMA [tris(2-pyridylmethyl)amine] in con-
junction with the additive AIBN,[5] which regenerates the
catalytically active copper(I) species by reduction of the
CuII complex.
Figure 1. Alkaloids embodying the azabicyclic morphan frame-
work.
In the synthesis of nitrogen-containing heterocycles,[6,7]
the use of α,α-dichloro β-dicarbonylated substrates as pro-
radicals[8] has been far less studied (Scheme 1) than the use
Scheme 1. Atom transfer radical cyclization (ATRC) of dichloro-
malonamides.
[a] Laboratori de Química Orgànica, Facultat de Farmàcia, IBUB,
University of Barcelona,
Av. Joan XXIII s/n, 08028 Barcelona, Spain
E-mail: faiza.diaba@ub.edu
Results and Discussion
josep.bonjoch@ub.edu
http://www.ub.edu/farmaco/en/quimica/llistat_recerca/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301590
The dichlorocarbamoylacetates (α,α-dichloro-β-amido
esters) required for this study were prepared from the
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F. Diaba, A. Martínez-Laporta, J. Bonjoch
FULL PAPER
known aminocyclohexane derivatives 1[10] and 2–3,[2a] by took place without standard ligands when N,N-dimethyl-
following the synthetic sequences depicted in Scheme 2.
formamide (DMF) was used as the solvent[11] with 30%
catalyst loading (42% combined yield, diastereomeric mix-
ture: entry 2).
Table 1. ATRC from α-carbamoyl-α,α-dichloro esters 8–10 using
CuCl.[a]
Entry Compd. Ligand
(%)
Additive
(%)
Solvent
DCE
Yield (%)[c]
12 13
11
[b]
1
8
TPMA
(30)
AIBN
(50)
29
–
42
2
8
9
none
TPMA
(30)
none
AIBN
(50)
DMF
DCE
18
28
24
–
–
49
[d]
3[c]
4
5
9
10
none
TPMA
(30)
none
AIBN
(50)
DMF
DCE
35
–
36
55[e]
6
10
none
none
DMF
56[e]
Scheme 2. Preparation of the starting dichloromalonamides 8–10.
Reagents and conditions: (a) MsCl, iPr2EtN, CH2Cl2, room temp.,
3 h; (b) tBuOK, tBuOH, 90 °C, 24 h; (c) 10% HCl, THF, reflux,
2 h; (d) EtO2CCl2COCl, Et3N, CH2Cl2, room temp., overnight;
(e) TMSCN, CsF, CH3CN, room temp., overnight; (f) POCl3, pyr-
idine, benzene, reflux, 5 h; (g) 10% HCl, THF, reflux, 5 h; (h) iso-
propenyl acetate, TsOH, reflux, 5 h.
[a] Reaction conditions (unless noted otherwise): CuCl (30%) and
either 60 °C, 48 h, DCE or 80 °C overnight DMF. [b] When AIBN
was omitted, 12a was isolated (ca. 25%) and the yield of 13a de-
creased. [c] In this series, 14 (9%) and 15 (15%) were isolated under
these reaction conditions (Figure 3). [d] When AIBN was omitted,
12b was isolated (ca. 22%) and the yield of 13b decreased. [e] Mix-
ture of compounds 16 and 17 (1:1).
Cyclization of Alkene 8
Cyclization of α,β-Unsaturated Nitrile 9
Representative results of the studies carried out with
amido ester 8, which bears an alkene as the radical acceptor
(Scheme 3), are summarized in Table 1.Thus, in the pres-
ence of 0.3 equiv. of CuCl and TPMA and 0.5 equiv. of
AIBN at 60 °C in 1,2-dichloroethane (DCE) (entry 1), di-
chloride 8 underwent the desired cyclization reaction to give
the expected atom transfer product 11a (29%) and the aza-
tricyclic compound 13a (42%). The latter presumably arose
from the epimer 12a by a sequence of homolytic cleavage
of the axial C–Cl bond at C-4 promoted by CuCl, reduction
of the intermediate radical into the CuII enolate, and intra-
molecular cyclopropane ring formation by displacement of
the axial chlorine atom at C-6. This intramolecular SN2 re-
action has been previously observed in dichlorides with a
1,3-relationship.[6] Interestingly, the cyclization process also
The cyclization process using dichloroamido ester 9, in
which the radical acceptor shows a lower electron density
than in 8, proceeded in a similar manner (Table 1, entry 3;
Scheme 4). Of the two isomeric morphans, 11b was stable
in the reaction medium whereas the epimer 12b, with the
axial chlorine at C-4, quickly evolved to the cyclopropane
13b. In this series, using the reaction conditions of CuCl/
DMF, the cyclopropanation process from 12b was also ob-
served[12] (Table 1, entry 4). The relative configuration of
11b was determined by X-ray crystal structure analysis
(Figure 2). For a detailed NMR analysis of morphans 11–
12, see below. The structure of 11b unambiguously showed
that the radical cyclization leading to the compound with
the chlorine atom equatorially located at C-4 gave a stable
Scheme 3. ATRC from dichloroamido ester 8.
Scheme 4. ATRC from dichloroamido ester 9.
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Radical Cyclization Reactions
epimer in the reaction medium and did not undergo the Cyclization of Enol Acetate 10
cyclopropanation process observed from the epimer 12b, in
Finally, we examined the CuI-catalyzed annulation of
which the chlorine atom at C-4 was axially located.
enol acetate 10 (Scheme 5), with an electron-donating group
upon the alkene radical acceptor. Interestingly, treatment of
10 either under the standard cyclization conditions using
TPMA and AIBN or without additives (Table 1, entries 5
and 6) afforded ketone derivatives 16 and 17 as a 1:1 mix-
ture of epimers in 55% yield. They were formed when the
initial annulation products (i.e., α-chloro acetoxy intermedi-
ates, see Scheme 1) evolved into the more stable ketone
either under the reaction conditions or during workup.
Scheme 5. ATRC from dichloroamido ester 10.
Reduction Processes from Dihalides 11 and 12
We examined the behavior of the synthesized dichloro-
morphans in reduction processes by using either a hydro-
genation reaction or treatment by zinc metal. Catalytic hy-
drogenation of either 11a or 12a, as well as the epimeric
mixture of both, quantitatively gave rise to the cycloprop-
ane derivative 13a (Scheme 6). The formation of cycloprop-
ane compounds from 1,3-dichlorides by using metals has
been reported,[14] but to the best of our knowledge there
are no examples of the use of Pd as a promoter in a hydro-
genation process.
Figure 2. ORTEP drawing of morphan 11b. Elipsoid plots drawn
with 50% probability.
The minor compounds morphan 14, arising from a dehy-
drohalogenation process from 11a, and normorphan 15,
generated directly from the carbocyclic starting material 9,
were also isolated (Figure 3). The unexpected normorphan
15 came from the initial α-dicarbonylic radical after a 1,4-
hydrogen transfer, which generated a benzylic radical that
reacted with the unsaturated nitrile leading to the normor-
phan derivative. It is notable that, to the best of our knowl-
edge, this reaction pathway has never been observed in radi-
cal reactions using N-benzylacetamides other than in our
previous studies on related N-(1-phenylethyl)trichloroacet-
amides.[13] The stereochemistry of 15 was initially only ten-
tative due to the formation of a mixture of epimers, each
with two rotamers, at the stereogenic carbon atom in the
side chain, which gave a complex NMR spectrum. After the
reduction of both C–Cl bonds, the NMR spectroscopic
data allowed the unequivocal assignment of the relative
configuration of both normorphans (see below).
