Unusual rearrangement and dearomatization reactions in Cu(I)-catalyzed atom transfer radical cyclizations from N-(1-phenylethyl)trichloroacetamides

Article abstract of DOI:10.1016/j.tet.2013.04.042

Atom transfer radical cyclization of N-(α-methyl)benzyl substituted trichloroacetamide upon α,β-unsaturated nitriles in compounds 1, using CuCl, trispyridylmethylamine (TPMA), and AIBN as a reducing agent, gives morphan derivatives (2 and 3) and the unusual normorphans 4 and 5, as well as the unexpected azaspirodecanes 6. Stereospecific formation of normorphans involves memory of chirality in the cyclization step and azaspirodecanes are generated by a radical dearomative ipsocyclization followed by a radical dimerization.

Full text of DOI:10.1016/j.tet.2013.04.042

Tetrahedron 69 (2013) 4883e4889
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Unusual rearrangement and dearomatization reactions in
Cu(I)-catalyzed atom transfer radical cyclizations from
N-(1-phenylethyl)trichloroacetamides
*
*
Faïza Diaba , Juan A. Montiel, Josep Bonjoch
ꢀ
ꢀ
Laboratori de Química Organica, Facultat de Farmacia, IBUB, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Atom transfer radical cyclization of N-(a-methyl)benzyl substituted trichloroacetamide upon a,b-un-
Received 28 January 2013
Received in revised form 8 April 2013
Accepted 12 April 2013
saturated nitriles in compounds 1, using CuCl, trispyridylmethylamine (TPMA), and AIBN as a reducing
agent, gives morphan derivatives (2 and 3) and the unusual normorphans 4 and 5, as well as the un-
expected azaspirodecanes 6. Stereospecific formation of normorphans involves memory of chirality in
the cyclization step and azaspirodecanes are generated by a radical dearomative ipsocyclization followed
by a radical dimerization.
Available online 16 April 2013
Keywords:
Amides
Ó 2013 Elsevier Ltd. All rights reserved.
ATRC
Memory of chirality
Nitrogen heterocycles
Radical reactions
1. Introduction
Trichloroacetamides are carboradical precursors that have been
applied in the synthesis of nitrogen-containing heterocycles em-
bodying a lactam ring by intramolecular atom transfer1e4 and hy-
dride reductive5e7 radical processes. The most frequently used
catalysts for atom transfer radical cyclizations (ATRC) are Cu(I)2,8e10
and Ru(II)1,3,4,11,12 reagents with several ligand types, with far fewer
10c,13
reported examples of FeeFeCl3
or NieAcOH.14 For radical re-
Scheme 1. ATRC leading to 2-azabicyclo[3.3.1]nonane I.
ductive cyclizations, the Bu3SnH/AIBN procedure is the most gen-
eral,15 TTMSS also being used as the reducing agent.16,17
and V were also isolated (Scheme 2).20 To understand this forma-
tion of normorphan compounds from an unusual initial 1,4-
hydrogen transfer, the reaction was also studied from a theoreti-
cal point of view using density functional theory (DFT) methods.21
With the aim of gaining further insight into this curious mode of
Recently, we have shown under several reaction conditions that
Cu(I) is a useful catalyst for the synthesis of polyfunctionalized 2-
azabicyclo[3.3.1]nonanes18 starting from N-trichloroacetamides
tethered with cyclohexenes (Scheme 1).19
As a continuation of this work, we were interested in exploring
this ATRC process using trichloroacetamide 1 (a mixture of epimers
1a and 1b) as the starting material in which the N-benzyl sub-
reactivity exhibited by N-(a-methylbenzyl)trichloro-acetamides,
we decided to study the behavior of diastereomers 1 under the
reaction conditions of Cu(I)-tris(2-pyridylmethyl)amine (TPMA)
and evaluate if the 1,4-hydrogen transfer is also a competitive re-
action pathway in the ATRC.
stituent was replaced by an a-methylbenzyl substituent. In a pre-
vious study we found that the reaction of 1, using Bu3SnH as the
promoter of a reductive cyclization process evolved unexpectedly,
since besides the envisaged morphans II and III, normorphans IV
2. Results and discussion
We began our studies under Cu(I) radical-generating conditions
with the reaction of 1 (55:45 mixture of epimers 1a and 1b, re-
spectively)22 using CuCl (30% catalyst) and TPMA (30%) in
* Corresponding authors. E-mail addresses: faiza.diaba@ub.edu (F. Diaba),
josep.bonjoch@ub.edu (J. Bonjoch).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.042

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F. Diaba et al. / Tetrahedron 69 (2013) 4883e4889
morphans 2 and 3, and normorphans 4 and 5 are included in Figs 2
and 3 (see below).
An overview of all the processes from trichloroacetamide 1a is
depicted in Scheme 4 (the same processes also occurred from the
diastereomer 1b, although the four types of compounds were ob-
tained in a different ratio, as shown in Table 1). The ATRC from
trichloroacetamides 1, like the reductive cyclization, led to the
competitive generation of morphan (2e3) and normorphan com-
pounds (4e5). The initially formed 1-(carbamoyl)dichloromethyl
radical with the amide Z conformation underwent cyclization upon
the
a,b-unsaturated nitrile and after chlorine atom transfer dia-
stereoselectively gave 2. The configuration of the new stereogenic
center bearing the transferred chlorine atom was in an axial dis-
position in the resulting rigid azabicyclic ring.
