C(sp3)?C(sp3) Bond Formation via Electrochemical Alkoxylation and Subsequent Lewis Acid Promoted Reactions

Article abstract of DOI:10.1002/adsc.202100749

A two-step transition metal-free methodology for the C(sp³)?C(sp³) functionalisation of saturated N-heterocyclic systems is disclosed. First, aminal derivatives are generated through the anodic oxidation of readily accessible carboxylic acids. Then, in the presence of BF₃ ? OEt₂, iminium ions are unmasked and rapidly alkylated by organozinc reagents under flow conditions. Secondary, tertiary and quaternary carbon centers have been successfully assembled using this methodology. Such an approach is especially relevant to drug discovery since it increases C(sp³)-functionalities rapidly within a molecular framework. As proof of concept, our methodology was applied to derivatization of peptides and an API. (Figure presented.).

Full text of DOI:10.1002/adsc.202100749

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doi.org/10.1002/adsc.202100749
C(sp3)À C(sp3) Bond Formation via Electrochemical Alkoxylation
and Subsequent Lewis Acid Promoted Reactions
Enol López,a Carlo van Melis,b Raúl Martín,a Alessia Petti,b Antonio de la Hoz,a
Ángel Díaz-Ortíz,a Adrian P. Dobbs,b Kevin Lam,b,* and Jesús Alcázarc,*
a
Facultad de Ciencias y Tecnologías Químicas, Universidad de Castilla-La Mancha, Av. Camilo José Cela 10, 13071, Ciudad
Real, Spain
E-mail: antonio.hoz@uclm.es
School of Science, The University of Greenwich, Chatham Maritime ME4 4TB, United Kingdom
b
E-mail: K.Lam@greenwich.ac.uk
Lead Discovery, Janssen Research and Development, Janssen-Cilag, S.A., Jarama 75 A, 45007 Toledo, Spain
c
E-mail: jalcazar@its.jnj.com
Manuscript received: June 15, 2021; Revised manuscript received: July 14, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100749
transition metal catalysts such as Ni, Pd or Ir, which
Abstract: A two-step transition metal-free method-
ology for the C(sp3)À C(sp3) functionalisation of
makes them unappealing from a green chemistry point
of view.[4] The growing impetus of the chemical
saturated N-heterocyclic systems is disclosed. First,
aminal derivatives are generated through the anodic
community for developing ecologically friendlier
methodologies has prompted us to investigate the
oxidation of readily accessible carboxylic acids.
combined use of electrosynthesis with low-toxicity
Then, in the presence of BF3 ·OEt2, iminium ions
are unmasked and rapidly alkylated by organozinc
organometallics. Indeed, electrosynthetic organic
chemistry has been shown to be an outstanding
reagents under flow conditions. Secondary, tertiary
technology for developing more sustainable method-
and quaternary carbon centers have been success-
ologies in medicinal chemistry.[5] This green and
fully assembled using this methodology. Such an
valuable tool uses electricity, one of the cheapest
approach is especially relevant to drug discovery
since it increases C(sp3)-functionalities rapidly with-
in a molecular framework. As proof of concept, our
methodology was applied to derivatization of pep-
tides and an API.
reagents,
to
achieve
complex
organic
transformations.[6]
Many drug-like lead compounds are embedding N-
heterocyclic scaffolds such as pyrrolidines, morpho-
lines or piperazines.[7] The ability for late-stage
functionalisation of nitrogen-containing systems with
C(sp3)-fractions tremendously speeds up the drug
discovery process by rapidly opening new chemical
spaces with promising biological activity.[8]
We have previously reported the electrochemical
methoxymethylation of α-alkoxy carboxylic acids to
synthesize MOM-type ethers in a practical, green, safe
Keywords: Electrochemistry; Flow chemistry; Tran-
sition-metal free; Drug discovery; Organozinc re-
agents
Although C(sp3)À C(sp3) bond formation is fundamental and scalable method either in batch or flow.[9] Based
in medicinal and organic chemistry, it remains a key on this precedent, we investigated the anodic gener-
challenge. In particular, incorporating C(sp3)-moieties ation of aminals from α-nitrogen carboxylic acid
into bioactive molecules is essential to escape from the derivatives. A Lewis acid-promoted generation of an
“flatland” in drug discovery programs.[1] For instance, iminium ion, followed by an organometallic reagent
quaternary carbon centres are highly relevant owing to addition would lead to the rapid formation of function-
the new 3D chemical diversity they can bring.[2] alized N-heterocycles.[10] The high functional group
Several transition-metal catalysed alkyl-alkyl cross- compatibility of organozinc derivatives makes them
coupling reactions have been reported to achieve this more suitable than Grignard reagents[11] to introduce a
goal.[3] Unfortunately, despite their synthetic benefits, new C(sp3)À C(sp3) center on the nitrogen-containing
these reactions usually require toxic and expensive
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scaffolds. Our general approach is depicted in prompted us to consider flow chemistry as an
Scheme 1. alternative for a better control of the reaction parame-
We began by electrochemically oxidising N-Boc- ters. As shown in Table 1, a residence time of 1 min
protected proline in methanol using our previously was enough to improve the yield obtained in previous
developed conditions (Scheme 2). Much to our delight, batch experiments (Entry 1). Nevertheless, best con-
1a was isolated in 90% yield without the need for any ditions were obtained when the reaction was run at
purification. 3-Substituted proline aminal derivatives room temperature and just 1 equivalent of BF3 ·OEt2
were produced in excellent yields (1b and 1c) (Entry 4). Under these conditions starting material was
following the same procedure. Furthermore, morpho- completely consumed and provided the best balance
line and piperazine derivatives proved to be compatible regarding isolated yield. Increasing the equivalents of
and their aminals were successfully electrosynthesised Lewis acid or organozinc reagent did not improve the
(1e and 1f). Alternatively, direct Shono oxidation can reaction outcome (See supporting info for more de-
be used for the preparation of these intermediates as tails).