Scheme 6. Hydrogenation processes from morphans 11 and 12
(series a–b).
In contrast, epimeric dichloro derivatives with an equato-
rial cyano group at C-6 (11b and 12b) instead of a hydrogen
atom, as in 11a and 12a, behaved differently in the hydro-
genation process.[15] In this case, both dichlorides gave the
same morphan compound 18 without any detectable cyclo-
propanation. The epimer 12b evolved easily to morphan 18,
whereas catalytic hydrogenation of 11b was slow. It is note-
worthy that the stereochemical result at C-4 was the same
regardless of the configuration of this carbon atom in the
starting material. In the stereochemical arrangement of 18,
in which the ethoxycarbonyl group was in an axial disposi-
Figure 3. Compounds 14 and 15 and numbering of morphan and
normorphan derivatives.
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F. Diaba, A. Martínez-Laporta, J. Bonjoch
FULL PAPER
tion, the 1,3-diaxial interaction with the equatorial substitu- indicating its equatorial location. The stereochemistry at C-
ent at C-6 was avoided. 6 in 11b and 12b, in which C-6 is quaternary, was estab-
Interestingly, when the hydrogenation was carried out lished by X-ray analysis of the former (Figure 2). This
from the chloro compounds 16 and 17, irrespective of which stereochemical assignment is consistent with mechanistic
epimer was used, a mixture of amido esters 19, epimers at considerations, since the configuration at C-6 arose from
C-4, was isolated. (Scheme 7). This probably reflects the the transfer of the chlorine atom from the less hindered face
fact that when C-6 has an sp2 hybridization both epimers of the cyclohexane ring generated after the radical cycliza-
of 19 show similar stability, since the 1,3-diaxial interaction tion, which locates the chlorine in an axial disposition.
between the equatorial substituents at C-4 and C-6 in
morphan compounds does not take place.
On the other hand, the configuration at the quaternary
C-4 position (disubstituted with chloro and ethoxycarbonyl
groups) in 11, 12 (both series a/b), 16 and 17 was deduced
from the chemical shift of the axial H-9 in the piperidone
ring, which always appears upfield (δ = 1.95–2.05 ppm)
when it has a 1,3-diaxial relationship with the ester at C-4,
compared with the chemical shift observed (δ = 2.55–
2.8 ppm) in the epimeric counterparts. A greater deshield-
ing effect of the chlorine atom with respect to the ethoxy-
carbonyl group on hydrogen atoms with a 1,3-diaxial rela-
tionship was also observed in the chemical shift of H-6eq
when comparing the values in 11a (δ = 5.0 ppm) and 11b
(δ = 4.3 ppm). It is also noteworthy that, in compounds
with the chlorine atom equatorial with respect to the piper-
idone ring, the chemical shift of H-5 was always more de-
shielded than in the corresponding epimer in which the
chlorine atom was axial. In the 13C NMR spectra of com-
pounds with the ester group located axially (11a, 11b, and
16) the ester carbonyl group resonated at lower field (ca.
1.5 ppm) than in the corresponding epimers in which the
ester groups were located equatorially.
The stereostructure of normorphan 20, and hence of its
precursor normorphan 15, was ascertained on the basis of
the NMR spectroscopic data by comparison with a nor-
morphan analogue lacking the phenyl group at C-7.[10] The
13C NMR chemical shift of C-8 (δ = 31.9 ppm) in 20 was
shifted upfield with respect to that found in the compound
unsubstituted at C-7 (δ = 35.5 ppm). This result indicates a
compression upon H-8eq, which is only possible with the
stereochemistry assigned to 20, considering that the cyano
group at C-2 is located equatorially.
Scheme 7. Hydrogenation processes from morphans 16–17 and
normorphan 15.
The minor normorphan product 15 was also submitted
to the hydrogenation process to ascertain the configuration
at the benzylic methine at C-7 (see below for NMR studies);
in this case, normorphan 20 was isolated (Scheme 7).
The reduction of chlorinated morphans by using Zn af-
forded similar results. Whereas the reduction of the epi-
meric mixture of morphans 11a and 12a again gave the cy-
clopropane derivative 13a (now as a methyl ester, due to a
transesterification process in the reaction medium),[16] the
reduction of nitrile 12b gave 18 together with small quanti-
ties of its epimer at C-6 and cyclopropane 13b (as a methyl
ester). The reduction of chloro ketones 16 and 17 afforded
the same epimeric mixture as in the hydrogenation process
(i.e., 19).
Conclusions
The synthetic studies have revealed the ability of radical
species with electron-withdrawing groups to undergo cycli-
zation processes leading to morphan compounds, irrespec-
tive of the nature of the radical acceptor. Because the intra-
molecular addition products are 1,3-dichlorides, under
some conditions we observed an additional dehalogenation
step leading to cyclopropanes embedded in the morphan
nucleus.
NMR Studies
The stereochemistry of all synthesized morphans was es-
1
tablished on the basis of their H and 13C NMR spectro-
scopic data by considering the electronic, anisotropic, and
steric effects of the chlorine[17] and ester substituents. The
relative configuration at C-6 for the 6-monosubstituted
morphans 11a and 12a (for numbering of these compounds,
see Figure 3) was easily established by the coupling constant
Experimental Section
General Methods: 1H and 13C NMR spectra were recorded in
1
CDCl3 solution. H chemical shifts are reported as δ values (ppm)
relative to internal Me4Si, and 13C NMR spectra are referenced to
pattern arising from H-6, which appears as a broad singlet, the deuterated solvent signal (CDCl3: δ = 77.00 ppm). All NMR
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Radical Cyclization Reactions
spectroscopic data assignments are supported by COSY and HSQC
experiments. Infrared spectra were recorded with a Nicolet 320
FTIR spectrophotometer. TLC was performed on SiO2 (silica gel
60 F254, Merck). The spots were located under UV light or by stain-
ing with a 1% KMnO4 aqueous solution. Chromatography refers
to flash chromatography and was carried out on SiO2 (silica gel 60,
SDS, 230–400 mesh). CuCl (99.99%) was purchased from Sigma–
Aldrich and was used as received. All reactions were carried out
under an argon atmosphere with anhydrous, freshly distilled sol-
vents, under anhydrous conditions. Drying of the organic extracts
during reaction workup was performed over anhydrous Na2SO4.
(CH), 64.7 (OCH2), 80.3 (CCl2), 124.5 (=CH), 126.6 (=CH), 126.2,
126.9, 128.5 (Ph), 137.6 (ipso-C), 162.4 (CO), 163.7 (CO) ppm.
HRMS (ESI-TOF): calcd. for C18H22Cl2NO3 [M+ + 1] 370.0971;
found 370.0968.