In contrast, the same radical in its E conformation evolved
through different reaction pathways. The quantitatively most im-
portant was a stereospecific process involving a 1,4-hydrogen
transfer,20,24 which generated a benzylic radical that reacted with
the unsaturated nitrile leading to the normorphan derivative, in
which the stereogenic benzylic carbon underwent a configurational
inversion. It is notable that this reaction pathway has never
been observed in radical reactions using N-(1-phenylethyl)tri-
chloroacetamides25,26 other than in our previous studies on related
compounds.20,27 The stereochemistry of the compounds with the
normorphan ring established that the radical 1,4-H translocation
and further cyclization occur with memory of chirality. In-
terestingly, Curran has recently reported an example of memory of
Scheme 2. Reductive radical cyclization of 1 (Ref. 20).
dichloroethane (80 ꢀC, 4 h) (Table 1, entry 1). The reaction mixture
was highly complex, generating morphan, normorphan, and azas-
pirodecane rings (2e6), as depicted in Scheme 3. A careful chro-
matographic purification established that morphans 2 and 3 had
been formed in 25% yield and normorphans 4 and 5 in 29% yield in
a 1.2:1 ratio in both series. Minor amounts of compounds were also
obtained from a spiroannulation that led to dearomatized and di-
meric compounds 6 as a diastereomeric mixture. The use of mi-
crowave irradiation shortened the reaction time to 15 min (entry 2),
but resulted in worse yields of compounds 2e5, and only a slight
increase in compounds 6 generated by radical cyclization upon the
benzene ring. Interestingly, when CH3CN was used as a solvent and
ligand for Cu(I), a new type of compound was formed (entry 3).
Thus, only morphan-type compounds and the rearranged 2,2-
dichloro-2-phenylacetamide 7 were isolated, the latter being the
major product of these reaction conditions. Finally, we applied our
recently described ATRC reaction conditions for the synthesis of
morphans,20 in which AIBN was used to ensure the regeneration of
Cu(I) in the reaction medium.23 Thus, using CuCl/TMPA/AIBN in
a molar ratio of 0.1/0.1/0.5 with respect to trichloroacetamide and
operating at 60 ꢀC (entry 4), we obtained the best overall yield
(64%) for morphans and normorphans from 1, while the formation
of dearomatized compounds diminished (Scheme 3). Finally, we
carried out the reaction using air-stable copper(II) complexes
(Table 1, entry 5), which unlike copper(I)/TPMA complexes do not
need to be managed in inert atmosphere. Moreover, AIBN not only
reduces copper(II) to copper(I), but also acts as an oxygen scaven-
ger. However, using the best reaction conditions found for 1,
replacing CuCl by CuCl2, gave poor results, with a conversion of only
50%. Notably, non-dimeric compounds 8 (14%) and 9 (5%), arising
from a dearomative cyclization process, were isolated (Fig. 1). Ad-
ditionally, less than 5% of morphans and normorphans 2e5 were
also formed, the starting material 1 being recovered in 48% yield.
The most significant NMR data used for the structural elucidation of
chirality in rebound cyclizations of
of configuration, initiated from a 1,5-hydrogen transfer from an
-methine carboxamide to a vinyl radical.28 In our case the pathway
a-amide radicals with retention
a
involves a memory of chirality in rebound cyclizations of benzyl
radicals with inversion of configuration, initiated from a 1,4-
hydrogen atom transfer from a benzylic methine hydrogen to a 1-
(carbamoyl)dichloromethyl radical. Notably, in this ATRC protocol
working at 60 ꢀC (Method D) compound 1b was more prone to
giving the 1,4-hydrogen translocation than 1a, leading to normor-
phan 5, whereas at a higher temperature (Method A) 1a gave the
normorphan compound 4 in a higher ratio but lower yield.
As an explanation of this memory of chirality,28,29 we assume
that the radical intermediate arising from a 1,4-hydrogen atom shift
exhibits a high activation barrier for rotation around the CeN single
bond.30 Its absolute chirality is thus preserved during the course of
the reaction, which involves a configuration inversion at C-7 of the
normorphans. Undoubtedly, the phenyl group also contributes to
the geometric stabilization of the radical intermediate.31
To ensure that compound 4 was derived from the cyclization of
1a, with configuration inversion at the benzylic carbon, and was not
ent-4, arising from cyclization of 1b with configuration retention,
we decided to correlate trichloroderivative 4 with dechlorinated
normorphan 10. The absolute configuration of 10 (IV in Scheme 2)
was established some years ago20 by X-ray crystal structure analysis
23
and the specific rotation value is known, [
a
]
ꢁ66 (c 3, CHCl3).
D
Reduction of 4 with Zn32 gave nitrile 10, which unfortunately was
contaminated with its epimer at C-2, indicating that the reduction
was not highly diastereoselective (Scheme 5). The NMR data of the
Table 1
CuCl-catalyzed cyclization of trichloroacetamides 1a
Entry (method)
Reaction conditionsb,c
2/3 ratio
4/5 ratio
6
7e9
1 (A)
2 (B)
3 (C)
4 (D)
5 (E)
CuCl (0.3) TPMA (0.3) DCE, 80 ꢀC
25% (1.2:1)
19% (2:1)
15% (1.5:1)
25% (1.1/1.0)
<5%
29% (1.2:1)
25% (3:2)
d
17%
24%
d
CuCl (0.3) TPMA (0.3) DCE,
m
W 80 ꢀC
d
CuCl (0.6) CH3CN,
m
W 80 ꢀC
7 31%
d
CuCl (0.1) TPMA (0.1) AIBN (0.5) DCE, 60 ꢀC
CuCl2 (0.1) TPMA (0.1) AIBN (0.5) DCE, 60 ꢀC
39% (1:2)
<5%
10%
d
8 15% 9 5%
a
For structures of compound 2e7, see Schemes 3 and 4. For compounds 8e9, see Fig. 1.
Reaction times: (A) 4 h; (B) 15 min; (C) 15 min; (D and E) 48 h.
