Stereoselective and Enantiospecific Mono- and Bis-C?H Azidation of Tr?ger Bases: Insight on Bridgehead Iminium Intermediates and Application to Anion-Binding Catalysis

Article abstract of DOI:10.1002/chem.201700845

In the context of Tr?ger base chemistry, regio- and stereoselective C_sp3?H azidation reactions are reported. Azide functional groups are introduced at either one or the two benzylic positions selectively. Mild conditions and good yields are aff

Full text of DOI:10.1002/chem.201700845

A Journal of
Accepted Article
Title: Stereoselective and Enantiospecific Mono and Bis C-H azidation
of Tröger Bases. Insight on Bridgehead Iminium Intermediates
and Application to Anion-Binding Catalysis
Authors: Alessandro Bosmani, Sandip Pujari, Laure Guenee, Céline
Besnard, Amalia Isabel Poblador Bahamonde, and Jerome
Lacour
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Stereoselective and Enantiospecific Mono and Bis C-H azidation
of Tröger Bases. Insight on Bridgehead Iminium Intermediates
and Application to Anion-Binding Catalysis
Alessandro Bosmani,[a] Sandip A. Pujari,[a] Céline Besnard,[b] Laure Guénée,[b] Amalia I. Poblador-
Bahamonde,[a] Jérôme Lacour*[a]
Abstract: In the context to Tröger base chemistry, regio and
stereoselective Csp3-H azidation reactions are reported. Azide
functional groups are introduced at either one or the two benzylic
positions selectively. Mild conditions and good yields are afforded by
the combination of TMSN3 and iodosobenzene PhIO. The process
occurs with high enantiospecificity (es 96-99%) and, interestingly and
importantly, via bridgehead iminium intermediates as shown by
mechanistic and in-silico studies. Finally, mono and bis triazole
derivatives were prepared in high yields and enantiospecificity using
CuAAC reactions; some of the products being used as anion-binding
organocatalysts for the tritylation of amines and alcohols.
Introduction
In today’s organic chemistry, the azide functional group (-N3) is
commonly used for the introduction and manipulation of nitrogen
atoms.[1] Azides are typically incorporated by nucleophilic
substitutions on substrates pre-functionalized with leaving
groups.[2] Direct azide introduction by C-H functionalization is also
possible.[3] In most cases, the reactions are coupled to selective
oxidation processes.[4] In this framework, hypervalent iodine(III)
reagents are particularly useful.[5] For instance, C-H azidation of
tertiary carbon centers and carbonyl compounds can be achieved
using azidobenziodoxole and other iodine (III) reagents.[6] -
Functionalization of enol ethers and -azidation of N,N-dialkyl
anilines can be achieved using combinations of iodosobenzene
(PhIO) and TMSN3 (Figure 1, top).[7],[8] In this latter study, only
simple anilines were used and
a two-electron oxidation
mechanism iminium intermediates was postulated (Figure 1,
middle). It was therefore debatable whether this reaction could be
extended to more complex frameworks, and bicyclic derivatives
with bridgehead nitrogen atoms in particular, such as Tröger
bases 1a (Figure 1, bottom). In fact, Tröger bases (TB),[9] classical
Figure 1. Oxidative azidations using hypervalent iodine reagents
chiral molecules due to the presence of stereogenic nitrogen
atoms, are amenable to selective oxidation processes. On one
hand, in the presence of permanganate ions, original and
interesting twisted bisamide derivatives are synthesized in one
step.[10] On the other hand, treatments of 1a with catalytic
amounts of palladium(II)acetate, NBS and either KOAc or NaN3
afford -C-H acetylation and azidation processes.[11] In both
[a]
[b]
A. Bosmani, Dr. S. A. Pujari, Dr. A. I. Poblador-Bahamonde, Prof. J.
Lacour
Department of Organic Chemistry, University of Geneva
Quai Ernest Ansermet 30, 1211 Geneva 4 (Switzerland)
E-mail: jerome.lacour@unige.ch
Dr. C. Besnard, Dr. L. Guénée
cases, oxidations occurred at benzylic positions exclusively.[12]
A
Laboratory of Crystallography, University of Geneva
Quai Ernest Ansermet 24, 1211 Geneva 4 (Switzerland)
mechanistic rationale was proposed in the latter study suggesting,
as one possible pathway but without evidence, the formation of a
carbocation (iminium) intermediate. While half of the substrates
Supporting information for this article is given via a link at the end of
the document.
