Synthesis of Normorphans through an Efficient Intramolecular Carbamoylation of Ketones

Article abstract of DOI:10.1021/acs.orglett.5b01832

An unexpected C-C bond cleavage was observed in trichloroacetamide-tethered ketones under amine treatment and exploited to develop a new synthesis of normophans from 4-amidocyclohexanones. The reaction involves an unprecedented intramolecular haloform-typ

Full text of DOI:10.1021/acs.orglett.5b01832

Letter
pubs.acs.org/OrgLett
Synthesis of Normorphans through an Efficient Intramolecular
Carbamoylation of Ketones
Faïza Diaba,*,† Juan A. Montiel,† Georgeta Serban,‡ and Josep Bonjoch*,†
†Laboratori de Química Organ
̀ ̀
ica, Facultat de Farmacia, IBUB, Universitat de Barcelona, Av. Joan XXIII s/n, 08028-Barcelona, Spain
‡Pharmaceutical Chemistry Department, Faculty of Medicine and Pharmacy, University of Oradea, Nicolae Jiaga 29, 410028-Oradea,
Romania
S
* Supporting Information
ABSTRACT: An unexpected C−C bond cleavage was observed in
trichloroacetamide-tethered ketones under amine treatment and exploited
to develop a new synthesis of normophans from 4-amidocyclohexanones.
The reaction involves an unprecedented intramolecular haloform-type
reaction of trichloroacetamides promoted by enamines (generated in situ
from ketones) as counter-reagents. The methodology was applied to the
synthesis of compounds embodying the 6-azabicyclo[3.2.1]octane frame-
work.
ethodologies involving the inter- or intramolecular
Mformation of carbon−carbon bonds at the α-position
of ketones are important tools for the construction of molecular
frameworks in organic synthesis.1 Nevertheless, to our
knowledge, the α-carbamoylation of ketones remains an
“orphan” procedure.2,3 Whereas the feasibility of using
intramolecular amide enolate alkylation (IAEA) in lactam
synthesis is known,4 the umpolung version in which the amide
carbonyl acts as an acceptor against an α-carbonyl (ketone)
Figure 1. Normorphan compounds.
group, such as a nucleophile, is unreported. The only
procedures for the intramolecular C-carbamoylation described
Among the vast array of synthetic procedures to achieve
to date are carbamoyl radical,5 electrophilic,6 and Ru-catalyzed7
compounds embodying the 6-azabicyclo[3.2.1]octane skele-
ton,13,14 a scarcely used approach involves a ring-closing C1−
cyclizations upon alkenes (Scheme 1).
C7 bond formation. Apart from our studies on the radical
cyclization of α-aminomethyl radicals,15 and those of Grainger
Scheme 1. Intramolecular Carbamoylation
using carbamoyl radicals,5,11 there are no other precedents for
this disconnection in a synthetic plan toward the aforemen-
tioned bridged azabicyclic ring.
We began with the aim of extending our methodology for the
radical cyclization of trichloroacetamides upon electron-rich
alkenes, previously reported using enol acetates (i.e., 1A) as
radical acceptors,8b to the corresponding enamines, i.e. 1B
(Scheme 2). During this study, it was serendipitously
discovered that when ketone 18b was treated with pyrrolidine
(1.2 equiv) and a catalytic amount of TsOH in toluene at
reflux, normorphan 2 was isolated in 68% yield (Scheme 2)
instead of the expected enamine of 1. After this surprising
result, a synthetic study of the methodology toward 6-
azabicyclo[3.2.1]octanes using amine-promoted carbocycliza-
As part of our continuing interest in synthesizing lactams
from trichloroacetamides,8 we report here an efficient method
to synthesize the azabicyclic normorphan ring, based on an
tion of trichloroacetamide-tethered ketones was undertaken.
intramolecular carbamoylation of ketones. The 6-azabicyclo
Although organic reactions featuring trichloromethyl as a
[3.2.1]octane (normorphan) nucleus is the backbone of
peduncularine9 and actinobolamine,10 and appears as a
leaving group are well established (e.g., the haloform
structural subunit in several other alkaloids.11 Additionally,
various normorphans are pharmacologically interesting12
(Figure 1).