Conversion: (A) 100%; (B) 100%; (C) 66%; (D) 100%; (E) 50%.
b
c

F. Diaba et al. / Tetrahedron 69 (2013) 4883e4889
4885
Scheme 3. Cu(I)-catalyzed atom transfer cyclization reactions from trichloroacetamides 1. Yields refer to isolated compounds and the processes from 1a and 1b are considered
separately.
purified reaction mixture matched the published data of the two
rotamers of 10 and showed a new set of signals attributable to
compound 11.
Disappointingly, we were not able to obtain a pure sample of 10,
nor the specific rotation for the synthesized 10. However, the
23
specific rotation for the impure sample was [
a
]
ꢁ55 (c 1, CHCl3)
D
with a levorotatory character, as reported for 10. In conclusion, the
precedents for this reaction type and the experimental results33
reported here support the postulated memory of chirality for the
cyclization of trichloroacetamides 1 leading to normorphans, in-
volving a configuration inversion at the radical carbon.
Fig. 1. Compounds 8 and 9 isolated using CuCl2 as initial reagent.
A third reaction pathway appeared along with the standard
radical reaction and the 1,4-hydrogen transfer that allowed the
normorphan formation. Thus, a competitive reaction from the same
radical intermediate that underwent the 1,4-hydrogen trans-
location was the ipsocyclization on the benzene ring.34,35 Surpris-
ingly, the cyclohexadienyl radical was not trapped by a chlorine
atom, as occurred in compound 8 (Fig.1), but evolved to the dimeric
compounds 6 by a radical coupling. Although the stereochemistry
of the diastereomeric mixture 6 could not be ascertained due to the
difficulty in isolating pure samples of the isomeric compounds, the
structure of 6 was established. The molecular formula of 6,
C34H34Cl4N4O4 was deduced from high-resolution FABMS mea-
surements of its ammonium molecular cluster ion (m/z 688.1774)
and NMR data, which is discussed below. As far as we know, there
are no precedents for the formation of compounds, such as 6 from
a radical cyclization upon a benzene ring with loss of aromaticity
and later dimerization.36
Fig. 2. Key NMR data for stereochemical assignment of morphans 2 and 3.
Finally, the fourth structural type (i.e., 7) formed from 1 in the
radical conditions was only isolated in the reaction when using
microwave irradiation and acetonitrile as the solvent. The 1,4-aryl
migration reaction from carbon to carbon has been docu-
mented,37,38 although never previously observed in our studies
on radicals from N-benzyltrichloroacetamides. As depicted in
Scheme 4, the same radical intermediate formed in the spi-
roannulation process that gives the dimeric compounds 6 evolved
through a 1,4-phenyl migration to an
a-aminoethyl radical. This
was probably trapped by a chlorine atom transfer, giving a 1-
chloroethylacetamide, which through an acyliminium salt and
hydrolysis in the workup led to the acetamide 7 with concomitant
loss of acetaldehyde.
The spectroscopic data of morphans 2 and 3 are similar to those
of the previously reported dechlorinated compounds at C-6 and C-4
(Table 2 for 13C NMR data). Hence, the isomer showing H-8eq (
d
Fig. 3. Key NMR data for stereochemical assignment of normorphans.
0.61) and CH3 (d 15.6) at high fields was assigned the absolute

4886
F. Diaba et al. / Tetrahedron 69 (2013) 4883e4889
1a
H3C
radical
H3C
H
H3C
H
dimeric
coupling
Cu(I)
5-exo-trig
H
Cl
N
N
O
N
CCl2
Cl
O
CCl2
dearomative
cyclization
O
NC
CN
O
CN
CN
Cl
N
1,4-aryl
migration
6-exo-trig
1,4-H
transfer
Cl
H3C
H3C
H3C
H
H3C
H
H
Cl
N
N
CHCl2
N
O
Cl
O
CH3
Cl
O
Cl
Cl
N
CN
H
CN
Cl
Cl
CN
*Cl atom transfer
*Hydrolysis via
acyliminium ion
2
O
6
CN
C-N bond
rotation
O
O
CHCl2
CH3
CHCl2
H
H
H
N
H
N
Cl
N
5-exo-trig
Cl
O
CH3
memory
of chirality
H
7
CN
Cl
CN
CN
4
Scheme 4. Overview of the different pathways of the radical dichloromethylcarbamoyl generated from 1a using Cu(I).
also exerts a deshielding effect (ca. 0.5 ppm) on H-7ax, which has
an antiplanar disposition compared with the analogous compounds
lacking this heteroatom. The phenomenon was observed in both 2
(
d
2.01) and 3 (
d
2.29), compared with the values for the dech-
1.49 and 1.82,
lorinated compounds in which H-7ax appears at
d
d
respectively. This stereochemical assignment agrees with mecha-
nistic considerations, since the configuration at C-6 arose from the
transfer of the chlorine atom from the less hindered face of the
cyclohexane ring generated after the radical cyclization that locates
the chlorine in an axial disposition.
Scheme 5. Reduction of 4 leading to normorphan (e)-10.
The 1H and 13C NMR spectra patterns of normorphans 4 and 5, in
which most of the signals are duplicated due to the presence of Z
and E rotamers,41 resemble those of the previously reported nor-
morphans lacking the chlorine atom at C-2 (Table 3). Hence, isomer
4, showing chemical shifts dH 2.31 and dC 22.1 for the methyl group
at C-7 (major Z rotamer), was assigned the absolute configuration
Table 2
13C NMR chemical shifts (
d
) of morphansa
Compound C-1 C-3
C-4 C-5 C-6 C-7 C-8 C-9 CH CH3 CN
2
3
46.4 162.8 83.6 53.1 59.6 29.3 24.9 27.0 53.7 15.6 118.9
46.4 163.3 83.7 53.3 59.6 29.6 26.8 26.6 54.2 17.0 118.8
46.7 165.9 57.7 31.3 35.7 20.2 29.3 33.8 52.3 15.7 120.7
46.6 166.3 57.7 31.6 36.1 20.5 31.2 33.7 53.1 17.1 120.6
IIeClb
IIIeClb
Table 3
a
13C NMR chemical shifts ( ) of normorphansa
d
In CDCl3 (100 MHz). Values assigned on the basis of COSY and HMQC
experiments.
b
Compound C-1 C-2 C-3 C-4 C-5 C-7 C-8 CHCl2 CO
7-CH3 CN
Compounds IIeCl and IIIeCl show the structure of II and III depicted in Scheme
2, but with an equatorial chlorine atom at C-4 and are described in Ref. 20.