Ethyl
3-[Benzyl(4-cyanocyclohex-3-en-1-yl)amino]-2,2-dichloro-3-
oxopropanoate (9): Operating as above, starting from 6 (0.77 g), af-
ter chromatography, 9 (1.21 g, 85%) was obtained (Z/E rotamers,
4:1 ratio, estimated by 1H NMR) as an amorphous white solid;
m.p. 133–134 °C. IR (NaCl): ν = 3062, 3031, 2981, 2937, 2873,
˜
2215, 1759, 1739, 1679, 1655 cm–1. 1H NMR (CDCl3, 400 MHz):
δ (Z rotamer) = 1.36 (t, J = 7.2 Hz, 3 H, CH3), 1.81 and 1.96 (2m,
2 H), 2.34 (m, 4 H), 4.37 (m, 2 H, OCH2), 4.46 (m, 1 H), 4.49 (d,
J = 16.4 Hz, 1 H, CH2Ph), 4.46 (m, 1 H), 4.66 (d, J = 16.4 Hz, 1
H, CH2Ph), 6.48 (br. s, 1 H, =CH), 7.25 (m, 5 H, PhH) ppm. δ (E
rotamer; main different signals) = 2.87 (br. s, 1 H), 3.44 (m, 1 H),
4.70 and 4.80 (2d, J = 16.4 Hz, 1 H each, CH2Ph), 6.43 (br. s, 1 H,
=CH) ppm. 13C NMR (CDCl3, 100 MHz): δ (Z rotamer) = 13.7
(CH3), 26.2 (CH2), 27.1 (CH2), 29.6 (CH2), 46.3 (CH2Ar), 53.3
(CH), 64.8 (OCH2), 79.9 (CCl2), 112.1 (C=), 118.3 (CN), 136.9
(ipso-C), 142.1 (CH=), 162.4 (CO), 163.2 (CO) ppm. δ (E rotamer;
main different signals) = 24.0 (CH2), 27.6 (CH2), 52.5 (CH2Ph),
55.9 (CH), 118.7 (CN), 126.0, 127.1, 128.6 (Ar-CH), 111.6 (=C),
127.3, 128.1, 128.6 (Ph), 135.2 (ipso-C), 143.0 (=CH) ppm. HRMS
(ESI-TOF): calcd. for C19H21Cl2N2O3 [M+ + 1] 395.0924; found
395.0926.
N-Benzyl-N-(3-cyclohexenyl)amine (4): A solution of alcohol 1[10]
(3.85 g, 12.6 mmol) and iPr2EtN (6.5 mL, 37.9 mmol) in CH2Cl2
(50 mL) was cooled in an ice bath, then MeSO2Cl (1.5 mL,
18.95 mmol) was added dropwise. After stirring at 0 °C for 1 h and
at room temp. for 3 h, the reaction mixture was washed with brine
and the aqueous phase was extracted with CH2Cl2. The organics
were dried, concentrated, dissolved in tBuOH, and treated with
tBuOK (1 m in tBuOH, 63 mL, 63 mmol) in tBuOH (200 mL) at
90 °C for 24 h. The reaction mixture was concentrated and the resi-
due was diluted with CH2Cl2 and washed with brine. The organics
were dried, concentrated, and purified by chromatography (hexane/
EtOAc, 80:20) to give the corresponding alkene (2.43 g, 67%). A
mixture of the above alkene (4.06 g, 14.13 mmol), hydrochloric acid
(10%, 70 mL), and THF (50 mL) was heated to reflux for 2 h. The
reaction was allowed to reach room temp., then NaOH aqueous
solution (2.5 m) was added until pH 11, and the mixture was ex-
tracted with CH2Cl2. The organics were dried and concentrated to
yield the corresponding secondary amine 4 (2.30 g, 87%). For
NMR spectroscopic data see Quirante et al.[10]
Ethyl
3-{[4-(Acetyloxy)cyclohex-3-en-1-yl]benzylamino}-2,2-di-
chloro-3-oxopropanoate (10): Operating as above, starting from 3
(0.8 g), after chromatography, 7 (1.22 g, 81%) was obtained as a
yellowish viscous oil. IR (NaCl): ν = 3061, 3029, 1758, 1718, 1677,
˜
1
1654 cm–1. H NMR (CDCl3, 400 MHz): δ = 1.39 (t, J = 7.2 Hz,
3 H, CH3), 1.86–2.28 (m, 4 H), 2.42 (m, 4 H), 4.41 (q, J = 7.2 Hz,
2 H, CH2O), 4.60 (s, 2 H, CH2Ph), 4.74 (m, 1 H), 7.15–7.40 (m, 5
H, PhH) ppm. 13C NMR (CDCl3, 100 MHz): δ = 13.8 (CH3), 29.8
(CH2), 39.7 (CH2), 46.5 (CH2Ph), 56.5 (CH), 64.9 (CH2O), 80.2
(CCl2), 126.3, 127.2, 128.6 (Ph), 137.2 (ipso-C), 162.4 (CO), 163.4
(CO), 207.7 (CO) ppm. HRMS (ESI-TOF): calcd. for
C18H22Cl2NO4 [M+ + 1] 386.0920; found 386.0917.
4-(Benzylamino)cyclohex-1-encarbonitrile (6): To
a solution of
ketone 2 (4.1 g, 12.53 mmol) in CH3CN (15 mL) at room temp.,
were added successively CsF[18] (0.19 g, 1.25 mmol) and TMSCN
(1.78 mL, 13.79 mmol) and the mixture was stirred overnight. The
mixture was then filtered through a Celite pad and concentrated to
yield the corresponding cyanohydrin (not shown), which was used
in the next step without further purification. To a solution of the
above cyanohydrin in benzene (4 mL), were added pyridine (21 mL,
26.1 mmol) and POCl3 (3.73 mL, 40.75 mmol). The mixture was
heated to reflux for 5 h, concentrated, diluted in CH2Cl2, and
washed with HCl (1 n) and then brine. The organics were dried
and concentrated to give 5, which was redissolved in THF (50 mL)
and HCl (10%, 70 mL), and heated at reflux for 5 h. The mixture
was then basified with NaOH (2 n) and extracted with CH2Cl2.
The organics were dried and concentrated, giving 6 (1.8 g, 68%,
yield over three steps). For NMR spectroscopic data see ref.[2a]
A solution of ketone 7 (0.5 g, 1.29 mmol) and pTsOH (0.295 g,
1.55 mmol) in isopropenyl acetate (17 mL) was heated to reflux for
5 h. The mixture was then concentrated and purified by chromatog-
raphy to give enol acetate 10 (0.453 mg, 82%). IR (NaCl, neat): ν
˜
1
= 3062, 3029, 2984, 2935, 2852, 1758, 1679, 1655 cm–1. H NMR
(CDCl3, 400 MHz): δ = 1.38 (t, J = 7.2 Hz, 3 H, CH3), 1.94 (m, 2
H), 2.10 (s, 3 H, CH3CO), 2.14–2.46 (m, 4 H), 4.39 (q, J = 7.2 Hz,
2 H, CH2O), 4.42 (m, 1 H), 4.52 (d, J = 16.0 Hz, 1 H, CH2Ph),
4.67 (d, J = 16 Hz, 1 H, CH2Ph), 5.26 (br. s, CH=), 7.16–7.34 (m,
5 H, PhH) ppm. 13C NMR (CDCl3, 100 MHz): δ = 13.8 (CH3),
20.9 (CH3CO), 26.7 (CH2), 26.9 (CH2), 27.1 (CH2), 46.6 (CH2Ph),
54.5 (CH), 64.8 (OCH2), 80.1 (CCl2), 111.8 (CH=), 126.1, 127.0,
128.5 (Ph), 137.3 (ipso-C), 147.3 (C=), 162.6 (CO), 163.5 (CO),
169.2 (CO) ppm. HRMS (ESI-TOF): calcd. for C20H24Cl2NO5 [M+
+ 1] 428.1026; found 428.1021.
