Expedient Synthesis of Bridged Bicyclic Nitrogen Scaffolds via Orthogonal Tandem Catalysis

Article abstract of DOI:10.1002/anie.202106716

Bridged nitrogen bicyclic skeletons have been accessed via unprecedented site- and diastereoselective orthogonal tandem catalysis from readily accessible reactants in a step economic manner. Directed Pd-catalyzed γ-C(sp³)-H olefination of aminocyclohexane with gem-dibromoalkenes, followed by a consecutive intramolecular Cu-catalyzed amidation of the 1-bromo-1-alkenylated product delivers the interesting normorphan skeleton. The tandem protocol can be applied on substituted aminocyclohexanes and aminoheterocycles, easily providing access to the corresponding substituted, aza- and oxa-analogues. The Cu catalyst of the Ullmann-Goldberg reaction additionally avoids off-cycle Pd catalyst scavenging by alkenylated reaction product. The picolinamide directing group stabilizes the enamine of the 7-alkylidenenormorphan, allowing further product post functionalizations. Without Cu catalyst, regio- and diastereoselective Pd-catalyzed γ-C(sp³)-H olefination is achieved.

Full text of DOI:10.1002/anie.202106716

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À
C H Functionalization
Hot Paper
Expedient Synthesis of Bridged Bicyclic Nitrogen Scaffolds via
Orthogonal Tandem Catalysis
Sovan Biswas+, Ben F. Van Steijvoort+, Marjo Waeterschoot,
Narendraprasad Reddy Bheemireddy, Gwilherm Evano, and Bert U. W. Maes*
Abstract: Bridged nitrogen bicyclic skeletons have been
accessed via unprecedented site- and diastereoselective orthog-
onal tandem catalysis from readily accessible reactants in a step
economic manner. Directed Pd-catalyzed g-C(sp3)-H olefina-
tion of aminocyclohexane with gem-dibromoalkenes, followed
by a consecutive intramolecular Cu-catalyzed amidation of the
1-bromo-1-alkenylated product delivers the interesting nor-
morphan skeleton. The tandem protocol can be applied on
substituted aminocyclohexanes and aminoheterocycles, easily
providing access to the corresponding substituted, aza- and
oxa-analogues. The Cu catalyst of the Ullmann-Goldberg
reaction additionally avoids off-cycle Pd catalyst scavenging
by alkenylated reaction product. The picolinamide directing
group stabilizes the enamine of the 7-alkylidenenormorphan,
allowing further product post functionalizations. Without Cu
catalyst, regio- and diastereoselective Pd-catalyzed g-C(sp3)-H
olefination is achieved.
from discovery, through clinical testing, to drugs.[4] Consider-
ing these factors, bridged bicyclic nitrogen scaffolds have
a huge potential in drug discovery, as exemplified with
varenicline and tiotropium bromide commercial drugs fea-
tured in the top 200 pharmaceutical sales list of 2020.[5]
Among these bridged bicyclic nitrogen scaffolds, the
normorphan (6-azabicyclo[3.2.1]octane) skeleton is especially
attractive due to its rigidity, 3-dimensionality, high sp3 carbon
fraction (F sp3),[4] and low molecular weight.[6] Moreover, it
forms the backbone of several natural products (Figure 1)
Introduction
Conformational restriction by joining two rings is an
effective tool to modify pharmacological characteristics of
drug candidates and is a key, yet underrated, strategy in
medicinal chemistry.[1] The fixation of functional groups in
a biologically active conformation can provide more efficient
and selective ligands for various targets, often also featuring
improved ADME parameters (lipophilicity, solubility, meta-
bolic stability) in comparison to the non-restricted scaffolds.
Bridged bicyclic nitrogen scaffolds are conformationally
restricted analogues of saturated aminocarbo- and aminoaza-
cycles, ubiquitous structural motifs in natural products and
active pharmaceutical ingredients (APIs).[2,3] Moreover com-
plexity (as measured by fraction sp3) and the presence of
chiral centers correlates with success as compounds transition
Figure 1. Selected natural products (first row) and synthetic bioactive
molecules (second row) containing the normorphan nucleus.
