Latent Nucleophiles in Lewis Base Catalyzed Enantioselective N-Allylations of N-Heterocycles

Article abstract of DOI:10.1002/anie.201903392

Latent nucleophiles are compounds that are themselves not nucleophilic but can produce a strong nucleophile when activated. Such nucleophiles can expand the scope of Lewis base catalyzed reactions. As a proof of concept, we report that N-silyl pyrroles, i

Full text of DOI:10.1002/anie.201903392

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Accepted Article
Title: Latent Nucleophiles in Lewis Base Catalyzed Enantioselective N-
Allylation of N-Heterocycles
Authors: You Zi, Markus Lange, Constanze Schultz, and Ivan Vilotijevic
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10.1002/anie.201903392
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Latent Nucleophiles in Lewis Base Catalyzed Enantioselective N-
Allylation of N-Heterocycles
You Zi, Markus Lange, Constanze Schultz and Ivan Vilotijevic*
Abstract: Latent nucleophiles are compounds that are themselves
not nucleophilic but can produce a strong nucleophile when activated.
Such nucleophiles can expand the scope of Lewis base catalyzed
reactions. As a proof of concept, we report that N-silyl pyrroles,
indoles and carbazoles serve as latent N-centered nucleophiles in
substitution of allylic fluorides catalyzed by Lewis bases. Reactions
feature broad scope for both reaction partners, excellent
regioselectivity and produce the enantioenriched N-allyl pyrroles,
indoles and carbazoles when chiral cinchona catalysts are used.
heterocycles.[8] We envisioned that both (i) the problem of
activation of pyrroles, indoles and carbazoles as nucleophiles,
and (ii) the problems related to the regioselectivity in their
functionalization (N, C2 or C3) and substitutions of allylic fluorides
(SN2 vs. SN2’) can be addressed using latent N-silyl nucleophiles.
Here, we report that N-silyl pyrroles, indoles and carbazoles serve
as latent N-nucleophiles in substitutions of allylic fluorides and
enable enantioselective allylation of N-heterocycles.
Lewis base catalysts can serve to increase both electrophilicity
and nucleophilicity of reactants which allows them to trigger a
surprisingly diverse set of reactivity patterns.[1] Most Lewis base
catalyzed reactions involve an interaction between a nucleophile
and an electrophile. The fact that many of these reactions feature
a narrow scope with respect to the nucleophilic reaction partner is
often underappreciated. For example, in Lewis base catalyzed
allylic substitution reactions, the nucleophilic reaction partner
should be less nucleophilic than the catalyst and it should match
the catalyst’s Lewis base affinity.[2] If these criteria are not met,
mixtures of products of SN2 and SN2’ substitution reactions are
observed and/or reactions may proceed without involvement of
the catalyst which precludes the development of enantioselective
catalytic processes.[3] A potential solution could be provided by
latent nucleophiles, derivatives of otherwise nucleophilic
molecules which are not (or not markedly) nucleophilic but can be
activated to participate in the reaction.[4] When activation of a
latent nucleophile is dependent on activation of the electrophilic
partner, the reaction between the activated nucleophile and the
activated electrophile may outperform other competing pathways
and enable selective transformations (Scheme 1a). This concept
should allow us to expand the range of reactivity/catalysts to be
utilized in Lewis-base catalysis.
Scheme 1. a) The concept of latent nucleophiles in Lewis base catalysis. b)
Latent nucleophiles in N-allylation of pyrroles and indoles, possible products.