Ethyl 3-[Benzyl(cyclohex-3-en-1-yl)amino]-2,2-dichloro-3-oxoprop-
anoate (8): To a solution of secondary amine 4 (0.42 g, 2.35 mmol)
and Et3N (0.65 mL, 4.7 mmol) in CH2Cl2 (5 mL) cooled in an ice
bath, ethyl 2,2,3-trichloro-3-oxopropanoate[19] (0.62 g, 2.82 mmol)
was added dropwise. The reaction mixture was warmed to room
temp. while stirring overnight. The mixture was diluted with
CH2Cl2, washed with brine, dried, concentrated, and purified by
chromatography (hexane/EtOAc, 80:20) to give 8 (765 mg, 92%) as
General Procedures for Atom Transfer Radical Cyclization of
Dichloroacetamides 8–10
a waxy solid. IR (NaCl): ν = 3088, 3063, 3029, 2983, 2935, 2840,
˜
1761, 1740, 1680, 1655 cm–1. 1H NMR (CDCl3, 400 MHz): δ =
1.37 (t, J = 7.2 Hz, 3 H, CH3), 1.74 and 1.86 (2m, 2 H), 2.19 (m,
4 H), 4.33 (m, 1 H), 4.38 (q, J = 7.2 Hz, 2 H, CH2O), 4.52 (d, J =
15.6 Hz, 1 H, CH2Ph), 4.67 (d, J = 15.6 Hz, 1 H, CH2Ph), 5.56
(br. d, J = 10.0 Hz, 1 H, =CH), 5.63 (br. d, J = 10.0 Hz, 1 H, =CH),
Procedure A (CuI, TPMA, AIBN): To a suspension of CuCl
(15.2 mg, 0.15 mmol, 30%) in 1,2-dichloroethane (4 mL) were suc-
cessively added TPMA (44 mg, 0.15 mmol), AIBN (41.6 mg,
0.25 mmol, 50%), and nitrile 9 (200 mg, 0.51 mmol) and the mix-
ture was heated at 60 °C for 48 h in a sealed tube. The solution was
7.18–7.35 (m, 5 H, PhH) ppm. 13C NMR (CDCl3, 100 MHz): δ = then allowed to reach room temp., concentrated, and purified by
13.8 (CH3), 25.5 (CH2), 27.4 (CH2), 29.3 (CH2), 46.6 (CH2Ar), 55.3 chromatography (hexane/EtOAc, 8:2 to hexane/EtOAc, 3:7).
Eur. J. Org. Chem. 2014, 2371–2378
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2375

F. Diaba, A. Martínez-Laporta, J. Bonjoch
FULL PAPER
Procedure B (CuI, DMF): A mixture of CuCl (7.6 mg, 0.07 mmol,
30%) and nitrile 9 (100 mg, 0.26 mmol) in DMF (1 mL) was heated
at 80 °C overnight in a sealed tube. The solution was then concen-
trated and purified by chromatography by using the same condi-
tions as in procedure A.
164.1 (C-3), 165.7 (CO) ppm. HRMS (ESI-TOF): calcd. for
C19H21Cl2N2O3 [M+ + 1] 395.0924; found 395.0924.
Ethyl (1RS,2RS,5RS,8SR)-4-Benzyl-3-oxo-4-azatricyclo[3.3.1.02,8]-
nonane-2-carboxylate (13a): Yellowish oil. IR (NaCl): ν = 3061,
˜
3028, 2935, 2868, 1729, 1642 cm–1. 1H NMR (CDCl3, 400 MHz):
δ = 1.26 (dm, J = 12 Hz, 1 H, 6-Heq), 1.32 (t, J = 7.2 Hz, 3 H,
CH3), 1.50 (ddd, J = 12, 8, 4 Hz, 1 H, 6-Hax), 1.86 (m, 1 H, 7-Heq),
1.88 (dt, J = 13.2, 2.4 Hz, 1 H, 9-H), 1.96 (dm, J = 13.2 Hz, 1 H,
9-H), 2.08 (m, 1 H, 1-H), 2.10 (m, 1 H, 7-Hax), 2.13 (m, 1 H, 8-H),
3.40 (br. s, 1 H, 5-H), 4.25 (q, J = 7.2 Hz, 2 H, OCH2), 4.37 and
4.89 (2d, J = 14.8 Hz, 1 H each, CH2Ph), 7.23–7.32 (m, 5 H,
PhH) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.2 (CH3), 16.9 (C-
7), 22.7 (C-8), 24.6 (C-6), 25.5 (C-9), 26.2 (C-1), 35.4 (C-2), 49.3
(CH2Ph), 50.7 (C-5), 61.3 (OCH2), 127.4, 128.2, 128.5 (Ph), 137.8
(ipso-C), 166.5 (C-3), 170.0 (CO) ppm. HRMS (ESI-TOF): calcd.
for C18H22NO3 [M+ + 1] 300.1600; found 300.1597.
For the overall results, see Table 1.
Ethyl (1RS,4SR,5RS,6RS)-2-Benzyl-4,6-dichloro-3-oxo-2-azabicy-
clo[3.3.1]nonane-4-carboxylate (11a): Colorless oil. IR (NaCl): ν =
˜
3063, 3029, 2943, 2860, 1739, 1667 cm–1. 1H NMR (CDCl3,
400 MHz): δ = 1.32 (t, J = 7.2 Hz, 3 H, CH3), 1.77 (br. d, J =
14.8 Hz, 1 H, 8-Heq), 1.85–2.07 (m, 4 H, 7-CH2, 8-Hax and 9-H),
2.39 (dt, J = 14.0, 3.2 Hz, 1 H, 9-H), 2.87 (br. d, J = 3.2 Hz, 1 H,
5-H), 3.52 (br. s, 1 H, 1-H), 3.82 (d, J = 15.2 Hz, 1 H, CH2Ph),
4.31 (m, 2 H, OCH2), 4.99 (br. s, 1 H, 6-H), 5.49 (d, J = 15.2 Hz,
1 H, CH2Ph), 7.26–7.37 (m, 5 H, PhH) ppm. 13C NMR (CDCl3,
100 MHz): δ = 13.9 (CH3), 22.2 (C-8), 24.6 (C-7), 25.0 (C-9), 44.1
(C-5), 48.8 (CH2Ph), 50.9 (C-1), 57.7 (C-6), 63.7 (OCH2), 71.6 (C- Ethyl (1RS,2SR,5RS,8RS)-4-Benzyl-8-cyano-3-oxo-4-azatricyclo-
4), 127.7, 127.9, 128.7 (Ph), 136.5 (ipso-C), 164.6 (C-3), 168.2
(CO) ppm. HRMS (ESI-TOF): calcd. for C18H22Cl2NO3 [M+ + 1]
370.0971; found 370.0968.