and appears as a subunit in numerous alkaloids such as
D-normorphinans, C-norbenzomorphans, sarain A, and
hetisine.[7] They are interesting leads for drug development
based on their biological activity.[6,8] While a number of
synthetic strategies (Supporting Information, Figure S1) have
been developed in the past decades to access the normorphan
scaffold, the routes to 7-alkylidenenormorphans in which the
exocyclic enamine provides ample possibilities for post
functionalization is still limited. There are to date only three
synthetic approaches disclosed to these structures (Fig-
ure 2A).[7,9] While innovative in design, the routes still suffer
from drawbacks including the number of steps and associated
low overall yields, product selectivity issues, limited substrate
scope and divergence, notably to access C-substituted deriv-
atives and oxa- and aza-analogues from readily available
substrates. Hence, practical syntheses (small number of steps
from readily available precursors in high overall yield) of
these bridged bicyclic nitrogen scaffolds is highly warranted
to speed up the drug discovery process, still rate limited by
organic synthesis.[10] Disconnections based on an uncommon
[*] Dr. S. Biswas,[+] B. F. Van Steijvoort,[+] M. Waeterschoot,
Dr. N. R. Bheemireddy, Prof. Dr. B. U. W. Maes
Organic Synthesis Division, Department of Chemistry
University of Antwerp
Groenenborgerlaan 171, 2020 Antwerp (Belgium)
E-mail: bert.maes@uantwerpen.be
Prof. Dr. G. Evano
Laboratoire de Chimie Organique, Service de Chimie et Physico-
Chimie Organiques, Universitꢀ libre de Bruxelles (ULB)
Avenue F. D. Roosevelt 50, CP160/06, 1050 Brussels (Belgium)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202106716.
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Figure 2. Synthesis of 7-alkylidenenormorphans. A) Literature approaches. B) New approach and challenges.
3
À
C C bond formation via C(sp )-H functionalization and
tandem catalysis are attractive to achieve this goal, though to
date not yet explored.
Finally, while 1,1-dihalo-1-alkenes are attractive and versatile
coupling partners,[11] they are known to participate in site-
selective, double as well as alkynylative cross-coupling
reactions. This last mode strongly depends on the nature of
the halogen atom, on the polarity of the solvent and on the
nature of the ligands and bases utilized.[18] With a proper
selection of these parameters, we should be able to block the
undesired alkynylative coupling to D.
Based on our interest in C(sp3)-H functionalization
reactions, a practical synthesis was envisioned by combining
a directed C(sp3)-H alkenylation with a consecutive amina-
tion from readily available aminocyclohexane derivatives
1 and 1,1-dibromo-1-alkenes 2 (Figure 2B).[11] The combina-
3
À
tion of C C bond formation via unactivated C(sp )-H
functionalization with other catalytic reactions in tandem
catalysis has received little attention, despite its attractive- Results and Discussion
ness.[12–14] Moreover, for the construction of challenging
bridged bicycles it is not known. This enables an expedient
synthesis of 7-alkylidenenormorphans provided that high
levels of regio- and diastereoselectivities can be obtained.
Our approach would actually involve the directed remote
bromoalkenylation of 1 to 3 via transient palladium complex
I-3, followed by a Pd- or Cu-catalyzed intramolecular
amidation to the target normorphan 4 (Figure 2B). In our
design, the amide DG has a dual role as it also stabilizes the
enamine in the reaction product as its enamide, a valuable and
versatile functional group in organic synthesis.[15] There are
challenges associated to our strategy (Figure 2B). Based on
reports on the use of directing groups,[16] the picolinamide is
expected to provide g-regioselectivity, though competing
dehydrogenation cannot be excluded (not shown). Moreover,
besides the desired product 3, an alternative pathway from I-3
could result in a ring closure to C. However, we assumed that
this product selectivity could be controlled by both the
difference in ring strain and by the nature of the halogen.[17]
Initially, we focused on the g-C-H-haloalkenylation. Be-
sides being a challenging remote functionalization, the
presence of two halogens in the gem-dihalovinyl reactant
poses potential selectivity issues.[18,19] To the best of our
knowledge only one DG-assisted g-C(sp3)-H alkenylation in
cyclic systems has been reported. Chen described
a
Pd-catalyzed directed g-C(sp3)-H alkenylation of methyl
1-aminocyclohexane-1-carboxylate equipped with a picolina-
mide DG (1b) with cyclic vinyl iodides of different ring sizes,
such as 1-cyclohexenyl iodide (2aa) (Supporting Information,
Scheme S1).[20] When we applied these conditions for the
g-alkenylation of N-cyclohexylpyridine-2-carboxamide (1a),
lacking the geminal ester making use of the same DG, no
reaction was observed with 2aa and only unreacted 1a was
recovered (Scheme S1A). This indicates that a geminal ester
is crucial for the literature protocol. When 1a was reacted
with (2,2-dibromoethenyl)benzene (2a), a representative
1,1-dibromo-1-alkene, the desired product 3a was only
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Table 2: Optimization of the Cu-catalyzed intramolecular C-Br amida-
tion of 3a to 4a.[a]
obtained in 16% NMR yield with 84% 1a recovery
(Scheme S2). Clearly new reaction conditions are required
for the remote alkenylation of 1a.