4
Z major
E minor
55.9 58.3 32.9 27.7 55.8 72.7 29.7 65.2 161.5 22.1 119.5
58.1 58.1 33.5 24.6 57.7 70.6 28.5 64.5 164.5 25.0 119.9
configuration (1R,5R,6R). When the isomer showed H-8eq (
d 1.90)
5
56.8 59.3 32.2 27.7 56.2 72.3 31.9 66.1 161.8 28.6 117.2
59.8 59.1 32.6 25.7 57.2 70.3 30.9 64.8 164.9 32.6 116.9
and CH3 17.0) at lower fields, the absolute configuration
(d
(1S,5S,6S) was assigned for the three stereogenic atoms in the
carbocyclic ring. The stereochemistry at C-6 in compounds 2 and 3
IVeClb
47.7 30.2 21.5 29.7 56.2 72.2 34.3 65.2 161.1 22.5 121.1
50.5 30.2 23.1 28.5 58.0 70.1 33.2 64.8 164.1 24.5 121.4
(Fig. 2) was deduced from the chemical shift of H-8ax (
2.04, respectively), which appeared deshielded (ca. 0.7 ppm) with
respect to the chemical shift found in the analogous dechlorinated
d 1.60 and
VeClb
48.2 31.0 21.6 30.6 56.7 71.8 36.6 66.1 161.5 27.5 119.7
51.4 31.0 21.8 29.7 57.5 69.9 35.5 65.0 164.6 31.0 119.8
d
a
In CDCl3 (100 MHz). Values assigned on the basis of COSY and HMQC
compounds (d 0.90 and d
1.42).20,39 This deshielding anisotropic
experiments.
effect is due to the chlorine atom40 having a 1,3-diaxial relationship
with H-8ax in both morphans. Moreover, the axial chlorine atom
b
Compounds IVeCl and VeCl show the structure of IV and V (X¼Cl) depicted in
Scheme 2, and are described in Ref. 20.

F. Diaba et al. / Tetrahedron 69 (2013) 4883e4889
4887
(1S,2R,5R,7S), while isomer 5, showing chemical shifts dH 2.03 and
dC 28.6 for the methyl group at C-7 (major Z rotamer), was assigned
the absolute configuration (1R,2S,5S,7S). Again, the stereochemistry
of the quaternary carbon with chlorine and cyano groups was
assigned taking into account the 1H chemical shift of the axial
proton bearing a 1,3-diaxial relationship with the axial substituent
EtOAc 80:20 to hexane/EtOAc 50:50) to yield 62 mg of a 1:1.15
mixture of morphans 2 and 3 and normorphans 4e5, respectively,
(54% overall yield) and 18 mg (17%) of dimeric derivatives 6. The
individual yields with respect to the epimeric ratio of the starting
material 1 were: normorphan 4 (22%), morphan 2 (25%), morphan 3
(25%), and normorphan 5 (26%).
at C-2. Thus, the H-4ax resonates at d 1.90 and 1.94 in compounds 4
and 5, respectively, in a deshielded chemical shift (ca. 0.3 ppm)
with respect to the values reported for the dechlorinated normor-
phans (Fig. 3).
The NMR data for spiro dimeric compounds 6, each one being
a mixture of epimers presumably at the spiro carbon atom, while
not allowing a configurational assignment, did enable us to clearly
identify the formation of spirocyclohexanediene derivatives. Ad-
ditionally, the calculation of their dimeric structure was based on
the HRMS data. The 1H pattern of the olefinic signals and the
4.2.2. Method B. In a 10 mL vessel were placed nitrile 1 (100 mg,
0.27 mmol), CuCl (8 mg, 0.081 mmol, 30%), TPMA (23 mg,
0.080 mmol), and 1,2-dichloroethane (1 mL). The mixture was
stirred and heated to 80 ꢀC using microwave irradiation for 15 min.
After cooling to rt, water (1 mL) was added and the mixture was
stirred for an additional hour and extracted with CH2Cl2. The or-
ganics were dried, concentrated and purified by chromatography
(hexane/EtOAc 80:20 to hexane/EtOAc 50:50) to give 44 mg of
a 1:1.25 mixture of morphans (19%) and normorphans (25%) and
22 mg of compounds 6 (24%).
chemical shift (d w3.1) of allylic protons allowed the ground
structure of the spirocyclohexanediene ring to be deduced. The
counterpart of the five-membered lactam was inferred by the ab-
sorption at 1715 cmꢁ1 in the IR spectra and the 13C NMR chemical
4.2.3. Method C. In a 10 mL vessel were placed nitrile 1 (100 mg,
0.27 mmol), CuCl (16 mg, 0.161 mmol, 60%), and acetonitrile (1 mL).