Nucleophilic properties of pyrroles and indoles have been studied
and quantified.[5] Both pyrroles and indoles can serve as N-, C2-
and C3-nucleophiles and the issues with regioselectivity in their
functionalization are well documented.[6] We hypothesized that an
N-silyl substituent would attenuate the nucleophilicity of pyrroles
and indoles turning them into latent nucleophiles. Activation of N-
silyl latent nucleophiles could be mediated by fluoride ions. If
activation of the nucleophile is to be dependent on activation of
the electrophile, the fluoride ions should be generated during
activation of the electrophilic reaction partner. For this reason,
allylic fluorides were chosen as suitable coupling partners.[7] We
focused on fluorides derived from Morita Baylis Hillman (MBH)
adducts to enable a regio- and enantioselective allylation of N-
Our initial studies of different silyl groups in the latent nucleophiles
revealed that the commonly used silyl protecting groups all afford
the products of N-allylation in good yields when allylic fluoride 1a
(Scheme 2) was used in combination with the N-silyl pyrrole (see
supporting information document for the details of optimization
studies). In order to preempt interactions of Lewis base catalyst
with the silyl group of the latent nucleophile and avoid this type of
nucleophile
activation,[9]
the
bulky
1-(tert-
butyldimethylsilyl)pyrrole was chosen for further reaction
optimization which explored how the identity of the Lewis base
catalyst, solvent, catalyst loading, ratio of reaction partners and
temperature influence the reactions outcomes. N-centered Lewis
base catalysts showed generally better efficacy than the
corresponding P-centered Lewis bases. Slight excess of the
latent nucleophile in combination with 5 mol% of the DABCO as
catalyst afforded the desired products in high yields.
[*]
Y. Zi, M. Lange, C. Schultz, Prof. Dr. I. Vilotijevic
Institute of Organic Chemistry and Macromolecular Chemistry
Friedrich Schiller University Jena
Humboldtstr. 10, 07743 Jena, Germany
E-mail: ivan.vilotijevic@uni-jena.de
Upon optimization of the reaction conditions, the scope of the
reaction was evaluated first for the allylic fluorides and then for
the N-silyl nucleophiles. In reactions of fluorides 1 with 2a, good
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201903392
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yields were observed across the board regardless of the
electronic properties of the MBH fluoride (Scheme 2a). Both
electron rich (3e-3f) and electron poor (3i-3l) allylic fluorides
afforded the desired products in good yields with short reaction
time (<5 minutes). Alkyl fluorides also proved reactive but lower
yields were observed for primary alkyl substituents (3c, 3d). Aryl
halides, good substrates for further functionalization of the
reaction products, were all well tolerated (3g-3h) as were
alkyl/aryl ethers, esters, benzylic methylene groups, nitriles and
nitro compounds. Gratifyingly, no products of SN2’ substitution
were observed with any of the tested substrates.
Investigation of the scope for latent nucleophiles started with a
series of N-TBS-pyrroles which performed well and demonstrated
the generality of the process (Scheme 2b). Simple N-silyl pyrrole
and 2-substituted pyrroles all performed well as nucleophiles.
Increasing the steric demands of the nucleophile, like with 2,5-
dimethylpyrrole, rendered substitution reaction prohibitively slow.
Further evaluation of reaction scope included indoles and
carbazole. Various substituted indoles performed well in the
reactions giving the desired products of substitution in good yields
regardless of the electronic influences of the substituents (3p-3u).
2-methylindole, 3u, indicated the sensitivity of this reaction to
steric bulk. Despite this limitation, the desired product was
obtained in the yield of 47% which could be improved by
increasing catalyst loading. N-silyl carbazole performed even
better with 82% isolated yield (3o). Importantly, these reactions
were highly regioselective with respect to both coupling partners.
Neither products of C2-/C3-allylation of pyrrole/indole nor SN2’
substitution were observed in any of these experiments.
A
series of experiments where various combinations of
substituted nucleophilic and substituted electrophilic partner were
subjected to the optimized reaction conditions further established
generality of this process (Scheme 2c) and demonstrated that
even MBH fluorides with ortho substituents are competent
substrates in these reactions (products 3x and 3y). With selected
examples, catalyst loading could be lowered to as little as 1 mol%
of DABCO without deterioration of yields, although longer reaction
times were observed qualitatively in these reactions. Scalability
was tested for the reaction of 1a (1.00 g) and 2a (1.03 g) which
proceeded with equal efficiency and no changes. Good scalability
together with a plethora of methods for further functionalization of
products[10] make this method attractive for applications in target
oriented synthesis.