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gave cleanly mono adducts 2, bis-azido derivatives 3 were
obtained in the other cases, sometimes as major product. Herein,
it is shown that mono or bis-azidation Tröger bases can be
achieved selectively using the combination of PhIO and TMSN3
as reagents. In products 2 or 3, azides are introduced  to the N-
atoms. In addition, the reactions proceed with full
A mixture of 2a and 3a (1.2:1 ratio) was however isolated.
As expected, increasing the amount of PhIO and TMSN3 (4.2 and
5 equiv respectively), and performing the reactions at higher
concentration favored the bis azidation (2a:3a up to 1:4.1, entries
2 and 3). Changing solvent from CHCl3 to CH2Cl2 was detrimental
(entry 4) but increasing the concentration further to 0.5 M afforded
3a exclusively (entry 5, 71% isolated yield). With these optimized
conditions for 3a in hand, the focus was shifted towards a
selective preparation of mono azidation product 2a. Dilution of the
reaction medium to 0.025 M and decreasing the amount of
PhIO/TMSN3 (2.4 equiv each) improved the 2a:3a ratio (3.5:1,
entry 6). Changing the solvent from CHCl3 to CH3CN and diluting
further the reaction medium increased the selectivity up to 7.4:1
(entries 7 and 8). Finally, for the isolation of the mono azide
adduct, toluene was found to be optimal affording 2a in 57%
isolated yield (2a:3a >10:1, entry 9).[14] Interestingly, compounds
2a and 3a are produced as single diastereomers. The relative
configuration was determined by NMR spectroscopy and
confirmed by X-ray crystallography (Table 1). Not surprisingly, the
azide functional groups in 2a and 3a are introduced on the convex
side (exo) of the cyclic heterocycles. Such a result is consistent
with previous observations in TB chemistry.[9h,11,15],[16] With these
optimized conditions, care was also taken to perform the two
azidation processes on enantiopure (‒)-1a.[17] To our satisfaction,
chiral stationary phase (CSP) HPLC analysis (Chiralpak IC,
diastereoselectivity (diastereomeric ratio d.r.
> 49:1) and
enantiospecificity (es 96-99%). Interestingly, evidence was found
for bridgehead iminium species. In fact, substitution of azide
groups by indoles under Lewis acid activation and DFT
calculations validate the existence of such strained intermediates.
Care was finally taken to develop an application of compounds 2
in anion-binding catalysis using products derived by double
copper-catalyzed alkyne azide cycloadditions (CuAAC, Huisgen-
Click).[13]
Results and Discussion
Initial observation, optimization and scope
As mentioned, PhIO and TMSN3 react in the presence of (planar)
N,N-dialkyl anilines to generate -azido derivatives.[7b] With this
reactive combination, bis azido adducts can be obtained
selectively by essentially doubling the quantity of reagents. This
methodology was thus deemed interesting for the targeted
purpose. Tröger base 1a (R = Me, Table 1) was treated with PhIO
(2.4 equiv) and TMSN3 (2.4 equiv) in CHCl3 (0.1 M) at ‒20 °C. To
our satisfaction, C-H azidation proceeded smoothly with complete
regiocontrol in favor of a functionalization of the benzylic positions
over the aminal bridge.
Hexane/Isopropyl alcohol 90/10) indicated
a
very high
enantiospecificity as products (‒)-2a and (‒)-3a were obtained as
single enantiomers (ee 98.5% and > 99% respectively). For these
two reactions (eq. 1 & 2), a retention of configuration of the Tröger
base core is assumed.

Table 1. Optimization of the mono and bis azidation of Tröger Base 1a [a]
PhIO
(equiv)
TMSN3
(equiv)
Entry
Solvent
Conc. (M)
2a:3a
1
2
3
4
5
6
7
8
9
CHCl3
CHCl3
CHCl3
CH2Cl2
CHCl3
CHCl3
CH3CN
CH3CN
Toluene
0.1
2.4
4.2
4.2
4.2
4.2
2.4
2.4
2.4
2.4
2.4
5.0
5.0
5.0
5.0
2.4
2.4
1.8
2.4
1.2:1
0.1
1:1.8
0.2
1:4.1
Then, Tröger bases 1b-1f were subjected to mono azidation
conditions (Figure 2). Not surprisingly, the oxidative process was
more effective with TB carrying electron donating groups (2b, 2c:
54, 51%) than with electron withdrawing substituents (2d, 2e: 19,
10%).[18] Interestingly, 2f was formed in quite higher yield (83%)
using PhIO and TMSN3 in only 1.5 equivalents each. This result
is in line with a previously-detailed reactivity of 1f with nitrenes, in
which substantial amounts of C-H amination at benzylic positions
were noticed over the “classical” aminimide formation.[19] It can be
rationalized by the presence of the ortho substituents that shield
sterically the nitrogen atoms. Bis azidation reactions to products
0.2
1:2.6
1:>20 (71) [b]
0.5
0.025
0.025
0.0125
0.025
3.5:1
6.6:1
7.4:1
>10:1 (57) [b]
[a] Reaction conditions: 1a (1.0 equiv), PhIO, TMSN3, solvent ‒20 °C. [b]
Isolated yields in parenthesis. Stick view of the crystal structure of rac-2a.