The mixture was stirred and heated to 80 ꢀC using microwave ir-
radiation for 15 min. After cooling to rt, water (1 mL) was added, the
mixture was stirred for an additional hour and then extracted with
CH2Cl2. The organics were dried, concentrated, and purified by
chromatography (hexane/AcOEt 85:15 to hexane/EtOAc 70:30) to
give 33 mg of recovered starting material 1, 15 mg (15%) of a 1.5:1
mixture of morphans 2 and 3 and 26 mg (31%) of 7.
shifts of the four carbons at
(d), as average values.
d 166.3 (s), 89.3 (s), 53.5 (s), and 40.2
3. Conclusion
In summary, under the atom transfer reaction cyclization con-
ditions, the radical reaction course from 1 followed three different
pathways. One evolved as expected to morphans 2 and 3 through
an ATRC. Another led to normorphans 3 and 4 through an initial 1,4-
hydrogen transfer and rebound cyclization with memory of chi-
rality followed by chorine trapping of the generated radical. In
a third pathway, the initially formed 1-(carbamoyl)dichloromethyl
radical underwent ipsocyclization upon the benzene ring to give
a cyclohexadienyl radical. This in turn evolved to 6 as a di-
astereoisomeric mixture via radical coupling dimerization or, in
specific reaction conditions, to the dichloroacetamide 7, via a 1,4-
aryl radical migration.
4.2.4. Method D (method of choice). To a suspension of CuCl
(2.7 mg, 0.027 mmol 10%) in 1,2-dichloroethane (2 mL) were
successively added TPMA (8 mg, 0.027 mmol), nitrile 1 (100 mg,
0.27 mmol), AIBN (22 mg, 0.13 mmol 50%) and the mixture was
heated at 60 ꢀC for 2 days in a sealed tube. The solution was then
allowed to reach rt, stirred with 2 mL of water for an additional
hour and extracted with CH2Cl2. The organics were dried, con-
centrated and the residue purified by chromatography (hexane/
EtOAc 80:20 to hexane/EtOAc 50:50) to yield 70 mg of a 45:55
mixture of morphans and normorphans and 9 mg (10%) of dimeric
derivatives 6.
The separation of the different morphans and normorphans was
achieved using an additional chromatography (cyclohexane/EtOAc
90:10). Normorphan 4 (15 mg, 26%), morphan 2 (14 mg, 25%),
morphan 3 (12 mg, 25%), and finally normorphan 5 (23 mg, 52%)
were sequentially eluted. Overall yield of the process was 64% (2:3
ratio morphan/normorphan compounds).
4. Experimental section
4.1. General procedures
1H and 13C NMR spectra were recorded in a CDCl3 solution at
400 MHz and 100 MHz, respectively. In addition, 2D NMR COSY and
HMQC experiments were performed on a Varian instrument.
Chemical shifts are reported as
d values (ppm) relative to internal
Me4Si. Infrared spectra were recorded on a Nicolet 205 FT-IR
spectrophotometer. HRMS were determined on a Agilent LC/
MSD-TOF apparatus. Optical rotations were taken on a Per-
kineElmer 241 polarimeter with a 1 mL (L¼1 dm) cell TLC was
performed on SiO2 (silica gel 60 F254, Merck). The spots were lo-
cated by UV light and a 1% KMnO4 or 1.5% K2PtCl6 aqueous solution.
Chromatography refers to flash column chromatography and was
performed on SiO2 (silica gel 60, SDS, 230e400 mesh). TPMA refers
to tris(2-pyridylmethyl)amine. Unless noted, the reactions were
carried out in argon atmosphere.
4.2.5. Method E. To a suspension of CuCl2 (4.6 mg, 0.034 mmol 10%)
in 1,2-dichloroethane (2 mL) were successively added TPMA (10 mg,
0.037 mmol), nitrile 1 (129 mg, 0.34 mmol), and AIBN (29 mg,
0.17 mmol 50%), and the mixture was heated at 60 ꢀC for 2 days
under air in a sealed tube. The solution was allowed to reach rt,
stirred with 1 mL of water for an additional hour and extracted with
CH2Cl2. The organics were dried, concentrated and the residue pu-
rified by chromatography (hexane/EtOAc 80:20 to hexane/EtOAc
50:50) to yield 62 mg of 1 (48%),19 mg (15%) of 8, and 7 mg (5%) of 9.
4.3. Spectral data for compounds 2e7
4.2. Cyclization reaction procedure
4.3.1. (1R,5R,6R)-4,4,6-Trichloro-2-[(S)-1-phenylethyl]-3-oxo-2-
4.2.1. Method A. To a suspension of CuCl (9.2 mg, 0.093 mmol 30%)
in 1,2-dichloroethane (2 mL) were successively added TPMA
(27 mg, 0.093 mmol) and nitrile 1 (55:45 mixture of epimers 1a and
1b, 115 mg, 0.31 mmol), and the mixture was heated at 80 ꢀC for 4 h
in a sealed tube. The solution was allowed to reach rt, water (2 mL)
was added and extracted with CH2Cl2. The organics were dried,
concentrated and the residue purified by chromatography (hexane/
azabicyclo[3.3.1]nonane-6-carbonitrile (2). [
a
]
23 ꢁ63 (c 0.6, CHCl3);
D
IR (NaCl, neat): 3059, 3030, 2926, 2855, 2243, 2216, 1670, 1602,
1494, 1446, 1369, 1297, 1270, 1206, 1159, 1095, 990, 826, 805, 779,
735, 701, 635, 612, 573 cmꢁ1; 1H NMR (CDCl3, 400 MHz):
d 0.61 (dm,
1H, J¼14.4 Hz, H-8eq), 1.60 (m, 1H, H-8ax), 1.61 (d, 3H, J¼6.8 Hz,
CH3), 2.00 (m, 2H, H-7), 2.58 (td, 2H, J¼3.2, 1.2 Hz, H-9), 3.34 (m, 1H,
H-5), 3.68 (m, 1H, H-1), 5.94 (q, 1H, J¼6.8 Hz, CH), 7.30e7.42 (m, 5H,

4888
F. Diaba et al. / Tetrahedron 69 (2013) 4883e4889
ArH); 13C NMR (CDCl3, 100 MHz):
d
15.6 (CH3), 24.9 (C-8), 27.0 (C-9),
enecarbonitrile) (6). IR (NaCl, neat): 3034, 2976, 2939, 2251, 2216,
29.4 (C-7), 46.5 (C-1), 53.1 (C-5), 53.7 (CH), 59.6 (C-6), 83.6 (C-4),
118.9 (CN), 127.8, 128.6, 128.9 (Ar), 138.7 (ipso-C), 162.8 (C-3). HRMS
(ESI-TOF): calcd for C17H18Cl3N2O 371.0479 (Mþþ1). Found
371.0478.