[3.3.1.02,8]nonane-2-carboxylate (13b): White solid; m.p. 79–80 °C.
1
IR (NaCl): ν = 3061, 3030, 2938, 2871, 2235, 1735, 1652 cm–1. H
˜
NMR (CDCl3, 400 MHz): δ = 1.37 (m, 1 H, 6-Heq), 1.39 (t, J =
7.2 Hz, 3 H, CH3), 1.58 (ddd, J = 13.6, 8.8, 4.8 Hz, 1 H, 6-Hax),
1.95 (br. s, 2 H, 9-CH2), 2.64 (br. s, 1 H, 1-H), 3.48 (br. s, 1 H, 5-
H), 4.34 (d, J = 14.0 Hz, 1 H, CH2Ph), 4.36 (m, 2 H, OCH2), 4.85
(d, J = 14.0 Hz, 1 H, CH2Ph), 7.24–7.35 (m, 5 H, PhH) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 14.0 (CH3), 17.5 (C-8), 21.2 (C-7),
24.2 (C-6), 24.2 (C-9), 28.5 (C-1), 41.3 (C-2), 49.5 (C-5), 49.9
(CH2Ph), 62.7 (OCH2), 119.6 (CN), 128.0, 128.2, 128.8 (Ph), 136.7
(ipso-C), 162.7 (C-3), 165.7 (CO) ppm. HRMS (ESI-TOF): calcd.
for C19H21N2O3 [M+ + 1] 325.1547; found 325.1555.
Ethyl (1RS,4SR,5RS,6RS)-2-Benzyl-4,6-dichloro-6-cyano-3-oxo-2-
azabicyclo[3.3.1]nonane-4-carboxylate (11b): White solid; m.p. 124–
125 °C (Et O/CH Cl , 9:1). IR (NaCl): ν = 3062, 3030, 2981, 2960,
˜
2
2
2
2940, 2214, 1741, 1670 cm–1. 1H NMR (CDCl3, 400 MHz): δ =
1.34 (t, J = 7.2 Hz, 3 H, CH3), 1.95 (m, 2 H, 8-CH2), 2.04 (br. d,
J = 15.2 Hz, 1 H, 9-H), 2.33 (m, 2 H, 7-CH2), 2.54 (dt, J = 15.2,
3.2 Hz, 1 H, 9-H), 3.29 (br. s, 1 H, 5-H), 3.50 (br. s, 1 H, 1-H), 3.88
(d, J = 14.8 Hz, 1 H, CH2Ph), 4.34 (m, 2 H, OCH2), 5.45 (d, J =
14.8 Hz, 1 H, CH2Ph), 7.27–7.38 (m, 5 H, PhH) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 13.8 (CH3), 23.3 (C-8), 26.6 (C-9), 30.1 (C- Ethyl (1RS,4SR,5RS)-2-Benzyl-4-chloro-6-cyano-3-oxo-2-azabicy-
7), 46.0 (C-5), 49.0 (CH2Ph), 49.2 (C-1), 59.6 (C-6), 64.2 (OCH2),
clo[3.3.1]non-6-ene-4-carboxylate (14): Yellow solid; m.p. 148–
69.8 (C-4), 118.9 (CN), 128.0, 128.1, 128.8 (Ph), 136.1 (ipso-C),
149 °C. IR (NaCl): ν = 3060, 3028, 2935, 2218, 1739, 1664 cm–1.
˜
163.6 (C-3), 167.2 (CO) ppm. HRMS (ESI-TOF): calcd. for 1H NMR (CDCl3, 400 MHz): δ = 1.34 (t, J = 7.2 Hz, 3 H, CH3),
C19H21Cl2N2O3 [M+ + 1] 395.0924; found 395.0916.
1.95 (ddd, J = 14.4, 4.4, 1.6 Hz, 1 H, 9-H), 2.22 (dm, J = 14.4 Hz,
1 H, 9-H), 2.38 (dm, J = 20.6 Hz, 1 H, 8-H), 2.61 (dd, J = 20.6,
4.4 Hz, 1 H, 8-H), 3.45 (br. s, 1 H, 5-H), 3.72 (br. s, 1 H, 1-H), 3.82
(d, J = 15.2 Hz, 1 H, CH2Ph), 4.34 (m, 2 H, OCH2), 5.54 (d, J =
15.2 Hz, 1 H, CH2Ph), 6.77 (t, J = 3.6 Hz, 1 H, 7-H), 7.28–7.38
(m, 5 H, PhH) ppm. 13C NMR (CDCl3, 100 MHz): δ = 13.9 (CH3),
26.7 (C-9), 31.2 (C-8), 38.9 (C-5), 48.1 (C-1), 49.2 (CH2Ph), 63.8
(OCH2), 70.5 (C-4), 113.5 (C-6), 118.8 (CN), 127.9, 128.0, 128.8
(Ph), 136.2 (ipso-C), 144.3 (C-7), 163.2 (C-3), 167.4 (CO) ppm.
HRMS (ESI-TOF): calcd. for C19H20ClN2O3 [M+ + 1] 359.1157;
found 359.1157.
Ethyl (1RS,4RS,5RS,6RS)-2-Benzyl-4,6-dichloro-3-oxo-2-azabicy-
clo[3.3.1]nonane-4-carboxylate (12a): Colorless oil. IR (NaCl): ν =
˜
3089, 3061, 3029, 2953, 2938, 2867, 1736, 1658 cm–1. 1H NMR
(CDCl3, 400 MHz): δ = 1.40 (t, J = 7.2 Hz, 3 H, CH3), 1.71 (br. d,
J = 14.8 Hz, 1 H, 8-Heq), 1.84 (m, 1 H, 7-Heq), 1.87 (tdd, J = 14,
4.4, 2.4 Hz, 1 H, 8-Hax), 2.33 (ddt, J = 16, 12.4, 3.2 Hz, 1 H, 7-
Hax), 2.38 (t, J = 3.2 Hz, 2 H, 9-CH2), 2.77 (m, 1 H, 5-H), 3.58
(br. s, 1 H, 1-H), 3.87 (d, J = 14.8 Hz, 1 H, CH2Ph), 4.31 (m, 1 H,
6-H), 4.39 (m, 2 H, OCH2), 5.28 (d, J = 14.8 Hz, 1 H, CH2Ph),
7.26–7.37 (m, 5 H, PhH) ppm. 13C NMR (CDCl3, 100 MHz): δ =
14.0 (CH3), 22.5 (C-8), 23.5 (C-7), 25.0 (C-9), 47.2 (C-5), 48.7 Ethyl 2-Chloro-3-(2-chloro-2-cyano-7-phenyl-6-azabicyclo[3.2.1]oct-
(CH2Ar), 51.3 (C-1), 57.8 (C-6), 63.4 (OCH2), 69.1 (C-4), 127.8, 6-yl)-3-oxopropanoate (15): IR (NaCl): ν = 1768, 1668 cm–1. 13C
˜
128.8 (Ph), 136.5 (ipso-C), 164.6 (C-3), 166.7 (CO) ppm. HRMS
(ESI-TOF): calcd. for C18H22Cl2NO3 [M+ + 1] 370.0971; found
370.0971.
