Rapid Access to Azabicyclo[3.3.1]nonanes by a Tandem Diverted Tsuji–Trost Process

Article abstract of DOI:10.1002/chem.202003762

A three-step synthesis of the 2-azabicyclo[3.3.1]nonane ring system from simple pyrroles, employing a combined photochemical/palladium-catalysed approach is reported. Substrate scope is broad, allowing the incorporation of a wide range of functionality relevant to medicinal chemistry. Mechanistic studies demonstrate that the process occurs by acid-assisted C?N bond cleavage followed by β-hydride elimination to form a reactive diene, demonstrating that efficient control of what might be considered off-cycle reactions can result in productive tandem catalytic processes. This represents a short and versatile route to the biologically important morphan scaffold.

Full text of DOI:10.1002/chem.202003762

Accepted Article
Accepted Article
Title: Rapid Access to Azabicyclo[3.3.1]nonanes via a tandem diverted
Tsuji-Trost process
Authors: Kevin Iain Booker-Milburn, hannah steeds, jonathan knowles,
wai yu, jeffrey richardson, and katie cooper
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202003762
Link to VoR: https://doi.org/10.1002/chem.202003762
01/2020

10.1002/chem.202003762
Chemistry - A European Journal
COMMUNICATION
Rapid Access to Azabicyclo[3.3.1]nonanes via a tandem diverted
Tsuji-Trost process
Hannah G. Steeds,[a] Jonathan P. Knowles,*[b] Wai L. Yu,[a] Jeffery Richardson,[c] Katie G. Cooper[d] and
Kevin I. Booker-Milburn*[a]
[a]
Prof. K.I. Booker-Milburn,* H.G. Steeds, Dr. W.L. Yu
School of Chemistry
University of Bristol
Cantock’ Close
Bristol, UK, BS8 1TS
E-mail: k.booker-milburn@bristol.ac.uk
Dr. J.P. Knowles*
[b]
University of Northumbria
Newcastle upon Tyne, UK, NE1 8ST
E-mail: jonathan.p.knowles@northumbria.ac.uk
Dr. J. Richardson
DCRT European Innovation Hub
Lilly UK, Erl Wood Manor, Windlesham , GU20 6PH, UK
Dr. Katie Cooper
[c]
[d]
AstraZeneca
Pharmaceutical Technology & Development
Macclesfield Campus
Cheshire, SK10 2NA, UK
Supporting information for this article is given via a link at the end of the document.
1
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10.1002/chem.202003762
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Abstract: A three-step synthesis of the 2-azabicyclo[3.3.1]nonane
Following our recently reported synthesis of lycorane
ring system from simple pyrroles, employing
a
combined
alkaloid 4,[12] employing
a
key Heck cyclisation on
a
photochemical/palladium-catalyzed approach is reported. Substrate
scope is broad, allowing the incorporation of a wide range of
functionality relevant to medicinal chemistry. Mechanistic studies
demonstrate that the process occurs via acid-assisted C-N bond
cleavage followed by β-hydride elimination to form a reactive diene,
demonstrating that efficient control of what might be considered off-
cycle reactions can result in productive tandem catalytic processes.
This represents a short and versatile route to the biologically
important morphan scaffold.
photochemically-derived substrate, we were led to consider
whether simple homologation of the carbon tether might lead
directly to the homologated alkaloid series. However, initial
investigation of the Heck reaction of iodide 10a in fact yielded
deiodinated material 10b under the majority of conditions (Table
1). In no case was the desired Heck product detected, with use
of previously successful phosphite ligands[13] leading to the
unexpected phosphonate ester 10c (Entry 4), presumably via
reductive elimination to a phosphonium salt intermediate.[14]
However, the use of triphenylphosphine and dppf (Entries 7 and
8) led to the formation of bicyclic amine 11. This process
appeared to result from C-N bond cleavage with concurrent
amine migration and reduction of the iodide moiety. Further
screening of reaction conditions demonstrated that bicyclic
amine 11 was formed in good yield through the use of DPEPhos
(Entry 9), and that iPr2NEt was required for this process to occur,
with either no base or Et3N proving unsuccessful (Entries 10 and
11).