1716, 1671, 1640, 1431, 1371, 1310, 1223, 1172, 1087, 980, 910, 857,
732, 693, 647 cmꢁ1; 1H NMR (CDCl3, 400 MHz):
d 1.16 (m, 6H, CH3),
1.88 (br, 2H), 2.40 (m, 8H), 2.84 and 3.04 (2m, 1H each, CH2), 3.10
and 3.15 (2 br s, 1H each, CH), 3.57 (br s, 2H, CHN), 3.64 (m, 2H,
CHMe), 5.52 (m, 2H, ]CH), 5.80e6.20 (m, 6H, ]CH), 6.58 (br s, 2H,
4.3.2. (1S,5S,6S)-4,4,6-Trichloro-2-[(S)-1-phenylethyl]-3-oxo-2-
azabicyclo[3.3.1]nonane-6-carbonitrile (3). IR (NaCl, neat): 3058,
2919, 2850, 2216, 1671, 1495, 1435, 1368, 1296, 1269, 1204, 1160,
]CH); 13C NMR (CDCl3, 100 MHz):
d 14.2, 14.4 (CH3), 24.1, 25.3, 27.1,
27.2, 27.9, 28.9 (CH2), 40.0, 40.3, 40.5 (CH), 49.4, 49.5 (CH), 53.4,
53.5 (C), 59.5, 59.6, 59.7, 59.8 (CHMe), 89.2, 89.7 (C), 112.1, 112.2 (C),
118.7,118.8 (CN),123.7, 123.9, 124.0,124.3 (]CH),131.5, 132.4, 132.6,
133.2, 133.6 (]CH), 142.4, 142.6, 142.7 (]CH), 166.2, 166.3, 166.4
(CO). HRMS (ESI-TOF): calcd for C34H38Cl4N5O4 688.1774
(MþNH4)þ. Found 688.1779.
990, 824, 733, 699, 632, 575 cmꢁ1 1H NMR (CDCl3, 400 MHz):
;
d
1.64 (d, 3H, J¼7.2 Hz, CH3), 1.90 (dm, 1H, J¼14.8 Hz, H-8eq), 2.04
(m, 1H, H-8ax), 2.29 (m, 2H, H-7), 2.33 (dm, 1H, J¼14.8 Hz, H-9),
2.43 (dt, 1H, J¼14.8, 3.2 Hz, H-9), 3.34 (br s, 2H, H-1 and H-5), 5.95
(q, 1H, J¼7.2 Hz, CH), 7.30e7.44 (m, 5H, ArH); 13C NMR (CDCl3,
100 MHz):
d
17.1 (CH3), 26.6 (C-9), 26.8 (C-8), 29.6 (C-7), 46.4 (C-1),
4.3.6. 2,2-Dichloro-N-(4-cycanocyclohex-3-en-1-yl)-2-phenyl-
53.3 (C-5), 54.2 (CH), 59.6 (C-6), 83.7 (C-4), 118.8 (CN), 127.2, 128.3,
129.0 (Ar), 138.7 (ipso-C), 163.3 (C-3). HRMS (ESI-TOF): calcd for
C17H18Cl3N2O 371.0479 (Mþþ1). Found 371.0490.
acetamide (7). IR (NaCl, neat): 3331, 2924, 2851, 2215, 1681, 1517,
1446, 1315, 1265, 1195, 1086, 888, 827, 727, 691 cmꢁ1 1H NMR
;
(CDCl3, 400 MHz): d 1.77 (m, 1H), 2.01 (m, 1H), 2.17 (m, 1H), 2.40 (m,
2H), 2.69 (dm, J¼19.2 Hz, 1H), 4.11 (m, 1H), 6.57 (m, 1H), 6.72 (br s,
4.3.3. (1S,2R,5R,7S)-2-Chloro-6-(1,1-dichloroacetyl)-7-phenyl-7-
1H, NH), 7.42 (m, 3H, ArH), 7.70 (m, 2H, ArH); 13C NMR (CDCl3,
methyl-6-azabicyclo[3.2.1]octane-2-carbonitrile (4). [
a
]
23 ꢁ46 (c 1.0,
100 MHz): d 25.1 (CH2), 26.5 (CH2), 31.5 (CH2), 44.9 (CH), 88.0 (CCl2),
D
CHCl3); IR (NaCl, neat): 3058, 3004, 2961, 2244, 1678, 1494, 1465,
1446, 1399, 1265, 1243, 1210, 1175, 1057, 844, 808, 733, 701, 664,
549 cmꢁ1; 1H NMR (CDCl3, 400 MHz), 8:2 mixture of Z/E rotamers:
112.6 (C), 118.6 (CN), 126.5, 128.5, 130.0 (AreCH), 139.1 (ipso-C),
141.6 (CH), 165.2 (C]O). HRMS (ESI-TOF): calcd for C15H15Cl2N2O
309.0556 (Mþþ1). Found 309.0555.