Hence, we started
a de novo optimization of the
g-C(sp3)-H alkenylation reaction of 1a with 2a as model
substrate. When 10 mol% Pd(OAc)2, 1.5 equiv 2a, and
1.0 equiv K2CO3 in 1,2-dichloroethane (DCE) were stirred
at 1208C for 24 h, 52% conversion of 1a and 48% of the
desired product 3a was obtained (Table 1, entry 1). With
0.4 equiv of PivOH as additive, both the conversion of 1a and
yield of 3a were increased to 69% and 51%, respectively
(Table 1, entry 2). Use of Ag2CO3 significantly reduced the
yield, while Cs2CO3 gave a similar conversion and yield
(Table 1, entries 3 and 4). When Rb2CO3 was employed, 3a
was formed in a slightly higher yield with a good mass balance
(Table 1, entry 5). A number of carboxylic acid additives were
subsequently screened (Supporting Information, Table S2).
Sterically hindered aliphatic adamantanecarboxylic acid gave
similar yields as pivalic acid, but acetic acid decreased both
the conversion and product yield (Table 1, entries 6 and 7). To
allow a more rigorous stirring, the reaction concentration was
reduced to 0.13 M, which increased the yield to 71% (Table 1,
entry 8). Solvent screening confirmed DCE to be the best
solvent (Table S3; Table 2, entries 9–11). Adding the acid in
its carboxylate salt form (PivOK) and using 2.0 equiv of 2a
delivered 3a in 82% yield (Table 1, entries 12 and 13).
Several ligands were also considered, but no improvement
was observed (Scheme S5). Interestingly, re-evaluation of
Entry
Catalyst
Conv. [%][b] 3a
Yield [%][b] 4a
1
2
3
Pd(OAc)2
Cu(OAc)2·H2O
CuI
14
100
100
0
87
88 (85)
[a] Reaction conditions: 3a, catalyst (10 mol%), K2CO3 (1.0 equiv),
PivOK (0.2 equiv), 1,2-DCE (0.13 M), 1208C, 24 h, sealed pressure tube.
[b] 1H NMR yield with 1,3,5-trimethoxybenzene as internal standard
(isolated yields in parentheses).
K2CO3 gave the same result and the loading of PivOK could
even be further reduced delivering product 3a in 82% yield
(Table 1, entries 15 and 16). The C(sp3)-H alkenylation
reaction proved fully site- (g) and diastereoselective (Z
alkene, cis cyclohexane). The robustness versus water was
also studied. When 10 equiv H2O were added the desired
product 3a was also formed, albeit in a slightly lower yield
(67%) and unreacted 1a was recovered in 30% (Table 1,
entry 17).
With the optimized reaction conditions identified, we
evaluated the scope of the g-C(sp3)-H alkenylation reaction
protocol with other 1,1-dibromo-1-
alkene coupling partners (2) with
Table 1: Optimization of the Pd-catalyzed g-C(sp3)-H alkenylation of 1a with 2a.[a]
1a (Scheme 1). When 1-(2,2-dibro-
moethenyl)arenes (2b–g), bearing
different substituents at the 2-, 3-
and 4-positions of the phenyl ring
were used, the reaction condition
proved to be suitable giving the
desired products 3b–g in good to
high yields (64–74%). The incor-
poration of electron-donating (3b–
d) as well as electron-withdrawing
(3e–g) substituents proved to be
compatible with the developed
protocol. The presence of an or-
tho-methyl group did not hamper
the reaction, delivering 3b in 74%
yield. The chloro functionality was
well tolerated, allowing post-deri-
vatizing of 3e at the arene moiety.
Only when a CF3 moiety was
introduced with 2g, no full conver-
sion (85%) and consequently
a lower product yield 3g (64%)
was observed. The application of
Entry
2a
[X equiv]
Base
Additive
[Y equiv]
Solvent (conc.)