Since their discovery palladium-catalyzed cross-coupling
reactions have seen increasing use in the synthesis of bioactive
molecules.[1] In particular, due to its reliability, the Suzuki cross-
coupling has become a key C-C bond forming reaction within
medicinal chemistry.[2] However, the resulting compounds are
often relatively planar in nature, despite evidence that increased
bioactivity might result from increased levels of sp3-hybridized
carbon.[3] The Tsuji-Trost allylation represents a palladium-
catalyzed process with potential to achieve more three-
dimensional molecules, necessarily connecting fragments via
sp3-hybridized centers.[4] Recent work has added to this potential
Table 1. Initial reaction screening.
with
increasingly
effective
systems
for
performing
enantioselective Tsuji-Trost reactions.[5] The power of such
reactions within tandem processes has also been demonstrated,
particularly in combination with photochemistry to create
complex, three-dimensional molecules from simple substrates
(Scheme 1a).[6]
Entry
1
Ligand
Solventa
MeCN
10b /%
11 /%
Tsuji-Trost reactions are also potentially less prone to side
reactions, such as competing protodehalogenation encountered
in Suzuki cross-couplings.[7] While competing β-hydride
elimination from intermediate π-allyl Pd complexes to form
dienes is known,[8] this process is less reported and potentially
reversible.[9] However, dienes themselves frequently serve as
useful synthetic intermediates,[11] raising the possibility that their
formation could form part of a productive catalytic cycle.[11]
Herein we report a diverted Tsuji-Trost process, where β-hydride
elimination to form a reactive diene results in a novel tandem
process, forming complex tertiary amines that represent the core
of the biologically significant morphan ring-system (Scheme 1b).
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(OPh)3
XantPhos
dppb
<5
<5
<5
89b
55
0
0
2
Toluene
Dioxane
MeCN
0
3
0
4
0
5
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
0
6
3c
21c
36c
76
0
7
dppf
0
8
PPh3
0
9
DPEPhos
DPEPhos
DPEPhos
CyDPEPhos
0
10d
11e
12
42
0
0
0
6c
[a] All reactions were performed at reflux for 20 h. [b] Yield for phosphonate
ester 10c, based on P(OPh)3. [c] Based on 1H-NMR using 1,3,5-
i
trimethoxybenezene as internal standard. [d] Et3N used instead of Pr2NEt. [e]
No amine added.
While this process was found to be relatively tolerant of
variation of the aryl group (see SI for details), the inclusion of a
sacrificial iodide moiety (i.e. X = I) proved essential for reactivity.
As noted previously, the protodehalogenation of aryl halides is
well documented within cross coupling reactions. Such a
process has the potential to generate stoichiometric quantities of
HX, which might then facilitate the observed cleavage of the C-N
Scheme 1. Previous synthetic utility of photochemically-synthesized vinyl
aziridines and their formation of azabicyclo[3.3.1]nonanes in a novel diverted
Tsuji-Trost process.[6]
2
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10.1002/chem.202003762
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bond.[16] Further evidence for this was obtained from a cross-
over reaction where a mixture of iodinated and non-iodinated
substrates led to product formation from both (see SI for details).
We therefore investigated various additives (Table 2).
Table 2. Optimization study of reaction additives.
Entrya
Amine (eq)
None
Additive (eq.b)
6 /%
1
None
0
2
iPr2NEt (2)
iPr2NEt (2)
iPr2NEt (2)
iPr2NEt (2)
iPr2NEt (2)
iPr2NEt (2)
iPr2NEt (2)
None
14 (1)
50
40
26c
23c
19c
0
3
14 (0.5)
4
15 (0.5)
5
4-iodoanisole (0.5)
PhI (0.5)
6
7
TBAI (1)
8
AcOH/TBAI (1)
iPr2NEt.HI (1)
iPr2NEt.HI (1)
CSA (1)
0
9
53
39c
43
70
10
11
12
iPr2NEt (0.2)
iPr2NEt (1)
iPr2NEt (1)
MSA (1)
[a] All reactions were performed at reflux for 20 h. [b] Equivalents relate to
molar quantity of starting material 12. [c] Yield based on 1H-NMR using 1,3,5-
trimethoxybenzene as internal standard. TBAI = tetrabutylammonium iodide.