Major rotamer (Z)
d 1.91 (m, 1H, H-4ax), 2.05 (m, 2H, H-8 and H-
4eq), 2.21 (d, 1H, J¼12.8 Hz, 1H, H-8), 2.31 (s, 3H, CH3), 2.46 (dd, 1H,
J¼15.6, 5.2 Hz, H-3eq), 2.70 (ddd, 1H, J¼15.6, 12.4, 6.4 Hz, 1H, H-
3ax), 2.79 (br s, 1H, H-1), 4.48 (t, 1H, J¼5.2 Hz, H-5), 6.25 (s, 1H,
CHCl2), 7.15 (dm, J¼7 Hz, 1H, ArH), 7.25e7.38 (m, 4H, ArH). Minor
rotamer (E) 1.88 (m, 2H, H-4ax and H-8), 2.17 (d, 1H, J¼12 Hz, H-8),
2.29 (s, 3H, CH3), 2.46 (m, 2H, H-3eq and H-4eq), 2.58 (ddd, J¼15.6,
12, 6.4 Hz, 1H, H-3ax), 2.79 (br s, 1H, H-1), 4.68 (t, 1H, J¼5.2 Hz, H-
5), 5.68 (s, 1H, CHCl2), 7.20e7.47 (m, 5H, ArH); 13C NMR (CDCl3,
4.3.7. 4-((S)-4,4,8-Trichloro-1-methyl-3-oxo-2-azaspiro[4.5] deca-
6,9-dien-2-yl)cyclohex-1-enecarbonitrile (8). IR (NaCl, neat): 3047,
2926, 2852, 2215,1719,1639,1428,1370,1309,1222,1188,1172,1086,
979, 924, 855, 835, 797, 730, 692 cmꢁ1; 1H NMR (CDCl3, 400 MHz):
d
1.13 and 1.15 (2 d, 3H, J¼6.4 Hz, CH3),1.89 (m,1H), 2.42 (m, 4H), 2.89
and 3.07 (2 m, 1H), 3.58 (m, 1H), 3.72 (q, 1H, J¼6.8 Hz), 5.00 (tt, 1H,
J¼3.6,1.2 Hz), 5.66 and 5.69 (2ddd,1H, J¼10.4, 2.4,1.2 Hz), 6.04 (dm,
1H, J¼10.4 Hz), 6.27 (dm, 1H, J¼10.4 Hz), 6.35 (dm, 1H, J¼10.4 Hz),
100 MHz): Major rotamer
d
22.1 (CH3), 27.7 (C-4), 29.7 (C-8), 32.9
6.58 (br s,1H); 13C NMR (CDCl3,100 MHz):
d 14.1 and 14.2 (CH3), 24.1
(C-3), 55.8 (C-5), 55.9 (C-1), 58.1 (C-2), 65.2 (CHCl2), 72.7 (C-7),
119.5 (CN), 125.0, 127.4, 128.6 (Ar), 142.6 (ipso-C), 161.5 (CO). Minor
and 25.4 (CH2), 27.2 and 27.3 (CH2), 27.9 and 28.9 (CH2), 49.2 and
49.5 (CH), 53.2 (C), 59.1 and 59.2 (CH), 87.8 (CCl2),112.1 and 112.2 (]
C),118.7 (CN),125.8 (]CH),126.3 (]CH),130.5 (]CH),132.2 (]CH),
142.3 and 142.5 (]CH), 166.1 (CO). HRMS (ESI-TOF): calcd for
C17H18Cl3N2O 371.0479 (Mþþ1). Found 371.0478.
rotamer
d 24.6 (C-4), 25.0 (CH3), 28.5 (C-8), 33.5 (C-3), 57.7 (C-5),
58.3 (C-1 and C-2), 64.5 (CHCl2), 70.6 (C-7), 119.9 (CN), 125.2, 128.5,
129.3 (Ar), 143.5 (ipso-C), 164.5 (CO). HRMS (ESI-TOF): calcd for
C17H18Cl3N2O 371.0479 (Mþþ1). Found 371.0476.
4.3.8. 4-((S)-4,4-Dichloro-1-methyl-3,8-dioxo-2-azaspiro[4.5] deca-
6,9-dien-2-yl)cyclohex-1-enecarbonitrile (9). IR (NaCl, neat): 3058,
2936, 2853, 2215, 1722, 1668, 1633, 1434, 1371, 1319, 1263, 1219,
4.3.4. (1R,2S,5S,7S)-2-Chloro-6-(1,1-dichloroacetyl)-7-phenyl-7-
methyl-6-azabicyclo[3.2.1]octane-2-carbonitrile (5). [
a
]
23 ꢁ51 (c 1.0,
D
CHCl3); IR (NaCl, neat): 3058, 3026, 2999, 2950, 2217, 1678, 1496,
1446, 1396, 1266, 1243, 1212, 1071, 10,027, 811, 764, 734, 703,
668 cmꢁ1; 1H NMR (CDCl3, 400 MHz), 7:3 mixture of Z/E rotamers:
1172, 1124, 1080, 1031, 980, 924, 871, 847, 734, 693 cmꢁ1 1H NMR
;
(CDCl3, 400 MHz):
d
1.20 and 1.21 (2 d, 3H, J¼6.8 Hz, CH3), 1.82 (m,
1H), 2.44 (m, 4H), 2.89 and 3.11 (2 m, 1H), 3.62 (m, 1H), 3.97 (q, 1H,
J¼6.8 Hz), 6.54 (dt, 1H, J¼10.4, 1.6 Hz), 6.59 (br s, 1H), 6.60 (dd, 1H,
J¼10.4, 1.6 Hz), 6.67 and 6.68 (ddd, 1H, J¼10.4, 3.2 Hz), 7.05 (ddd,
Major rotamer (Z)
d
1.94 (tdd, 1H, J¼12.4, 6, 1.6 Hz, H-4ax), 2.03 (s,
3H, CH3), 2.12 (dd, J¼15.6, 6.4 Hz, 1H, H-3eq), 2.25 (dm, 1H,
J¼12.4 Hz, H-4eq), 2.53 and 2.61 (2d, 2H, J¼12.8, H-8), 2.73 (ddd,
1H, J¼15.6, 12.4, 6.4 Hz, H-3ax), 2.91 (br s, 1H, H-1), 4.62 (t, 1H,
J¼5.2 Hz, H-5), 6.23 (s, 1H, CHCl2), 7.15 (dm, 1H, J¼6.8 Hz, ArH),
1H, J¼10.4, 3.2, 0.8 Hz); 13C NMR (CDCl3, 100 MHz):
d 14.3 (CH3),
24.0 and 25.5 (CH2), 27.1 and 27.3 (CH2), 27.8 and 29.0 (CH2), 49.9
(CH), 55.9 (C), 57.8 and 57.9 (CH), 86.6 (CCl2), 112.3 (]C), 118.5 (CN),
132.7 (]CH), 134.3 (]CH), 142.0 (]CH), 142.1 and 142.2 (]CH),
142.2 and 142.4 (]CH), 165.3 (CO), 184.1 (CO). HRMS (ESI-TOF):
calcd for C17H17Cl2N2O2 351.0661 (Mþþ1). Found 351.0650.