Conv. [%][b]
Yield [%][b]
1a
3a
1
2
3
4
5
6
7
8
9
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
K2CO3
K2CO3
–
DCE (0.2 M)
DCE (0.2 M)
DCE (0.2 M)
DCE (0.2 M)
DCE (0.2 M)
DCE (0.2 M)
DCE (0.2 M)
DCE (0.13 M)
1,4-dioxane (0.13 M)
toluene
52
69
18
68
68
69
48
77
72
71
48
51
14
54
60
59
28
71
59
52
PivOH (0.4)
PivOH (0.4)
PivOH (0.4)
PivOH (0.4)
AdCO2H (0.4)
AcOH (0.4)
PivOH (0.4)
PivOH (0.4)
PivOH (0.4)
Ag2CO3
Cs2CO3
Rb2CO3
Rb2CO3
Rb2CO3
Rb2CO3
Rb2CO3
Rb2CO3
10
(0.13 M)
tBuOH
(0.13 M)
DCE (0.13 M)
DCE (0.13 M)
DCE (0.13 M)
DCE (0.13 M)
DCE (0.13 M)
DCE (0.13 M)
11
1.5
Rb2CO3
PivOH (0.4)
14
4
12
13
14
1.5
2.0
3.0
2.0
2.0
2.0
Rb2CO3
Rb2CO3
Rb2CO3
K2CO3
K2CO3
K2CO3
PivOK (0.4)
PivOK (0.4)
PivOK (0.4)
PivOK (0.4)
PivOK (0.2)
PivOK (0.2)
88
92
93
92
92
70
75
82 (73)
83
81
82 (72)
67
15
a
very challenging heteroarene
16
17[c]
coupling partner bearing a protect-
ed indole (2h) was also evaluated.
Unfortunately, even with a double
amount of 2h, an incomplete con-
version was achieved (33% recov-
[a] Reaction conditions: 1a, 2a (1.5–3.0 equiv), Pd(OAc)2 (10 mol%), base (1.0 equiv), additive
(0–0.4 equiv), solvent (0.13–0.20 M), 1208C, 24 h, sealed pressure tube. [b] 1H NMR yield with
1,3,5-trimethoxybenzene as internal standard (isolated yields in parentheses). [c] H2O (10 equiv) was
added. DCE=1,2-dichloroethane, AdCO2H=1-adamantanecarboxylic acid.
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amidation additionally delivering the normorphans, 4l and
4m in 32% and 11%. Although, this auto tandem Pd catalysis
was only observed with the tetrahydro-2H-pyranamine ring
system, it supported the feasibility of our goal. The observa-
tion that two of the three heterocyclic substrates, 1c and 1d,
did not give full conversion of substrate, points to complex-
ation of the additional heteroatoms with the catalyst, hereby
inhibiting the catalytic activity. Clearly, there is a spatial effect
as these are g versus the amino group, while this is d in
substrate 1e providing full conversion. As observed on the
cyclohexanes, the excess 2a (up to 81%) was easily recovered.
As the auto tandem g-C(sp3)-H alkenylation and C-Br
amidation on our model reaction of 1a with 2a was not
observed under Pd catalysis, we further investigated the
subsequent cyclization of intermediate 3a into normorphan
4a (Table 2). Interestingly, when Cu(OAc)2·H2O was used,
full conversion of 3a was observed and the desired product
7-benzylidinenormorphan (4a) was obtained in 87% NMR
yield (Table 2, entry 2). The use of cheaper CuI proved
equally effective providing 4a in 85% isolated yield (Table 2,
entry 3). The bicyclic core structure and exclusive Z-alkene
configuration of 4a were unambiguously confirmed by 2D
NMR analysis (Supporting Information).
Considering our “one pot” goal, CuI and additional
K2CO3 were subsequently added to the optimal Pd-catalyzed
g-C(sp3)-H alkenylation reaction conditions of the model
reaction. Heating 1a with 2.0 equiv of 2a, 10 mol% of
Pd(OAc)2, 10 mol% CuI, 2.0 equiv of K2CO3 and 0.2 equiv
of PivOK in 1,2-DCE at 1208C for 24 h gave 4a in 76% NMR
yield. In order to maximize the yield of the tandem reaction,
the loading of CuI and K2CO3 were further fine-tuned
resulting in a rewarding 87% NMR yield (81% isolated
yield) of 4a (Scheme 2). Interestingly, the excess 2a was
recovered in 91% yield and no intermediate 3a was observed.
The result is quite remarkable considering the overall yield of
4a is higher in comparison to the two-step process starting
from 1a (61% overall: 72% of 3a from 1a and 85% of 4a
from 3a) (Scheme 1 and Table 2, entry 3). This supports the
efficiency of our tandem protocol towards synthesizing our
target normorphans beyond a step-economic way. The robust-
ness of the tandem one pot reaction in the presence of water
was also evaluated. When 10 equiv H2O were added, the
desired product 4a was also formed, albeit in a slightly lower
yield (67%) and unreacted 1a was recovered in 30%.