demonstrated with piperidine analogue 1d.[12]
We then explored the reaction scope and limitations
With the optimal electrochemical conditions for the of this new methodology. A wide range of functional-
formation of aminals in hand, we then focused our ized organozinc reagents were used in the presence of
attention on the addition of organozinc derivatives, 1a (Table 2). At first, we investigated the use of
prepared using our previously reported protocol,[13] on substituted benzylic zinc reagents. Coupling products
to the iminium ion formed from 1a promoted by the were obtained in reasonable to good yield with a wide
presence of a Lewis acid.[8] For our initial screening, variety of substituents, including halides (5 and 6),
1a and benzylzinc bromide were selected as model products bearing electron-withdrawing groups such as
substrates. They were reacted in the presence of an cyano, trifluoromethyl, sulfone and ester (7–10), or p-
array of Lewis acids in batch (see Table S1 in tert-butyl moiety as an electron-donating group (11).
Supporting information). Among them, BF3 ·OEt2 led Ortho and meta functionalized benzylic derivatives
to the best results. However, adding the Lewis acid also led the desired products in good yields (12–15).
portionwise over 5 minutes increased the yield from 25 Additionally, allyl organozinc reagent also provided
to 54%, which highlighted the need for a controlled the desired product 16.
delivery of this acid in the reaction media. This result
One of the main challenges in organic synthesis is
formation of all-carbon-substituted quaternary carbon
atoms.[14] Remarkably, this methodology allowed the
formation of challenging quaternary carbon centres.
Tertiary cyclobutyl, lactones, cyclohexyl and THP
groups bearing ester and cyano groups were success-
fully used to prepare the corresponding coupling
products (22–27) where a new sterically demanding
tertiary-quaternary carbon-carbon bond is been
formed.
Scheme 1. General approach to obtain α-functionalised nitro-
genated systems.
Table 1. Flow reaction screening.
Entry T ( C) tR (min) Equiv. BF3 ·OEt2 Yield[a]
°
1
2
3
4
5
6
0
0
0
rt
rt
rt
1
2
5
1
1
1
1
1
1
1
1.2
1.5
61%
63%
60%
71%(70%)
70%(66%)
71%(67%)
Scheme 2. Electrochemical alkoxylation. [a]Compound 1d was
obtained by Shono oxidation of N-Boc piperidine (reaction
conditions see Supporting Information).
[a] Yield was determined by NMR using 1,3,5-trimeth-
oxybenzene as internal standard (isolated yield in brackets).
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Table 2. Reaction scope.
[a] 3 equiv. of RZnBr were added.
[b] 2 equiv. of BF3 ·OEt2 were added.
[c] Obtained as RR,SS/RS,SR mixture 55/45.
[d] Obtained as RR,SS/RS,SR mixture 50/50.
[e] Obtained as RR,SS/RS,SR mixture 33/67.
[f] Obtained as RR,SS/RS,SR mixture 40/60.
[g] Obtained as 2R,4R/2S,4R mixture 30/70.
Finally, we investigated the use of substituted formed is the one where the organozinc is added to the
pyrrolidines and other nitrogen heterocyclic systems. core at the opposite side of the group present in it. This
Placing a phenyl group at 3-position of the pyrrolidine will open the possibility to explore an enantioselective
generated the expected coupled product 28 as a version of the reaction in the future. Similar reaction
mixture of diastereomers. Ethoxy aminals can also be conditions allowed for the preparation of piperidine,
used in this method as demonstrated with compound morpholine and piperazine derivatives 30, 31, 32 and
29 again as mixture of diasteroisomers. It is note- 33.