Received: June 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01832
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
metric amount of pyrrolidine (0.5 equiv) was used, the yield
improved further to reach 91−94% after only 5 min of reaction
in a 1 g scale synthesis (entry 4). Finally, it was found that the
pyrrolidine loading can be diminished to 20−25% with little
effect on the yield (entry 5). Additionally, the process was also
activated by the use of primary amines (e.g., benzylamine and
allylamine), although large amounts were required and the yield
was lower (entries 7−8).
Scheme 2. Enol Acetate vs Enamine Formation from
Trichloroacetamide 1
The new type of C−C bond formation here described is
probably based on a nucleophilic attack of an enamine
generated in situ on a trichloroacetamide carbonyl group,
with a concomitant release of the trichoromethyl anion as a
leaving group. Indeed, a peak corresponding to CHCl3 was
observed when recording the NMR spectrum of the crude
reaction mixture in deuterated benzene.
The applicability of the methodology was subsequently
explored on trichloroacetamides in which the benzyl group was
replaced by primary or α-branched alkyl groups (compounds
1b−1e). We tested two reaction conditions: the solvent-free
procedure under conventional heating (Method A), used in the
N-benzyl series, and a microwave protocol with toluene as a
solvent (Method B, Table 1, entries 9−15). When using
compounds other than the N-benzyl derivative 1a, Method A
afforded lower yields than Method B, which was attributed to
the low homogeneity of the trichloroacetamide (1b−1e) and
pyrrolidine mixture. The microwave procedure worked very
well with trichloroacetamides bearing linear substituents at the
nitrogen atom, while the yield decreased when the α-position
was branched (isopropyl or α-methylbenzyl substituents, as in
1e and 3).
reaction),16 they have not been reported from trichloroaceta-
mides using enamines as nucleophiles.
To improve the reaction conditions, microwave heating was
explored in initial experiments to accelerate the process. At 120
°C, after only 15 min, a full conversion was observed, but the
target 2 was isolated in only a moderate yield (53%, Table 1,
entry 1). No improvement was obtained by switching to
acetonitrile as the solvent (entry 2), but when the reaction was
carried out in solvent-free mode without the TsOH catalyst and
using conventional heating in a sealed tube, 2 was isolated in a
better yield (78%, entry 3). Moreover, when a substoichio-
a
Table 1. Synthesis of Normorphans 2
The methodology was also applied to enantiopure
trichloroacetamide 3. Unlike 1, 3 required 2 equiv of
pyrrolidine and a prolonged reaction time to achieve a full
conversion, leading to the diastereomers 4 and 5 in a 1:1.3 ratio
and acceptable yield (Scheme 3).
Scheme 3. Cyclization of Trichloroacetamide 3
a
b
entry
compd
method
amine (equiv)
time (min)
yield (%)
c
c
1
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
B
1.2
1.2
1.2
0.5
0.25
2
15
15
15
5
53
c
c
2
B
56
3
A
A
A
B
A
A
A
B
A
B
A
B
A
78
d
4
94
5
5
80
85
50
6
5
e
7
1
5
f
g
8
5
5
58
h
9
5
2
1
2
5
2
1
2
5
55
Evidence for the configuration of 4 (1S,5S) and 5 (1R,5R)
was provided by NOESY experiments, which showed off-
diagonal cross-peaks connecting H-4eq and CH3 in 4 and H-
4eq and aromatic protons in 5. This stereochemical elucidation
agrees with the chemical shift of H-4eq, which is shielded (δ
1.04) in 5 with regard to 4 (δ 2.20), indicating that H-4eq is
held below the benzene ring in 5 (see Supporting Information
(SI)).