Scheme 1. Scope of the Pd-catalyzed directed g-alkenylation of 1 with
2.[a] [a] Reaction conditions: 1, 2 (2.0 equiv), Pd(OAc)2 (10 mol%),
PivOK (0.2 equiv), K2CO3 (1.0 equiv), 1,2-DCE (0.13 M), 1208C, 24 h,
sealed pressure tube. Less than 10% of 1 recovered unless otherwise
mentioned. [b] 15% 1a recovered. [c] 4.0 equiv 2 used. [d] 33% 1a
recovered. [e] 87% 1a recovered. [f] 17% 1c recovered. [g] 35% 1d
recovered. [h] Product of auto tandem catalysis (see Scheme 2).
ery of 1a), delivering reaction product 3h in 43% yield.
Gratifyingly, 73–90% of the excess coupling partner 2a–f,h
was easily recovered upon chromatographic purification of
the reaction product 3, implying that only 1.15 to 1.38 equiv
were effectively consumed in the direct alkenylation reaction.
The only exception are volatile 1,1-dibromo-1-alkenes 2, such
as 2g, which are lost during work-up. Subsequently, aliphatic
alkenes were studied as reactants. Reaction of 1,1-dibromo-
3,3-dimethylbut-1-ene (2i) with 1a delivered product 3i in
92% yield with full conversion of 1a. Remarkably, the use of
(2,2-dibromoethenyl)cyclohexane (2j), failed to deliver the
desired product 3j, with 87% recovery of 1a (vide infra).
While Pd-catalyzed cross-coupling reactions of gem-dihalo-
vinyl systems with organometallics are known to provide
three products, that is, mono and double C-X functionalized
as well as alkynylated product,[18,19] we only obtain a single
compound 3 with Z configuration in our remote C-H
functionalization.
Next, we evaluated challenging saturated heterocyclic
substrates (Scheme 1). Commercially available 3-amino-1-
Boc-piperidine, tetrahydro-2H-pyran-3-amine and tetrahy-
dro-2H-pyran-4-amine were transformed into the corre-
sponding picolinamides and subjected to the optimal alkeny-
lation reaction conditions. With piperidine substrate 1c, 66%
conversion was achieved using standard conditions. With
4.0 equiv 2a loading, an improved conversion was achieved
(75%) and the desired product 3k was obtained in 34%
isolated yield. The pyran substrates (1d and 1e) afforded the
desired products 3l and 3m in 13% and 61%, respectively.
Interestingly, 3l and 3m further reacted in an intramolecular
With the optimized reaction condition for the tandem
process identified, the scope with respect to 1,1-dibromo-1-
alkenes (2) was evaluated. First, the same 1-(2,2-dibromo-
ethenyl)arenes (2b–g) as used in Scheme 1 were reacted with
1a using the optimal tandem reaction conditions. The
incorporation of electron-donating and electron-withdrawing
substituents proved to be compatible as good to high yields of
bicyclic products 4a–g (65–74%) were obtained, considering
two reactions occur in one step. Even the use of heterocyclic
1-(benzenesulfonyl)-5-(2,2-dibromoethenyl)-1H-indole (2h)
delivered 4h in 57% yield with no 1a remaining. In all
examples, excess 2 was recovered (35–64%). Interestingly,
while 2g and 2h gave full conversion of 1a in the orthogonal
tandem reaction, the corresponding Pd-catalyzed g-C(sp3)-H
alkenylation with these aromatic 1,1-dibromoalkenes did not
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substrate 1e was consumed completely. An attempt to obtain
a higher yield of 4l and 4m by using PivOH (instead of
PivOK), was unsuccessful. When the CuI amidation reaction
was performed with isolated 3l and 3m, the expected product
4l and 4m were obtained in 87% and 95% yield, respectively
(Scheme 3). Clearly, for substrates allowing auto tandem
catalysis the combination of Pd and Cu is less efficient.
Scheme 3. Cu-catalyzed intramolecular C-Br amidation of 3l and 3m.
As a next phase, we applied the tandem reaction protocol
on DG equipped C-substituted cyclohexanamines 1. Cyclo-
hexanamines B are either commercially available or readily
prepared in one step from (renewable) phenols A by
reductive amination (Figure 2B).[21] A methyl group was
selected for this purpose in a reaction with 2a (Scheme 4).