Having confirmed that the reactions using latent nucleophiles are
highly regioselective and feature broad scope for both reactive
partners when DABCO was used as the catalyst, investigation of
the enantioselective reactions using chiral Lewis base catalysts
commenced. Our studies had confirmed that N-centered Lewis
base catalysts performed better in these reactions and highlighted
the efficacy of DABCO which directed our optimization efforts
towards cinchona alkaloid-based catalysts. We investigated how
the identity of the chiral Lewis base catalyst, reaction temperature,
concentration, solvent and the ratio of reactive partners influence
the reaction outcomes (details provided in the supporting
information document). The optimized conditions included
(DHQD)2PHAL as a chiral Lewis base catalyst which is used in
Scheme 2. a) Scope of the allylic fluoride 1 in Lewis base catalyzed allylation
of 1-(tert-butyldimethylsilyl)pyrrole 2a. b) Scope of N-silyl pyrroles, indoles and
carbazoles in N-allylation with allylic fluoride 1a. c) Various combinations of
substituted N-silyl nucleophiles and substituted allylic fluorides. [a] The reaction
of 1 with 2 (1.1 equiv) and DABCO (5 mol%), was carried out in DCM at room
temperature. [b] NMR yield with Ph3CH as the internal standard. [c] 1.5 equiv of
2 and 10 mol% of DABCO was used.
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10.1002/anie.201903392
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COMMUNICATION
showed moderate effects on the yields and enantioselectivity
which was in some cases as high as 99:1 er (3ae’, 3w’, 3t’, 3s’).
Other regioisomers were not observed in any of the tested
reactions. The enantioselectivities could be further improved via
focused optimization for individual cases as demonstrated for 3p’
and 3s’ where enantiomeric ratios increased from 92:8 to 95:5
and from 83:17 to 94:6, respectively, simply by changing the
reaction solvent. The configuration of the stereogenic center of
the major enantiomer was assigned as S by comparison to the
previously reported data for 3t’[11] and the absolute configuration
of other products was assigned by analogy.[12]
Scheme 4. a) Synthesis of pyrrolizinones that are potentially useful in
Alzheimer’s disease treatment. b) Expanded scope of N-nucleophile:
phthalimide, tosylamide and diphenylamine can also be introduced as latent
nucleophile.
Substitution product containing pyrrole (3a) proved useful in the
short synthesis of pyrrolizinones shown to exert anti-amyloid and
radical scavenging effects (Scheme 4a).[13] Hydrogenation
followed by cyclization promoted by BBr3 afforded trans-7 in 56%
yield (the cis isomer isolated in minor quantities could be
separated and isomerized to increase the yield of trans-7). To
further demonstrate the generality and utility of the concept of
latent nucleophiles in Lewis base catalysis, a broader group of
silylated N-nucleophiles including phthalimide, tosylamide and
diphenylamine was tested and shown to be competent in
reactions with allylic fluorides (3af, 3ag, 3ah, Scheme 4b).
Scheme 3. Enantioselective chiral Lewis base catalyzed allylic substitutions of
allylic fluorides with N-silyl nucleophiles. [a] The reaction of 1 (2 equiv), with 2
and (DHQD)2PHAL (10 mol%), was carried out in PhCF3 at room temperature
under N2 atmosphere. [b] 1,4-dioxane was used as solvent. [c]
Dimethoxyethane was used as solvent.
the amount of 10 mol% in trifluorotoluene at room temperature. A
clear difference in the rates of the reactions catalyzed by chiral
cinchona alkaloids compared to those catalyzed by DABCO
resulted in slightly lower yields (Scheme 3). N-silyl pyrroles,
indoles and carbazoles all gave the products of N-allylation in
good yields and with good degrees of stereocontrol (3a’, 3p’, 3o’).