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3b, 3d, 3f-3h gave similar results with sometimes better yields (in
particular with 1d). In all cases and as expected, high levels of
diastereoselectivity and enantiospecificity were obtained (2b-2f:
d.r. > 49:1, es 96-99%).
computed on the proposed cation. The comparison of the ɸ angle
formed by the planes of the aromatic rings in the characteristic V-
shaped structure increases by 22° from the TB substrate to the
proposed iminium intermediate (ɸ = 102° vs. 124°) allowing the
accommodation of the positive charge (see key angles and
distances on Figure 3). In order to discard the possibility of a non-
classical structure for cation A, the distance between the charged
carbon and the plane formed by the neighboring N-H-Cring atoms
was calculated. The minimal disturbance (0.09 Å) invalidates
such a proposition. In addition, no pyramidalization of the
positively-charged carbon is observed.
Figure 3. Computed DFT (B3LYP) geometrical parameters (Å and °) for TB 1a
and iminium intermediate A.
The calculation of the LUMO orbitals of TB 1a and iminium ion A,
represented in Figure 4, assesses the charge distribution for each
system and underlines the differences. The LUMO of 1a depicts
empty * orbitals of both benzene moieties while intermediate A
mainly distributes its cationic character on the * orbital of C=N
bond, which is in agreement with the subsequent functionalization
observed experimentally.
Figure 2. Conditions: 1b-1h (1.0 equiv) and [a]: PhIO and TMSN3 (2.4 equiv),
toluene (0.025 M), ‒20 °C; [b]: PhIO and TMSN3 (1.5 equiv), toluene (0.025 M),
‒20 °C; [c]: PhIO (4.2 equiv), TMSN3 (5.0 equiv), CHCl3 (0.5 M), ‒20 °C.
Mechanistic studies, theoretical and experimental
At that stage, in view of the generality of the process, a study of
the reaction mechanism was undertaken. First, it was
demonstrated that only the combination of iodosobenzene and
TMSN3 afforded azido products 2 and 3 reliably. Substrate 1a was
treated with various combinations of PIDA or PIFA (2.4-4.2 equiv)
and TMSN3, or with isolated reagent 1-azido-1,2-benziodoxol-
3(1H)-one,[6f] to afford unreacted starting material in most cases
or minor trace amounts of acetoxy derivatives.[11] Knowing that the
PhIO/TMSN3 combination favors two-electron processes over
radical ones,[7] the previous proposition of cationic (iminium) ions
as intermediates for this type of reactions (A, Figure 1) was
considered favorably.[11] However, species of type A are
bridgehead iminium ions.[20],[21] Care was thus taken to evaluate
the formation and the stability of such species as the [3.3.1]
bicyclic skeleton of TB could be large enough to accommodate
the strain, and this using both theoretical and experimental
approaches.
Figure 4. DFT (B3LYP) computed LUMO orbitals of TB 1a (left) and iminium
intermediate A (right). The value of the isodensity surface is 0.04 au.
With these calculations indicating a viability for bridgehead
iminium species A, experimental evidences were looked for. In
one set of studies, the “reversibility” of the azide addition was
utilized to demonstrate the presence of intermediates A. In fact, it
is established that azides can behave as leaving groups in the
presence of Lewis acids and (stabilized) carbenium ions result
from the elimination.[1a,22][23] In presence of nucleophiles, the
electrophilic species can be trapped in-situ. The formation of
In fact, DFT calculations on TB 1a and proposed intermediate A
were carried out at the B3LYP level of theory. The geometry of
the substrate, which is in good agreement with crystallographic
data, presents longer N-CH2 and CH2-Cring distances that those
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products of elimination-then-addition is then considered as a
proof of occurrence of the cationic intermediates. Experimentally,
the two-step process was realized by treating mixtures of indoles
(2.0 equiv) and Tröger base 2a at -65 °C with trimethyl aluminum
(2.0 equiv). As expected, heterocycles 4aA to 4fA were afforded
– in good to excellent yields (77-93%, Figure 5). The formal
substitution of the azido group by indole moieties was ascertained
by NMR spectroscopy and X-ray analysis (4bA). Importantly, a
retention of configuration is observed at the benzylic position. This
indicates that a SN1-type mechanism is at play and that the indole
nucleophiles approach intermediates of type A from the convex
side selectively, as azides do under the regular reaction
conditions.[24]
electron-withdrawing substituents on the two aromatic rings
respectively (Me and NO2, Scheme 1).[25] To our surprise, a 1:2
mixture of regioisomers 2i and 2i’ was isolated. The reaction was
unusually slow and a moderate conversion and combined yield
(22%) was achieved. Structure determination of 2i and 2i’ was
realized by 2D NMR analysis, and HMBC experiments in
particular (see Figures S2-S8). Initially, model compound 1i was
built expecting that the oxidation of the electron-rich nitrogen atom
(para to Me) would be highly favored over the electron-poor N-
atom (para to NO2),[26],[27] and this would lead to the predominant
formation of 2i (Scheme 1, path a, via iminium ion A1). It is clearly
not the case with the preferred formation of 2i’ (path b via iminium
A2).