NMR (CDCl3, 100 MHz): δ = 13.9 and 14.1 (CH3), 23.8 and 24.0
(C-3), 27.2 and 27.4 (C-4), 31.3, 33.1, 35.0 (C-2 and C-8), 54.3 and
55.4 (CHClCO), 54.2 and 54.3 (C-5), 56.1, 56.3 (C-1), 63.0 and
63.6 (OCH2), 62.1 and 64.6 (C-7), 118.5, 119.0 (CN), 125.6, 125.7,
128.7, 128.8, 129.4, 129.5 (Ph), 138.1, 138.5 (ipso-C), 163.0, 163.8,
163.9, 164.9 (CO) ppm. Minor signals for rotamer of each epimer
were also observed. HRMS (ESI-TOF): calcd. for C19H21Cl2N2O3
[M+ + 1] 395.0924; found 395.0923.
Ethyl (1RS,4RS,5RS,6RS)-2-Benzyl-4,6-dichloro-6-cyano-3-oxo-2-
azabicyclo[3.3.1]nonane-4-carboxylate (12b): IR (NaCl): ν = 3087,
˜
3062, 3029, 2982, 2962, 2939, 2870, 2243, 1762, 1736, 1664 cm–1.
1H NMR (CDCl3, 400 MHz): δ = 1.40 (t, J = 7.2 Hz, 3 H, CH3),
1.82 (br. d, J = 14.4 Hz, 1 H, 8-Heq), 1.93 (tdd, J = 14.4, 4.4,
2.4 Hz, 1 H, 8-Hax), 2.13 (dm, J = 15.2 Hz, 1 H, 7-Heq), 2.53 (t, J Ethyl
= 3.2 Hz, 2 H, 9-CH2), 2.78 (ddd, J = 15.2, 12.4, 5.2 Hz, 1 H, 7- [3.3.1]nonane-4-carboxylate (16): White solid. IR (NaCl): ν = 3063,
Hax), 3.08 (br. s, 1 H, 5-H), 3.59 (br. s, 1 H, 1-H), 4.19 (d, J = 3029, 2931, 2853, 1754, 1720, 1662 cm–1. 1H NMR (CDCl3,
(1RS,4SR,5RS)-2-Benzyl-4-chloro-3,6-dioxo-2-azabicyclo-
˜
14.8 Hz, 1 H, CH2Ph), 4.45 (q, J = 7.2 Hz, 2 H, OCH2), 5.10 (d, J
400 MHz): δ = 1.34 (t, J = 7.2 Hz, 3 H, CH3), 1.82 (tdd, J = 14,
5.2, 2.4 Hz, 1 H, 8-Hax), 2.01 (dt, J = 14.4, 3.2 Hz, 1 H, 9-H), 2.30
= 14.8 Hz, 1 H, CH2Ph), 7.25–7.38 (m, 5 H, PhH) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 13.5 (CH3), 23.4 (C-8), 25.1 (C-9), 29.1 (C- (dm, J = 14.0 Hz, 1 H, 8-Heq), 2.50 (dd, J = 15.6, 5.2 Hz, 1 H, 7-
7), 49.3 (CH2Ar), 49.8 (C-1), 49.9 (C-5), 59.1 (C-6), 64.0 (CH2O),
Heq), 2.58 (dq, J = 14.4, 3.2 Hz, 1 H, 9-H), 2.72 (ddd, J = 15.6,
68.9 (C-4), 117.7 (CN), 127.8, 128.0, 128.9 (Ph), 136.2 (ipso-C),
14.0, 7.2 Hz, 1 H, 7-Hax), 3.31 (br. s, 1 H, 5-H), 3.70 (br. s, 1 H, 1-
2376
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2371–2378

Radical Cyclization Reactions
H), 4.03 (d, J = 15.2 Hz, 1 H, CH2Ph), 4.36 (m, 2 H, OCH2), 5.54
(d, J = 15.2 Hz, 1 H, CH2Ph), 7.28–7.39 (m, 5 H, PhH) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 13.9 (CH3), 29.9 (C-8), 31.0 (C-9),
(C-9), 34.3 (C-7), 35.0 (C-7), 47.6 (C-5), 48.4 (CH2Ph), 48.6
(CH2Ph), 50.0 (C-1), 50.2 (C-4), 50.5 (C-1), 52.6 (C-4), 61.9
(OCH2), 62.1 (OCH2), 127.7, 127.9, 128.1, 128.8, 128.9 (Ph), 136.5
35.0 (C-7), 49.2 (CH2Ph), 50.6 (C-1), 55.1 (C-5), 63.9 (OCH2), 67.1 (ipso-C), 136.8 (ipso-C), 165.0 (C-3), 165.4 (C-3), 168.6 (CO), 169.4
(C-4), 127.9, 128.0, 128.9 (Ph), 136.2 (ipso-C), 164.3 (C-3), 167.2
(CO), 204.3 (CO) ppm. HRMS (ESI-TOF): calcd. for
C18H21ClNO4 [M+ + 1] 350.1154; found 350.1152.
(CO), 208.2 (CO), 208.9 (CO) ppm. HRMS (ESI-TOF): calcd. for
C18H22NO4 [M+ + 1] 316.1543; found 316.1551.
The same stereochemical result was observed when the hydrogen-
ation reaction was performed from 16 or 17 (20 mg in each case).
Ethyl
(1RS,4RS,5RS)-2-Benzyl-4-chloro-3,6-dioxo-2-azabicyclo-
[3.3.1]nonane-4-carboxylate (17): White solid. IR (NaCl): ν = 3062,
˜
Ethyl (1RS,2SR,5RS,7SR)-3-(2-Cyano-7-phenyl-6-azabicyclo[3.2.1]-
3028, 2938, 1760, 1715, 1659 cm–1. 1H NMR (CDCl3, 400 MHz):
δ = 1.31 (t, J = 7.2 Hz, 3 H, CH3), 1.79 (tdd, J = 13.6, 5.2, 2.4 Hz,
1 H, 8-Hax), 2.03 (dt, J = 14.4, 2.8 Hz, 1 H, 9-H), 2.25 (m, 1 H, 8-
Heq), 2.50 (dd, J = 15.6, 5.2 Hz, 1 H, 7-Heq), 2.87 (m, 1 H, 9-H),
2.91 (ddd, J = 15.6, 13.6, 7.2 Hz, 1 H, 7-Hax), 3.12 (br. s, 1 H, 5-
H), 3.73 (br. s, 1 H, 1-H), 4.09 (d, J = 15.2 Hz, 1 H, CH2Ph), 4.29
(q, J = 7.2 Hz, 2 H, OCH2), 5.36 (d, J = 15.2 Hz, 1 H, CH2Ph),
7.28–7.37 (m, 5 H, PhH) ppm. 13C NMR (CDCl3, 100 MHz): δ =
13.7 (CH3), 29.5 (C-9), 29.6 (C-8), 35.3 (C-7), 48.9 (CH2Ph), 50.9
(C-1), 56.9 (C-5), 63.9 (OCH2), 68.2 (C-4), 127.8, 128.0, 129.0 (Ph),
136.2 (ipso-C), 164.5 (C-3), 166.1 (CO), 205.6 (CO) ppm. HRMS
(ESI-TOF): calcd. for C18H21ClNO4 [M+ + 1] 350.1154; found
350.1152.