Methyl substitution at each position of the cyclohexanamine
Scheme 2. Scope of the orthogonal tandem reaction of 1 with 2.[a]
[a] Reaction conditions: 1, 2 (2.0 equiv), Pd(OAc)2 (10 mol%), CuI
(20 mol%), PivOK (0.2 equiv), K2CO3 (3.0 equiv), 1,2-DCE (0.13 M),
1208C, 24 h, sealed pressure tube. Less than 10% of 1 was recovered
unless otherwise mentioned. [b] 4.0 equiv 2 used. [c] 28% 1a recov-
ered. [d] PivOH (0.2 equiv) was used instead of PivOK. [e] 18% 1a
recovered. [f] 26% 1d recovered.
(benzotrifluoride 2g: 15% 1a) (1H-indole 2h: 33% 1a).
Next, we used the aliphatic coupling partners bearing a tert-
butyl (2i) and cyclohexyl (2j) group. When 2i was used, the
product 4i was obtained in a moderate yield (53%) with 28%
of 1a recovered using standard reaction conditions. To our
delight, the conversion and yield was improved significantly
when PivOH was used instead of PivOK, resulting in full
conversion and 70% isolated yield of 4i. Remarkably 2j,
which did not work in the Pd-catalyzed g-alkenylation
reaction (Scheme 1), surprisingly reacted well in the tandem
reaction, delivering 67% of 4j. The use of PivOH in this case
did not affect the yield.
Subsequently, challenging heterocyclic amine substrates
1c–e were studied in the tandem protocol, potentially
allowing one to directly access aza- and oxa-analogues of
normorphan (Scheme 2, 4k–4m). Gratifyingly, piperidine-3-
amine (1c) delivered 4k in 76% yield. This outcome is
surprising as the corresponding Pd-catalyzed g-(sp3)-H alke-
nylation of 1c suffered from an incomplete conversion (17%
1c recovery) and low yield (34% 3k) (Scheme 1). Subse-
quently, regioisomeric tetrahydro-2H-pyranamines equipped
with picolinamide DG (1d,e) were used. These substrates
afforded the desired products 4l and 4m in 48% and 35%
yields, respectively. In case of 4l, an incomplete conversion
was observed as 26% of 1d was recovered. In case of 4m, the
Scheme 4. Orthogonal tandem reaction with cis and trans methyl-
substituted cyclohexanamines 1.[a] [a] Reaction conditions: 1, 2
(4.0 equiv), Pd(OAc)2 (10 mol%), CuI (20 mol%), PivOK (0.2 equiv),
K2CO3 (3.0 equiv), 1,2-DCE (0.13 M), 1208C, 24 h, sealed pressure
tube. Less than 10% of 1 recovered unless otherwise mentioned.
[b] 83% unreacted 1 f (NMR yield). [c] 95% unreacted 1g-cis (NMR
yield). [d] 24% 1g-trans recovered. [e] 67% unreacted 1h-cis (NMR
yield).
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Scheme 5. Orthogonal tandem reaction with diastereomeric mixtures of methyl-substituted cyclohexanamines 1.
ring was considered. The corresponding cis- and trans-
diastereoisomers of 2-, 3- and 4-methylcyclohexanamine
regioisomers were either commercially available or synthe-
sized from the corresponding methylcyclohexanol (Support-
ing Information). Tandem reaction with 1-methyl substrate 1 f
did not deliver the desired product 4n, only starting material
was recovered. This seems to be related to the methyl as when
another substituent was used, that is, 1-CO2Me analogue 1b,
the desired bicyclic product 4o was obtained in 56% isolated
yield with complete conversion. Reaction with cis-2-Me (1g-
cis) could generate two regioisomeric products (4p-cis and
4q-cis), however no reaction was observed and 95% 1g-cis
was recovered. Trans-2-Me substrate 1g-trans could deliver
two regioisomers (4p-trans and 4q-trans) and the expected
4p-trans product was formed in 16% yield. Regioisomeric
4q-trans was not observed. Instead 2-((Z)-benzylidene)octa-
hydro-1H-indole 5 was isolated, formed via C-H activation on
the 2-Me. We assume that also in substrates 1g-cis and 1 f,
competitive C-H activation on the methyl is occurring but it
does not lead to functionalization. When 3-methyl substrate
was used, cis-isomer 1h-cis did not react, but trans-isomer 1h-
trans transformed smoothly delivering 4r-trans in 60% yield
with complete conversion. The former cis-3-Me 1h-cis needs
to adapt an energetically unfavorable conformation featuring
a 1,3-diaxial interaction between DG and Me, rationalizing
why it does not allow C-H activation. With 4-methyl
substitution, both diastereomeric substrates (1i-cis and 1i-
trans) reacted smoothly delivering 91% and 77% isolated
yields of 4s-cis and 4s-trans, respectively.