10
11
12
12
13
14
15
5
96
78
82
50
60
71
88
5
5
10
5
5
i
B
5
The two diastereomers 4 and 5 were submitted to LiAlH4
reduction to provide the corresponding amino alcohols 6 and 7,
respectively (not shown; see SI), which after debenzylation
gave enantiopure normorphan 8 and its enantiomer ent-8
(Scheme 4). We then used these new sterically demanding
secondary amines (i.e., 8)17 to explore the asymmetric
organocatalyzed synthesis of normorphan 2.
a
Unless otherwise noted, the reaction was carried out with 200 mg of
1a or 100 mg of 1b−1e, using pyrrolidine as the amine. Method A: The
reaction was carried out from trichloroacetamide 1 at 100 °C in
solvent-free mode. Method B: μW, 100 °C in toluene (1 mL). Yields
refer to pure compounds isolated by flash chromatography. At 120
b
c
°C, μW, p-TsOH (0.06 equiv), and solvent (2 mL): toluene or
d
e
acetonitrile (entries 1 and 2). 1 g scale. Benzylamine was used.
f
g
h
When trichloroacetamide 1 was treated with 8, the chemical
yield of the carbamoylation was good (70% yield), but the
Allylamine was used. 35% of 1 was recovered. 31% of 1 was
i
recovered. 200 mg scale.
B
DOI: 10.1021/acs.orglett.5b01832
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Synthesis of Enantiopure 8 and ent-8
Scheme 6. Synthesis of anti-Bredt Azabicyclo 14
enantioselectivity was very poor [(+)-2 < 20% ee). A short
screening of organocatalysts gave disappointing results (see SI);
although chemical yields ranged from good to excellent, the
enantiomeric excess was again unsatisfactory, except for (S)-
prolinamide. When the latter was used (0.5 equiv, DMSO, rt,
64 h), the reaction afforded (−)-2 in 50% yield and 63% ee.
These preliminary results are in line with previously noted
difficulties in the organocatalyzed desymmetrization of 4-
aminocyclohexanones.18,19
azabicyclo[4.3.1]dec-5-ene)25 was elucidated by NMR data and
secured by X-ray crystallographic analysis (Figure 2).
At this point, to examine the scope of the intramolecular
carbamoylation reaction, the synthesis of more structurally
complex normorphan compounds was undertaken (Scheme 5).
Scheme 5. Synthesis of Other Normorphans
Figure 2. X-ray structure of 14.
Not unexpectedly, trichloroacetate 15 behaved differently
under pyrrolidine treatment, leading to the corresponding
carbamate 16 (see ref 26).26 Thus, the presence of the nitrogen
atom (i.e., the trichloroacetamide group) is essential for the
accomplishment of the process since the oxygenated analog did
not provide a cyclization product.
In summary, a direct synthesis of the 6-azabicyclo[3.2.1]-
octane ring, prevalent in a range of biologically active
compounds, from an unprecedented α-carbamoylation of
ketones is reported. The process involves an intramolecular
reaction of trichloroacetamides promoted by enamines
(generated in situ from ketones) as counter-reagents. The
lactam functionalization of this heterocycle promises several
future applications, notably including the conversion of this
building block to the corresponding homoderivative bearing a
morphan nucleus.27
When the α-methyl-substituted cyclohexanone 920 was treated
with benzylamine to promote the carbamoylation of the ketone,
the process took place regioselectively from the less substituted
carbon, leading to the normorphan 10, which was also obtained
after treating 9 with a secondary amine such as pyrrolidine (1.5
equiv, solvent-free, 73%). Interestingly, an epimerization at C3
occurred in the basic reaction medium.
The reaction was extended to additional substrates, including
the azaspiranic trichloroacetamide 11,21 which led to the
azatricyclic compound 12 as an epimeric mixture (2:1 ratio) in
a good overall yield. This new heterocycle constitutes the ring
core of the structurally unique pentacyclic alkaloid cepha-
locyclidin A.22 The structure of the major compound 12a was
determined by X-ray crystallographic analysis (see SI).
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectroscopic and analytical data,
NMR spectra of new compounds, and X-ray data for 12a and
14 (CIF). The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01832.
Additionally, we were interested in extending this reaction to
achieve the six-membered ring scaffold from trichloroacetamide
1323 (Scheme 6). However, the enlargement of the side chain
bearing the trichloroacetamide moiety had a significant impact
on the reaction course. Thus, treatment of 13 with pyrrolidine
gave the anti-Bredt compound 1424 instead of lactam 13a. The
structure of this unprecedented type of anti-Bredt ring (3-
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: faiza.diaba@ub.edu.
*E-mail: josep.bonjoch@ub.edu.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.5b01832
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
Support for this research was provided by the Spanish
MINECO (Project CTQ2013-41338-P).
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