oct-6-yl)-3-oxopropanoate (20): IR (NaCl): ν = 3026, 2955, 2925,
˜
2855, 2235, 1734, 1651 cm–1. 1H NMR (CDCl3, 400 MHz): δ (E-
rotamer) = 1.28 (t, J = 7.6 Hz, 3 H, CH3), 1.39 (d, J = 12.0 Hz, 1
H, 8-Hax), 1.46 (m, 1 H, 4-H), 2.12 (m, 2 H, 3-CH2), 2.17 (m, 1 H,
8-Heq), 2.41 (m, 1 H, 4-H), 2.54 (br. s, 1 H, 1-H), 2.86 (ddd, J =
9.0, 7.2, 2.4 Hz, 1 H, 2-H), 3.07 and 3.18 (2d, J = 15.6 Hz, 1 H
each, NCOCH2), 4.19 (q, J = 7.6 Hz, 2 H, OCH2), 4.66 (t, J =
5.2 Hz, 1 H, 5-H), 5.07 (s, 1 H, 7-Heq), 7.20–7.42 (m, 5 H,
PhH) ppm; minor signals for Z rotamer were also observed at δ =
3.43 and 3.53 (2d, J = 15.0 Hz, NCOCH2), 4.39 (t, J = 5.2 Hz, 5-
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.1 (CH3), 22.6 (C-
3), 27.3 (C-4), 31.9 (two peaks, C-2 and C-8), 42.4 (CH2CO), 47.8
(C-1), 54.3 (C-5), 61.6 (OCH2), 63.9 (C-7), 121.3 (CN), 125.7,
128.1, 129.1 (Ph), 140.2 (ipso-C), 165.3 (CO), 167.4 (CO) ppm.
HRMS (ESI-TOF): calcd. for C19H23N2O3 [M+ + 1] 317.1703;
found 327.1702.
Ethyl
(1RS,4RS,5RS,6SR)-2-Benzyl-6-cyano-3-oxo-2-azabicyclo-
[3.3.1]nonane-4-carboxylate (18): A mixture of morphans 11b and
12b (25 mg, 0.06 mmol) was hydrogenated using Pd-C (3 mg) and
NaOAc (15 mg, 0.18 mmol) in ethanol (2.5 mL). After purification,
morphan 18 (14 mg, 70%) was isolated as a white solid; m.p. 114–
Single-Crystal X-ray Analysis of 11b: The structures were solved by
direct methods by using the SHELXS computer program and re-
fined by full-matrix least-squares method with SHELX97.[20]
CCDC-967928 (for 11b) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
115 °C. IR (NaCl): ν = 3063, 3028, 2872, 2237, 1734, 1645, 1734,
˜
1
1651 cm–1. H NMR (CDCl3, 400 MHz): δ = 1.33 (t, J = 7.2 Hz,
3 H, CH3), 1.42 (tdd, J = 14.4, 4.4, 2.4 Hz, 1 H, 8-Hax), 1.60 (dm,
J = 13.6 Hz, 1 H, 9-H), 1.72 (qd, J = 14, 4.4 Hz, 1 H, 7-Hax), 1.89
(dm, J = 14.0 Hz, 1 H, 8-Heq), 2.00 (dm, J = 14.0 Hz, 1 H, 7-Heq),
2.39 (ddt, J = 13.6, 3.6, 2.4 Hz, 1 H, 9-H), 2.65 (br. s, 1 H, 5-H),
2.82 (dt, J = 13.2, 4.0 Hz, 1 H, 6-H), 3.52 (br. s, 1 H, 1-H), 3.74
(br. s, 1 H, 4-H), 3.90 (d, J = 14.8 Hz, 1 H, CH2Ph), 4.26 (m, 2 H,
OCH2), 5.39 (d, J = 15.2 Hz, 1 H, CH2Ph), 7.24–7.37 (m, 5 H,
PhH) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.1 (CH3), 20.8 (C-
7), 27.1 (C-8), 28.6 (C-9), 32.7 (C-6), 34.0 (C-5), 48.3 (CH2Ph), 49.6
(C-1), 49.9 (C-4), 62.0 (CH2O), 120.0 (CN), 127.6, 128.7 (Ph), 136.6
(ipso-C), 165.8 (CO), 170.4 (CO) ppm. HRMS (ESI-TOF): calcd.
for C19H23N2O3 [M+ + 1] 327.1703; found 327.1700.
Crystal Data, X-ray Data Collection and Refinement Results of
Morphan 11b: C19H20Cl2N2O3; M = 395.27; monoclinic; space
group P21/c; a = 10.688(6) Å, b = 32.756(15) Å, c = 12.276(8) Å, α
= 90°, β = 117.00(4)°, γ = 90°; V = 3829(4) Å3; Z = 8; D =
1.371 Mgm–3; λ(Mo-Kα)
= 0.71073 Å; F(000) = 1648; T =
293(2) K. The sample (0.12ϫ0.09ϫ0.08 mm) was studied with a
diffractometer with an image plate detector. The data collection
(θmax = 32.33°, range of hkl: h –12Ǟ11, k –44Ǟ47, l –15Ǟ18) gave
16555 reflections with 6288 unique reflections from which 4408
with IϾ2.0σ(I).
Ethyl 2-Benzyl-3,6-dioxo-2-azabicyclo[3.3.1]nonane-4-carboxylate
(19): A 1:1 mixture of morphans 16 and 17 (40 mg, 0.11 mmol),
NaOAc (26.7 mg, 0.33 mmol), and a catalytic amount of Pd-C
(4 mg, 10%) in ethanol (3 mL) was stirred under a hydrogen atmo-
sphere overnight. The catalyst was removed by filtration through
Celite and the filtrate was concentrated and purified by chromatog-
raphy (hexane/EtOAc, 9:1 to 6:4) to give 19 (27 mg, 73%) as a 1:1
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra of all compounds, three
dimensional drawings of morphans 11, 12, 16–18 with the NMR
spectroscopic data embedded, and additional X-ray crystallo-
graphic data and ORTEP plots of 11b.
epimeric mixture. IR (NaCl):
ν = 2928, 2871, 1737, 1715,
˜
1644 cm–1. H NMR (CDCl3, 400 MHz): δ = 1.28 (t, J = 7.2 Hz,
3 H, CH3), 1.32 (t, J = 7.2 Hz, 3 H, CH3), 1.70–1.86 (m, 2 H, 8-
Hax of both), 1.96 (dm, J = 14.0 Hz, 1 H, 9-H), 2.10 (dt, J = 13.6,
3.2 Hz, 1 H, 9-H), 2.18 (dt, J = 13.6, 3.2 Hz, 1 H, 9-H), 2.22 (m,
2 H, 8-Heq of both), 2.45 (m, 3 H, 7-Heq, 7-CH2), 2.59 (dq, J =
14.0, 3.2 Hz, 1 H, 9-H), 2.88 (ddd, J = 15.2, 14, 7.2 Hz, 1 H, 7-
Hax), 2.98 (br. s, 1 H, 5-H), 3.04 (br. s, 1 H, 5-H), 3.49 (s, 1 H, 4-
H), 3.69 (br. s, 2 H, 1-H of both), 3.76 (d, J = 6 Hz, 1 H, 4-H),
4.03 and 4.13 (d, J = 15.2 Hz, 1 H, CH2Ph), 4.13 (d, J = 15.2 Hz,
1 H, CH2Ph), 4.15–4.30 (m, 4 H, OCH2 of both), 5.32 (d, J =
15.2 Hz, 1 H, CH2Ph), 5.49 (d, J = 15.2 Hz, 1 H, CH2Ph), 7.29–
7.38 (m, 10 H, PhH of both) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 13.9 (CH3), 14.0 (CH3), 29.2 (C-9), 29.5 (C-8), 29.6 (C-8), 32.7
1
Acknowledgments
Support of this research was provided by the Spanish Ministry of
Economy and Competitiveness (project number CTQ2010-14846/
BQU). M. Font-Bardia (University of Barcelona) and T. Calvet
(CCiTUB) are thanked for performing the X-ray analysis.