(Scheme 5). Reductive amination of methylphenols[21] gives
a mixture of diastereoisomers, which are inseparable using
classical separation on silica gel. However, the product
mixtures of the orthogonal tandem catalysis are expected to
not feature this problem, which rationalizes why starting from
these mixtures is an advantage. When a mixture of 1h-cis and
-trans was used (70:30 cis/trans), only 1h-trans reacted in
accordance with the experiments performed on the pure
diastereoisomers. Unreacted cis-3-Me (1h-cis) was easily
separated from target product 4r-trans. Orthogonal tandem
catalysis on the diastereomeric mixture of 1i-cis and -trans
(55:45 cis/trans) gave a mixture of normorphans, that is, 4s-cis
and 4s-trans, which were easily purified by silica chromato-
graphy.
Several examples of the 1,1-dibromo-1-alkene (2) scope
showed that the orthogonal tandem reaction worked better
than the corresponding Pd-catalyzed g-alkenylation reaction
alone on 1a. This interestingly points to the CuI influencing
the conversion of the g-functionalization reaction in the
tandem process. PdII coordinates with the picolinamide DG
and the alkene moiety in the intermediate 3 in an h2
manner.[22] If this coordination is strong it will inhibit catalysis
by scavenging the PdII catalyst and CuI catalyst can help to
release PdII from 3. This rationalizes the experiments with
electron rich alkenes 2h and 2j with substantial amounts of
substrate remaining in the g-alkenylation, respectively 33%
and 87% of 1a. Though 2i is an aliphatic and therefore also
electron rich alkene, the sterically hindered t-Bu group
hampers h2 coordination, explaining efficient reactions that
were observed in both protocols. To experimentally support
our hypothesis of catalyst inhibition by intermediate 3 during
the reaction, we performed the standard reaction (1a to 3a) in
Next, we tested whether mixtures of DG equipped cis-
and trans-diastereoisomers of methylcyclohexanamines
1
could be used in our orthogonal tandem protocol
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forming a h2-coordination complex I-4, which can result in
incomplete conversion of substrate in Pd-catalyzed
1
g-alkenylations. In the presence of CuIX and additional base,
compound 3 enters into the second catalytic cycle and releases
PdIIL2 from complex I-4. The amidation cycle starts with an
initial coordination of the amide moiety of 3 to CuIX, forming
I-5. The resulting copper-amide complex then undergoes an
intramolecular oxidative addition generating I-6, which
2
À
allows for a subsequent C(sp ) N bond formation by
reductive elimination of the desired product 4.[23] An alter-
native to this mechanism would involve a Cu-catalyzed
intermolecular bromoalkenylation of the amide of 1a,[24]
followed by an intramolecular Pd-catalyzed C-H alkenyla-
tion. This is however unlikely, considering acyclic secondary
amides are poor substrates in intermolecular Ullmann-Gold-
berg cross-coupling reactions and the E isomer of 7-alkylide-
nenormorphan 4a is expected. In accordance with this
reaction of 1a with 2a under Cu catalysis proved unsuccessful
(Scheme 6B).
Scheme 6. Control experiments.
The enamides 4 are interesting products for further post
transformations.[15] In the framework of this work, the double
bond was selectively transformed into imide 6 by a RuIII-
catalyzed oxidative cleavage (Scheme 7).[25] Both aryl and
alkyl substituents on the enamide allowed this transformation
as exemplified by a reaction with 4a and 4j. The aza
normorphan 4k also reacted under the same reaction
conditions delivering 43% 6b. Subsequent cleavage of the
imide in 6 by basic hydrolysis furnished the corresponding
lactams 7a,b. These possess interesting synthetic potential via
for example, reductive functionalization of amides into
a-branched alkanamines.[26]
the presence of 0.2 equiv of 3h featuring an electron rich
double bond (Scheme 6A). Conversion clearly reduced (only
70% compared to full in absence of 3h) and 3a was formed in
only 62% (compared to 82% in absence of 3h).
Figure 3 shows the proposed concomitant catalytic cycles
for the formation of 4 from 1 via 3. At first, a bidentate
palladium complex I-1 is formed upon coordination of 1 with
PdIIL2 in the presence of base. Subsequent g-C(sp3)-H
activation via a concerted metalation-deprotonation (CMD)
pathway generates complex I-2. Next, the 1,1-dibromoalkenyl
coupling partner 2 site-selectively oxidatively adds to the
metal center, forming a PdIV complex (I-3). Reductive
elimination of alkenylated product 3 from I-3 regenerates
PdIIL2. Compound 3 is capable of scavenging PdIIL2 by
Figure 3. Proposed mechanism of orthogonal tandem catalysis involving PdII-catalyzed g-alkenylation of 1 and subsequent CuI-catalyzed amidation
of 3.