7.30e7.46 (m, 4H, ArH). Minor rotamer (E)
d
1.88 (tdd, 1H, J¼13, 6,
1.6 Hz, 1H, H-4ax), 2.07 (s, 3H, CH3), 2.13 (m, 1H, H-3eq), 2.33 (m,
1H, H-4eq), 2.54 (m, 2H, CH2-8), 2.61 (m, 1H, H-3ax), 2.91 (br s, 1H,
H-1), 4.83 (t, 1H, J¼5.2 Hz, H-5), 5.71 (s, 1H, CHCl2), 7.30e7.59 (m,
5H, ArH); 13C NMR (CDCl3, 100 MHz): Major rotamer
d 27.7 (C-4),
28.6 (CH3), 31.9 (C-8), 32.2 (C-3), 56.2 (C-5), 56.8 (C-1), 59.1 (C-2),
66.1 (CHCl2), 72.3 (C-7), 117.2 (CN), 126.3, 127.7, 128.2, 128.8, 129.1
4.4. (1R,2S,5R,7S)-6-Acetyl-7-methyl-7-phenyl–6-azabicyclo
[3.2.1]octane-2-carbonitrile (10)
(AreCH), 135.7 (ipso-C), 161.8 (CO). Minor rotamer d 24.6(C-4), 30.9
(C-8), 32.6 (CH3), 32.6 (C-3), 57.2 (C-5), 59.1 (C-2), 59.8 (C-1), 64.8
(CHCl2), 70.3 (C-7), 116.9 (CN), 125.4, 128.4, 128.9, 129.8, 130.6
(AreCH), 136.7 (ipso-C), 164.9 (CO). HRMS (ESI-TOF): calcd for
C17H18Cl3N2O 371.0479 (Mþþ1). Found 371.0485.
To a solution of 4 (27 mg, 0.07 mmol) in MeOH (2 mL) were
added at 0 ꢀC NH4Cl (23 mg, 0.43 mmol) followed by Zn (47.5 mg,
0.73 mmol) portionwise. The mixture was allowed to reach rt,
stirred for a further 2 h, filtered on a Celite pad, and concentrated.
The residue was taken up in CH2Cl2 and the resulting solution was
washed with brine, and dried. Purification by chromatography
(CH2Cl2/AcOEt 90:10 to CH2Cl2/EtOAc 80:20) gave 14 mg (72%) of
4.3.5. 4,40-(4,4,40,40-Tetrachloro-1,10-dimethyl-3,30-dioxo-[8,80-bi2,20-
diazaspiro[4.5]decane]-6,60,9,90-tetraene-2,20-diyl)bis(cyclohex-1-

F. Diaba et al. / Tetrahedron 69 (2013) 4883e4889
4889
dehalogenated normorphan 920 and its epimer 10 as a minor
compound.
22. Due to the troublesome separation of enantiopure epimers 1a and 1b, we
decided to carry out the studies with the epimeric mixture since the reaction
products were easier to separate.
23. Radicals formed from the decomposition of the free radical initiator 2,20-azobi-
sisobutyronitrile (AIBN) at 60 ꢀC continuously regenerate the catalytically active
lower oxidation state copper complex (activator) by the abstraction of a halogen
atom from the higher oxidation state complex (deactivator), see Ref. 9.
24. For the rare 1,4-hydrogen atom transfer in radical processes, see: (a) Journet,
M.; Malacria, M. Tetrahedron Lett. 1992, 33, 1893e1896; (b) Gulea, M.;
Lopez-Romero, J. M.; Fensterbak, L.; Malacria, M. Org. Lett. 2000, 2, 2591e2594;
(c) Cassayre, J.; Zard, S. Z. J. Organomet. Chem. 2001, 624, 316e326.
25. Ishibashi, H.; Kameoka, C.; Kodama, K.; Kawanami, H.; Hamada, M.; Ikeda, M.
Tetrahedron 1997, 53, 9611e9622.
Acknowledgements
This research was supported by the Ministry of Economy
and Competitiveness (MINECO, Spain) through project CTQ2010-
14846/BQU.
Supplementary data
26. Rodríguez-Soria, V.; Quintero, L.; Sartillo-Piscil, F. Tetrahedron 2008, 64,
2750e2754.
27. Quirante, J.; Torra, M.; Diaba, F.; Escolano, C.; Bonjoch, J. Tetrahedron:
Asymmetry 1999, 10, 2339e2410.
28. Sasmal, A.; Taniguchi, T.; Wipf, P.; Curran, D. P. Can. J. Chem. 2013, 90, 1e5.
29. (a) Buckmelter, A. J.; Kim, A. I.; Rychnovsky, S. D. J. Am. Chem. Soc. 2000, 122,
9386e9390; (b) Griesbeck, A. G.; Kramer, W.; Lex, J. Angew. Chem., Int. Ed. 2001,
40, 577e579.
Copies of the 1H and 13C NMR spectra for all new compounds.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.04.042.
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