A series of experiments showed that both electron rich and
electron poor allylic fluorides performed well in these reactions
(3ab’, 3ac’, 3ad’, 3h’ and 3k’) with yields of approximately 80%
and enantiomeric ratios higher than 90:10. Reactions with alkyl
substituted fluorides proved to be too slow which allowed for
competitive decomposition of the alkyl fluorides leading to lower
yields although the enantiomeric ratios for the isolated
substitution products remained high. Modifying the latent
nucleophiles with electron withdrawing or donating groups
Our attention turned to the mechanistic features of these
processes. The reactions could proceed via allyl ammonium
intermediates often evoked in substitutions of MBH acetates and
14]
carbonates (Scheme 5a).[11,
Alternatively, a silyl assisted
cleavage of the C-F bond with simultaneous intramolecular
delivery of the nucleophile (Scheme 5a) could take place.[15]
When allylic fluoride 1a was treated with DABCO in the absence
of N-TBS-pyrrole, the formation of ammonium salt 4 was
observed by NMR in situ (Scheme 5b).[16] In a crossover
experiment where deuterium labeled indole 2af was used in
equimolar mixture with N-TBS-indole 2p, both were incorporated
in the reaction product (Scheme 5c), suggesting that they may
equilibrate through an indolide anion. To scrutinize other
reasonable pathways that would result in the same outcome, two
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10.1002/anie.201903392
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electrophile/nucleophile pair in the reaction mixture and
demonstrates the importance of the latent character of the
nucleophile. Finally, excellent regioselectivities and good
stereocontrol observed in the presence of chiral Lewis base
catalysts suggests that addition of the activated nucleophile to
non-activated electrophile does not occur.
In conclusion, the use of N-silyl pyrroles, indoles and carbazoles
as latent nucleophiles enables the highly regioselective N-
allylation of these heterocycles using allylic fluorides. When
widely available chiral cinchona alkaloid based catalysts are used,
the allylation products are isolated with high degrees of
enantioselectivity. This is the first general enantioselective
method to introduce pyrroles in Lewis base catalyzed substitution
reactions. The mechanistic details of this process suggest that the
concept of latent nucleophiles in Lewis base catalysis hinges on
the concurrent activation of both reaction partners which allows
for expanded reaction scope and improved selectivity. This
concept may be generally applicable in a variety of reactions that
depend on the use of heteroatom-centered nucleophiles.
Acknowledgements
Financial support from the Carl-Zeiss Foundation (endowed
professorship to I.V.), Friedrich Schiller University Jena and the
State of Thuringia (graduate fellowship to M.L.) is gratefully
acknowledged. We thank Prof. Dr. Hans-Dieter Arndt for helpful
discussions in preparation of this manuscript. We are grateful to
Philipp Schüler, Dr. Peter Bellstedt and Dr. Nico Ueberschaar for
their support with HPLC, NMR and MS analysis respectively.
Scheme 5. Selected experiments aimed at evaluation of reaction mechanism.
a) Previously proposed intermediates and transition states in related reactions,
NR1R2R3 – amine/chiral cinchona catalyst, R= CF3, alkynyl, N-methyltetrazole.
b) Formation of ammonium salt 1a without silyl assistance. c) Crossover
experiment using labeled indole and a latent indole nucleophile. d) Switch in
regioselectivity with TBAF as a catalyst e) Proposed reaction mechanism
Keywords: latent nucleophile • Lewis base catalysis •
nucleophilic substitution • allylation • nitrogen heterocycles
control experiments were carried out to confirm that (i) the indole
itself does not react with the allylic fluoride under the reaction
conditions and (ii) TBS group is not transferred between 2af and
2p in the presence of DABCO. Finally, when TBAF was used as
a catalyst, the reaction proceeds with high rates (reaction time <
20 minutes) and only the products of SN2’ substitution were
observed (Scheme 5d). Based on these experiments, we propose
the mechanistic sketch outlined in Scheme 5e. The allylic fluoride
undergoes conjugate addition of the catalyst which, after E1cb
elimination of the fluoride ion, results in the allylic ammonium
intermediate 4’. Fluoride ion then adds to the silyl group of the N-
silyl pyrrole/indole and after elimination forms the silyl fluoride
(observed in the reaction mixture by NMR) and the anionic N-
nucleophile 6. Activated electrophile, allyl ammonium
intermediate 4’ undergoes conjugate addition of 6 to form the
product after elimination of the catalyst. The observed selectivity
for the product of direct substitution of the fluoride is the
consequence of two consecutive conjugate addition/eliminations.
The addition rates of anion 6 to electrophile 4’ are proposed to be
high because the products of SN2’ substitution were not observed
in DABCO catalyzed reactions even though competing addition of
6 to 1, resulting in the formation of SN2’ products, occurs with high
rates when TBAF is used as the catalyst.[17] This highlights the
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