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served. The synthesis of other bridged nitrogen bicyclic
skeletons via the new strategy disclosed, as well as the
generality of the copper effect for other vinylation reactions,
is under study in our laboratories.
Acknowledgements
The research was funded by FWO-Flanders (Research project
Grant No. G0A2820N and WOG), the Federal Excellence of
Science (EoS) program (BIOFACT, Grant No. 30902231), the
European Unionꢀs Horizon 2020 research and innovation
programme under the Marie Skłodowska-Curie Actions
(Grant No. 837718), and the Hercules Foundation.
B.U.W.M. acknowledges the Francqui Foundation for an
appointment as Collen-Francqui professor. All authors thank
G. Van Haesendonck, Prof. F. Lemiꢁre, and Dr. D. Buyst for
analytical support and, D. De Vos for the synthesis of some
starting materials.
Scheme 7. Post-functionalization: lactam 7 synthesis.
Conclusion
In summary, valuable 7-alkylidenenormorphans have
been obtained in a step-economic and efficient way via
selective orthogonal tandem catalysis. The “one pot” process
involves a remote intermolecular Pd-catalyzed g-C(sp3)-H
alkenylation on commercial cyclohexanamine, equipped with
Conflict of Interest
The authors declare no conflict of interest.
a
picolinamide directing group, with readily available
1,1-dibromo-1-alkenes followed by a Cu-catalyzed C(sp2)-Br
amidation reaction on the 3-(1-bromo-1-alkenyl)cyclohexan-
1-amine intermediate. Selectivity obtained includes site (C-H
in 1, C-Br in 2), diastereoselectivity (cis-alkenylation,
Keywords: alkenylation · bridged bicyclic nitrogen scaffolds ·
normorphan · remote functionalization · tandem catalysis
À
Z-alkene), as well as product selectivity [3 (C C bond) versus
À
C (C N bond), 4 (amidation) versus D (elimination)].
Diastereomeric mixtures of substituted cyclohexanamines
can be directly applied in our protocol providing easily
separable reaction mixtures, as exemplified for methylcyclo-
hexanamines. Considering these diastereoisomers are ob-
tained via reductive amination of the corresponding phenols
and are generally inseparable, this offers ample application
potential for chemical libraries synthesis. The protocol can
also be applied on commercial aminoheterocycles immedi-
ately providing access to the corresponding aza- and oxa-
analogues of 7-alkylidenenormorphans. Besides acting as
a directing group, the amide directing group stabilizes the
enamine in the reaction product as its enamide. Enamides are
valuable entities in organic synthesis which can provide access
to various C7-derived normorphans. This is exemplified by
oxidation of the products into the corresponding lactams.
When only Pd catalyst is used, g-C(sp3)-H olefination is
occurring, providing the intermediate 3-(1-bromo-1-alkenyl)-
cyclohexan-1-amines of the tandem protocol as a single regio-
and diastereoisomer (Z alkene, cis-cyclohexane). These novel
alkenylated products are synthetically useful precursors for
further transformations and the subject of further studies in
our laboratories. Remarkably, when electron rich and non-
sterically hindered alkenes are used, the tandem protocol
actually works better than the g-C(sp3)-H alkenylation. Our
results show this is due to off-cycle scavenging of Pd catalyst
by the alkene moiety of the 3-(1-bromo-1-alkenyl)cyclohex-
an-1-amine, which is released by Cu catalyst present in the
tandem protocol, rationalizing the better conversion ob-
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Manuscript received: May 19, 2021
Accepted manuscript online: June 18, 2021
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Version of record online: && &&
,
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Research Articles
À
C H Functionalization
S. Biswas, B. F. Van Steijvoort,
M. Waeterschoot, N. R. Bheemireddy,
G. Evano, B. U. W. Maes*
&&&& — &&&&
Expedient Synthesis of Bridged Bicyclic
Nitrogen Scaffolds via Orthogonal
Tandem Catalysis
Bridged bicyclic nitrogen scaffolds are
conformational restricted analogues of
important aminocarbo- and amino-
heterocycles. Fixation of functional
groups in a biologically active con-
formation provides efficient and selective
ligands for various targets, featuring
improved ADME parameters. Long syn-
thetic sequences relying on traditional
organic chemistry currently limit the drug
discovery process. New step-economic
synthetic procedures are therefore highly
sought after.
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