[1] For a review, see: J. Bonjoch, F. Diaba, B. Bradshaw, Synthesis
2011, 993–1018.
[2] a) J. Quirante, C. Escolano, M. Massot, J. Bonjoch, Tetrahe-
dron 1997, 53, 1391–1402; b) J. Quirante, C. Escolano, A. Me-
rino, J. Bonjoch, J. Org. Chem. 1998, 63, 968–976; c) J. Quir-
Eur. J. Org. Chem. 2014, 2371–2378
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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F. Diaba, A. Martínez-Laporta, J. Bonjoch
FULL PAPER
ante, C. Escolano, F. Diaba, J. Bonjoch, J. Chem. Soc. Perkin
Trans. 1 1999, 1157–1162.
[3] For reviews, see: a) A. J. Clark, Chem. Soc. Rev. 2002, 31, 1–
11; b) W. T. Eckenhoff, T. Pintauer, Catal. Rev. Sci. Eng. 2010,
52, 1–59.
[4] F. Diaba, A. Martínez-Laporta, J. Bonjoch, A. Pereira, J. M.
Muñoz-Molina, P. J. Pérez, T. R. Belderrain, Chem. Commun.
2012, 48, 8799–8801.
[5] Radicals formed from decomposition of the free radical initia-
tor 2,2Ј-azobis(isobutyronitrile) (AIBN) at 60 °C continuously
regenerate the catalytically active lower oxidation state transi-
tion metal complex (activator) by abstraction of a halogen
atom from the higher oxidation state complex (deactivator),
see: C. Ricardo, T. Pintauer, Chem. Commun. 2009, 3029–3031.
[6] Using stoichiometric CuI reaction conditions from acyclic
starting materials, see: N. Baldovini, M.-P. Bertrand, A. Car-
rière, R. Nouguier, J.-M. Plancher, J. Org. Chem. 1996, 61,
3205–3208.
[10] J. Quirante, X. Vila, C. Escolano, J. Bonjoch, J. Org. Chem.
2002, 67, 2323–2328.
[11] M. Pattarozzi, F. Roncaglia, V. Giangiordano, P. Davoli, F.
Prati, F. Ghelfi, Synthesis 2010, 694–700.
[12] For a sequential Ru/Mg ATRA/dechlorination reaction provid-
ing cyclopropanes, see: a) M. A. Fernández-Zúmel, C. Buron,
K. Sseverin, Eur. J. Org. Chem. 2011, 2272–2277; b) J. Risse,
M. Fernández-Zúmel, Y. Cudré, K. Severin, Org. Lett. 2012,
14, 3060–3063.
[13] a) J. Quirante, M. Torra, F. Diaba, C. Escolano, J. Bonjoch,
Tetrahedron: Asymmetry 1999, 10, 2339–2410; b) J. Quirante,
F. Diaba, X. Vila, J. Bonjoch, E. Lago, E. Molins, C. R. Acad.
Sci., Ser. IIc 2001, 4, 513–521; c) F. Diaba, J. A. Montiel, J.
Bonjoch, Tetrahedron 2013, 69, 4883–4889.
[14] For reductive coupling of 1,3-dihalides promoted by titano-
cene(II) species, see: T. Takeda, K. Shimane, T. Fujiwara, A.
Tsubouchi, Chem. Lett. 2002, 290–291.
[15] J. A. Seijas, M. P. Vázquez-Tato, L. Castedo, R. J. Estévez, G.
Ónega, M. Ruíz, Tetrahedron 1992, 48, 1637–1642.
[7] By using CuCl/bipyridine (0.5 equiv.) at 110 °C, toluene from
N-cyclohex-1-enyl derivatives, see: a) D. T. Davies, N. Kapur, [16] For the preparation of cyclopropanes from 1,3-diiodoalkanes
A. F. Parsons, Tetrahedron Lett. 1999, 40, 8615–8618; b) D. T.
Davies, N. Kapur, A. F. Parsons, Tetrahedron 2000, 56, 3941–
3949.
with zinc powder, see: a) D. Sakuma, H. Togo, Tetrahedron
2005, 61, 10138–10145. To the best of our knowledge, only one
low-yielding example using a 1,3-dichloroalkane has been re-
ported, see also: b) M. Heliwell, D. Fengas, C. K. Knight, J.
Parker, P. Quayle, J. Raftery, S. N. Richards, Tetrahedron Lett.
2005, 46, 7129–7134.
[8] For other examples of chlorine transfer cyclization of unsatu-
rated α-dicarbonylated compounds, see: a) T. K. Hayes, R. Vil-
lani, S. M. Weinreb, J. Am. Chem. Soc. 1988, 110, 5533–5543;
b) D. Yang, Y.-L. Yan, B.-F. Zheng, Q. Gao, N.-Y. Zhu, Org.
Lett. 2013, 15, 5757–5760.
[17] R. J. Abraham, M. A. Warne, L. Griffiths, J. Chem. Soc. Perkin
Trans. 2 1997, 881–886.
[9] For some recent atom transfer radical cyclizations from dichlo-
ro- or trichloroacetamides leading to nitrogen-containing ring
formation, see: a) Y. Motoyama, K. Kamo, A. Yuasa, H. Na-
gashima, Chem. Commun. 2010, 46, 2256–2258; b) F. I.
McGonagle, L. Brown, A. Cooke, A. Sutherland, Org. Biomol.
Chem. 2010, 8, 3418–3425; c) F. Bellesia, A. J. Clark, F. Fel-
luga, A. Gennaro, A. A. Isse, F. Roncaglia, F. Ghelfi, Adv.
Synth. Catal. 2013, 355, 1649–1660; d) Q. Li, G. Li, S. Ma, P.
Feng, Y. Shi, Org. Lett. 2013, 15, 2601–2603.
[18] S. S. Kim, G. Rajagopal, D. H. Song, J. Organomet. Chem.
2004, 689, 1734–1738.
[19] EtO2CCCl2COCl was prepared by chlorination (SO2Cl2) of
ethyl malonyl chloride on a 3 g scale by following a reported
procedure, see: G. Castelfranchi, E. Perrotti, Ann. Chim. 1957,
47, 1201–1224.
[20] G. M. Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112–122.
Received: October 23, 2013
Published Online: February 6, 2014
2378
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Eur. J. Org. Chem. 2014, 2371–2378