worthy that in both examples the major diasteroisomer
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Further demonstrating the applicability of the derivatives through anodic decarboxylation, which are
method, the scalability of the reaction was demon- then easily coupled to an organozinc reagent in the
strated with compounds 4 and 15 at 10 and 1 mmol presence of a Lewis acid. This procedure allows the
scale, respectively. The observed improvement in yield access to complex structures in two steps and only one
was associated with the longer steady state obtained. chromatographic purification from affordable com-
These results evidence the usefulness of this trans- pounds. For instance, homologation of amino acids or
formation even in gram scales. For the 10 mmol scale formation of quaternary-tertiary carbon-carbon bonds
reaction a 5 mL PFA coil and a T-mixer were used usually requires a multistep process to be achieved.
instead of the chip. This opens the possibility to use Most of the compounds shown above can be consid-
much larger reactors for a future industrial scale up.
ered as enriched C(sp3) scaffolds with two or more
We then investigated the use of aliphatic aminals as points for diversification, very attractive from a
starting materials, especially peptide derivatives medicinal chemistry point of view. Furthermore, this
(Scheme 3). Boc-L-Ser benzyl ester anodically decar- methodology can be also applied for late-stage
boxylated to form the aminal 1g in excellent yield. functionalization of peptides and API. Further applica-
The second step, involving the addition of the organo- tion and expansion of this methodology to industrial
zinc reagent, led to the formation of the desired open- scale will be matter of future publications.
chained product 34. Similarly, starting from Boc-Pro-
Gly-OH allowed the preparation of the functionalized
dipeptide derivative 35. This extends the scope of this
Experimental Section
methodology to more complex peptide scaffolds. General Procedure for the Electrochemical Decar-
Finally, as an example of late-stage functionalization, boxylation Reaction
we applied our methodology to the functionalization of
oxaceprol, an anti-inflammatory drug agent used to
An undivided electrochemical cell (total volume of 10 mL)
equipped with two rectangular-shaped graphite electrodes
(5 cm×1 cm) connected to an Electrasyn 2.0 setup was used for
the electrochemical decarboxylation. The carboxylic acid
(3 mmol) was dissolved in 5 mL of dried alcohol (MeOH or
EtOH) and neutralized with KOH (3 mmol). The solution was
treat arthritis, chronic joint disorders and inflammation
of connective tissues.[15] Decarboxylation of oxaceprol
leads to the formation of the corresponding aminal 1i.
The reaction of this aminal with 3,5-dimethyl benzyl
organozinc afforded the coupled compound 36. Such a then sonicated for 10 minutes to ensure its homogeneity. The
Electrasyn 2.0 was set up in galvanostatic mode with an
alternating (every 30 s) current of 100 mA. The solution was
then electrolyzed for 7 F/mol. The methanolic solution was then
washed with a 1 M KOH solution in water (50 mL) and
extracted with DCM (3×50 mL). The organic layers were
combined, washed with a saturated sodium carbonate solution
(50 mL), dried over Na2SO4, and carefully concentrated under
reduced pressure to yield the aminal without the need for any
further purification.
practical, rapid and mild late-stage functionalization
opens the door to a high degree of molecular diversity.
In summary, we have developed a rapid C(sp3)À C-
(sp3) bond formation for the late-stage functionalisation
of saturated N-heterocyclic systems. The critical step
of this methodology relies on forming stable aminal
General Procedure for the Lewis Acid Organozinc
Addition
A solution of the alkoxylated derivative (0.4 mmol, 1 equiv.)
with the corresponding solution of RÀ ZnBr (prepared following
General Procedure 2, see Supporting Information; 2 equiv.) was
mixed using a T-mixer with a solution of BF3 ·OEt2 (0.2 M;
1 equiv.) in dry CH3CN in a 1.5 mL microreactor at 0.75 mL/
min each line (rt, tR =1 min). The reaction mixture was
quenched in NH4Cl solution (5 mL, 2 M) and it was then
extracted with AcOEt (3×10 mL). The organic layers were
combined and dried over MgSO4 and the solvent was
concentrated in vacuo. The crude was purified by flash column
chromatography using the indicated solvent mixtures giving rise
to the corresponding coupling product.
Acknowledgements
The authors would like to thank Dr. Andrés Trabanco for
interesting discussions. Pablo Fernandez and Raquel Rodriguez
Scheme 3. Application of the methodology in late stage
functionalization. [a]Obtained as 2S,4S/2R,4S; mixture 31/69.
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for their assistance in the purification of products. Finally, we
are grateful to the Engineering and Physical Sciences Research
Council (Grant EP/S017097/1 to K.L.) for their financial
support, the University of Greenwich (Vice Chancellor’s PhD
Scholarship to A.P. and C. v.M.).
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C(sp3)À C(sp3) Bond Formation via Electrochemical Alkoxy-
lation and Subsequent Lewis Acid Promoted Reactions
Adv. Synth. Catal. 2021, 363, 1–6
E. López, C. van Melis, R. Martín, A. Petti, A. de la Hoz, Á.
Díaz-Ortíz, A. P. Dobbs, K. Lam*, J. Alcázar*