Scheme 1. Regioselective azidation of TB 1i. Conditions: 1i (1.0 equiv), PhIO
and TMSN3 (2.4 equiv), 0.025 M (CHCl3), -20 °C.
iminium
A1
iminium
A2
Figure 5. Conditions: 2a-2f (1.0 equiv), indole (2.0 equiv), Me3Al (2.0
equiv), -65 °C to 20 °C. Stick view of the crystal structure of rac-4bA.
Finally, to fine-tune the mechanistic rationale, two experiments
were performed. First, classical TB 1a was treated with
PhIO/TMSN3 in the presence of a stoichiometric amount of
TEMPO (eq. 3). The reaction proceeded to form 2a in 53% yield,
ie in virtually the same yield as under optimized conditions (57%).
This and the lack of products containing TEMPO fragments
suggest that the two-electron pathway occurs through hydride
abstraction and not by consecutive single electron transfer steps.
Figure 6. DFT (B3LYP) computed LUMO orbitals of iminium intermediates A1
(left) and A2 (right). The value of the isodensity surface is 0.04 au.
Geometry optimizations of iminium intermediates A1 and A2 were
modelled. The calculation of the LUMO orbitals shown in Figure 6
confirms that both cationic species continues to favor the build-up
of charge on the *C=N orbitals over the aromatic moiety.
Interestingly, the comparison of the relative energies indicates
that A2 is more stable than A1 by 2.4 kcal mol-1. This preferred
stability of A2 is in agreement with the favored formation of
product 2i’. Yet, the moderate ratio (2:1) in favor of 2i’ indicates
that kinetic factors, and not just thermodynamic, should be
considered to explain the selectivity.
Then, the reaction was performed with unsymmetrically-
substituted Tröger base 1i carrying electron-donating and
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Application to catalysis
Recently, Garcia Mancheño and her group have reported poly
triazoles moieties that behave as anion receptors and anion-
binding organo-catalysts.[28] In fact, molecules 5a and 5b complex
negative ions thanks to the acidic C-H bonds carried by the
triazole units (Figure 7). Then, using these compounds as
catalysts, dearomatization of N-heteroarenes and tritylations of
primary amines were developed.[28] This original reactivity of
compounds 5 led us to consider an application of azido
derivatives 2 in this domain.
Figure 8. Conditions: 2a, 2b or 2f (1.0 equiv) and [a]: alkyne (1.2 equiv),
CuSO4.5H2O (0.10 equiv), ascorbic acid (0.17 equiv), NaHCO3 (0.17 equiv)
THF:H2O (1:1, 0.56 M), 20 °C; [b]: alkyne (2.5 equiv), CuSO4.5H2O (0.20 equiv),
ascorbic acid (0.34 equiv), NaHCO3 (0.34 equiv) THF:H2O (1:1, 0.56 M), 20 °C;.
Figure 7. Polytriazole-based ligands 5 for anion binding catalysis.
However, prior to consider the formation of TB analogues of 5,
care was taken to study the CuAAC reactivity of mono 2 and bis-
triazole 3 derivatives. The results are summarized in Figure 8.
Under standard CuAAC conditions, good to excellent yields of
6aA-6fA and 7aA-7bA were obtained (64-91%).[29]. Using
enantioenriched (‒)-2a (ee 98.5%) and (‒)-3a (ee 99%) triazoles
6aA and 7aA were obtained in very high enantiospecificity (es >
99%) demonstrating an excellent stereochemical fidelity.