CSA = camphorsulfonic acid. MSA = methanesulfonic acid.
It can be seen that the use of an external electron-rich aryl
iodide led to efficient reaction (Entry 2). However stoichiometric
quantities were required (Entry 3), and the use of simpler, less
electron-rich species was less effective (Entries 4 – 6). Use of
iodide anion itself, either alone or in the presence of a weak acid
proved ineffective (Entries 7 and 8). However, the use of the HI
salt of iPr2NEt proved a real breakthrough, obviating the need for
a sacrificial aryl iodide (Entry 9). Exploring the required acid and
amine stoichiometry led to further refinement, with a buffered
system of 1 eq. each of methanesulfonic acid and iPr2NEt (Entry
12) proving optimal (see SI for complete acid study).
aPd-catalysed reactions were performed using 10 mol% Pd(OAc)2, 20 mol%
DPEPhos at 0.2 M concentration for 20 h. Amine to acid stoichiometry was 1:1.
Figure 1. Reaction scope and product derivatization.
The reaction proved very general, with a range of N-alkyl, N-
benzyl and N-homobenzyl substrates proceeding in good to
moderate yield (17a - i). Of particular note is the potential to
include a simple methyl group (17h), permitting access to N-
methyl morphan structures, and the medicinally important CF3
group (17c).[17] Given the importance of the morphan scaffold to
medicinal chemistry,[18] we also explored heterocyclic
substituents. The reaction proved to tolerate a range of electron-
rich (17l, o, r) and electron-poor (17j, n) heterocycles, albeit in
reduced yield. N-tosyl system (17t) was also explored but
proved unreactive.
With these conditions in hand, we explored the scope of this
reaction (Figure 1), the substrates being easily accessible via a
simple two-step process from pyrrole 1 (R = CO2 Bu), involving
photochemical conversion to tricyclic aziridine 7 followed by a
one pot retro-ene reaction/reductive amination sequence (see SI
for details).[6a,c]
t
The rapidity with which such complex, sp3-rich aza-systems
can be reached from a single parent pyrrole is a significant
highlight of the methodology, as is the ability to include reactive
3
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10.1002/chem.202003762
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functional groups as in 17p. Importantly, N-deprotection can be
readily achieved to form 19, permitting the installation of
additional functionality on nitrogen in only two further steps. This
could allow a practical approach to further expand the range of
R groups in 17. Exchange of PMB for the more versatile Cbz
protecting group is conveniently achieved in a single step, as
shown in the formation of 18. This could be a significant
advantage for a medicinal chemist wishing to prepare a 2D-
library of compounds by dual functionalization of the ester and
amine moieties in 17.
bridgehead (60% vs 35%), despite an anti-addition[19]/syn-
elimination[20] mechanism being expected to result in selective
cleavage of the C-D bond of 22 and the C-H bond of 23.
Assuming addition of palladium occurs anti to nitrogen, such
behaviour suggests that facile equilibration of palladium between
the endo and exo faces occurs within the π-allyl Pd complex
(vide infra). Further, a competition reaction between 22 and 12
(see SI for details) suggested no significant kinetic isotope effect
was operating, although a secondary KIE, for instance during
rate limiting -allyl complex formation, cannot be excluded.[21]
Based on these results, a mechanism is proposed in
Scheme 4. Initial acid-promoted cleavage of the C-N bond by
Pd(0) forms -allyl Pd complex 25. Based on the similar H/D
ratios in the products of deuterated compounds 22 and 23, this
undergoes equilibration between faces, presumably via
palladium O-enolate 26,[22] with β-hydride elimination thus being
possible from either face to form diene 28, and occurring
somewhat preferentially from the endo face (i.e. from complex
27). The exchange of Pd between the faces of the π-allyl
complex suggests this species has a significant lifetime, and this
combined with the absence of the appreciable primary KIE
generally associated with β-hydride elimination,[23] leaves open
the possibility that this step to form diene 28 may be reversible.
Trapping of this diene is possible through the inclusion of an
electrophile such as acetic anhydride (Scheme 2), and otherwise
this diene then undergoes irreversible 1,6-conjugate addition to
form intermediate 29 as a mixture of diastereomers. These
species undergo acid/base-promoted isomerization to the
observed product. Related conjugated addition processes have
been observed to occur under palladium catalysis.[24]
Scheme 2. Investigation of trapping and intermediates. [a] Yield determined
by 1H-NMR using 1,3,5-trimethoxybenzene as internal standard. Reaction time
of 20 h unless stated otherwise.
Having established the scope to be relatively broad, we
turned our attention to the reaction mechanism. Formally a
rearrangement, we considered that the process most likely
involved acid-assisted cleavage of the C-N bond forming a π-
allyl Pd intermediate, from which β-hydride elimination formed a
diene. This was tested by the addition of acetic anhydride to a
reaction of substrate 12, where uncyclized acetamide 20 was
formed in good yield. Stopping the reaction at an early stage
also showed the presence of intermediate 21, consistent with
intramolecular 1,6-addition to this diene. Re-subjection of 21 to
the reaction conditions showed conversion to 13 even in the
absence of palladium. Furthermore, brief treatment of 21 to the
optimized reaction conditions gave only 13 and no starting
material 12 was detected. This latter experiment likely indicates
that 1,6-addition is not reversible.
Scheme 4. Proposed mechanism.
In conclusion, we have demonstrated that a diverted Tsuji-
Trost process provides rapid access to biologically important
ring systems. This occurs via an unusual Pd-catalyzed
mechanism, exploiting processes often regarded as unwanted
side-reactions i.e. proto-dehalogenation,-hydride elimination
and Pd O-enolate equilibration. Overall, this methodology
provides three-step access to complex, biologically significant
molecules from simple aromatic starting materials. The versatility
of this chemistry could prove useful for medicinal chemists in the
construction of 2D-libraries based on the morphan scaffold, and
once again highlights the power of combining photochemical
synthesis with palladium catalysis.
Scheme 3. Deuterium labelling studies. [a] Substrate 24 contains a second
remote deuterium atom (NCHendoDexo) as a consequence of the synthetic
route, which remained unchanged in the reaction (see SI for full details).
We then prepared deuterated compounds 22 and 23 and
subjected these to the reaction conditions (Scheme 3). This led
to a somewhat surprising results, with both compounds showing
deuterium incorporation within the product; in fact, compound 24
showed a higher level of deuterium incorporation at the
Acknowledgements
4
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We thank EPSRC (EP/L015366/1; EP/S024107/1), AstraZeneca
(HGS) and Lilly UK (WLY) for funding. We thank Dr Hazel
Sparkes for x-ray crystallography (UoB) and Dr Chris Russell for
glovebox use (UoB).
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Keywords: Tsuji-Trost • Pd-catalysis • rearrangement •
morphan • heterocycles •
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Entry for the Table of Contents
tBuO2C
tBuO2C
t
Pd(0)/H+
hn/heat
CO2 Bu
N
N
then RCHO/H-
N
H
R
Diverted Tsuji-Trost
R
Easily diverted. A rapid entry to the biologically important morphan ring system highlights the powerful combination of
photochemistry and catalysis. The key palladium-catalysed transformation utilises a novel diverted Tsuji-Trost sequence. Mechanistic
studies demonstrate this process occurs via acid-assisted C-N bond cleavage followed by β-hydride elimination to form a reactive
diene.
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