With these results in hand, bis alkynyl pyridine 8a and benzene
8b were prepared (Figure 9).[30] Treatment of these substrates
with (‒)-2a under standard conditions yielded then (‒)-9a and (‒)-
9b in good yields, 71% and 75% respectively, and very high
enantiospecificity (es > 99%). In fact, the CuAAC coupling was
realized with enantiopure (‒)-2a to ensure the homochirality of 9a
and 9b, and avoid hence meso stereoisomers.
Figure 9. Synthesis of bistriazole (‒)-9a and (‒)-9b starting from (‒)-2a. Stick
view of the crystal structure of (‒)-9a, hydrogen atoms omitted.
The ability of 9a and 9b to bind chloride anions was studied by 1H
NMR titration using TBACl (tetrabutylammonium chloride) as
analyte. Care was taken to follow conditions reported by Garcia
Mancheño et al.[28] Part of the experiment with 9a is reported in
Figure 10; the most shifted NMR signal being the triazole C-H
protons as expected.[31] The data was treated with HypNMR
2008.[32] Not too surprisingly, in view of the electron-rich nature of
the TB framework, the values for the binding constants of 9a and
9b are quite low using acetone as solvent (Kacetone 11.5 ± 1.1 M-1
and 47.9 ± 1.1 M-1 respectively).[33]
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Figure 11. Tritylation of alcohol and primary amines with DMAP-trityl chloride
salt. Yields for reactions with 9a and 9b reported in blue and red colors
respectively. [a] In the absence of catalyst.
Conclusions
Regio and diastereoselective mono and bis C-H azidations of
Tröger bases were accomplished under mild reaction conditions
and high enantiospecificity (es 96-99%). Mechanistic studies
have further revealed the importance of bridgehead iminium
cations as reactive intermediates. Finally, mono and bis triazole
derivatives were prepared in high yields and enantiospecificity
using CuAAC reactions; some of the products being used as
anion-binding organocatalysts for the tritylation of amines and
alcohols.
Experimental section
Synthetic procedures and spectral characterization of new
compounds are reported in the electronic supporting information.
CCDC 1533697 to 1533700, products 2a, 4bA, 7aE, 9a, contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Figure 10. Titration of 9a and 9b. Top: 1H NMR spectra of 9a with various
amounts of TBACl. Bottom: Binding constants determined using the variation of
chemical shift of the triazole proton highlighted in yellow.
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
The phenyl derivative possesses a stronger binding than the
pyridine-based receptor; the lone-pair on nitrogen inducing
probably a repulsion with the anion. Nevertheless, the ability of
compounds 9 to behave as anion-binding catalysts was tested. In
fact, tritylations of primary amines and alcohols were investigated
using the adduct (salt) of DMAP and tritylchloride as reagent.[28b]
In the absence of compounds 9, no reactivity was observed with
amine substrates while, with benzyl alcohol, a moderate formation
of 10 was noticed (28%). On the other hand, reactions proceeded
smoothly under mild conditions (45 °C) in the presence of 9a and
9b to afford products 11a-11c in good yields (55-89%, Figure 11).
Long reaction times were however necessary in line with
previously-reported results.[28b]
We thank the University of Geneva and the Swiss NSF for
financial support. We also acknowledge the contributions of the
Sciences Mass Spectrometry (SMS) platform at the Faculty of
Sciences, University of Geneva. We would also like to thank
Carmine Chiancone for technical support.
Keywords: Anion-binding catalysis • Azide • Bridgehead • C-H
functionalization • Enantiospecificity • Iminium intermediate •
Tröger base
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[14] A complete lack of reaction is noticed if iodosobenzene PhIO is replaced
by
PIDA
(iodosobenzenediacetate)
or
PIFA
(iodosobenzeneditrifluoroacetate).
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[18] With p-nitro substituents, only traces of conversion are observed under
standard conditions.
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10.1002/chem.201700845
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
FULL PAPER
Alessandro Bosmani, Dr. Sandip A.
Pujari, Dr. Céline Besnard, Dr. Laure
Guénée, Dr. Amalia I. Poblador-
Bahamonde, Prof. Jérôme Lacour*
Page No. – Page No.
Stereoselective and Enantiospecific
Mono and Bis C-H azidation of Tröger
Bases. Insight on Bridgehead
Iminium Intermediates and
Application to Anion-Binding
Catalysis
Regio and stereoselective Csp3-H azidations of Tröger bases are reported. Both
mono and bis azide functionalizations are available using TMSN3 and PhIO as
reagent. High enantiospecificity is achieved (es 96-99%). Interestingly, bridgehead
iminium intermediates are evidenced by mechanistic and in-silico studies. With the
azido products in hand, tailored bis triazole derivatives were prepared for
application in anion-binding catalysis.
This article is protected by copyright. All rights reserved.