Phosphine-Catalyzed Synthesis of Chiral N-Heterocycles through (Asymmetric) P(III)/P(V) Redox Cycling

Article abstract of DOI:10.1002/ejoc.202100404

Phosphine-catalyzed tandem Michael addition/intramolecular Wittig reactions have been developed for the synthesis of chiral 2,5-dihydro-1H-pyrrole and tetrahydropyridine derivatives. These processes have been rendered catalytic in phosphine, thanks to the in situ reduction of phosphine oxide by phenylsilane. Furthermore, catalytic and asymmetric P(III)/P(V) processes were implemented using enantiopure chiral phosphines.

Full text of DOI:10.1002/ejoc.202100404

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Phosphine-Catalyzed Synthesis of Chiral N-Heterocycles via
(Asymmetric) P(III)/P(V) Redox Cycling
Authors: Charlotte Lorton, Nidal Saleh, and Arnaud Voituriez
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100404
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01/2020

10.1002/ejoc.202100404
European Journal of Organic Chemistry
COMMUNICATION
Phosphine-Catalyzed Synthesis of Chiral N-Heterocycles via
(Asymmetric) P(III)/P(V) Redox Cycling
Charlotte Lorton,[a] Nidal Saleh[a] and Arnaud Voituriez*[a]
[a]
Charlotte Lorton, Dr. Nidal Saleh and Dr. Arnaud Voituriez
Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198, Gif-sur-Yvette, France.
E-mail: Arnaud.voituriez@cnrs.fr
Homepage: http://www.icsn.cnrs-gif.fr/spip.php?article1115
Supporting information for this article is given via a link at the end of the document
Abstract:
Phosphine-catalyzed
tandem
Michael
asymmetric tandem processes. Indeed, the desymmetrization of
prochiral azido-1,3-diketones via
PIII/PV process was
addition/intramolecular Wittig reactions have been developed for the
synthesis of chiral 2,5-dihydro-1H-pyrrole and tetrahydropyridine
derivatives. These processes have been rendered catalytic in
phosphine, thanks to the in situ reduction of phosphine oxide by
phenylsilane. Furthermore, catalytic and asymmetric P(III)/P(V)
processes were implemented using enantiopure chiral phosphines.
a
established with the use of chiral phosphine endo-phenyl-
HypPhos, phenylsilane as reducing agent and 2-nitrobenzoic acid
as additive (Scheme 1b).[11] Different heterocycles were isolated
in good yields and excellent enantioselectivities. The same year,
we developed the first catalytic and asymmetric tandem Michael
addition/Wittig reaction.[12] Excellent yields and up to 95% ee have
been obtained for the synthesis of fluorinated cyclobutene and
spiro[3.4]octanone derivatives (Scheme 1c). In recent years, we
In the last decade, a great effort has been invested to develop
catalytic processes involving phosphines, via in situ reduction of
the phosphine oxide formed during the reaction.[1] Indeed, the use
of organosilane as reducing agent allows the chemoselective
reduction of the phosphine oxide byproduct and therefore the
regeneration of the trivalent phosphine, the “active” catalyst.
Based on this strategy, several different reactions were made
more sustainable, such as the Wittig,[2] Staudinger,[3] Mitsunobu,[4]
Appel[5] and Cadogan[6] reactions, among others.[7] Interestingly,
different tandem catalytic processes have also been developed.
Alongside with tandem transformations such as the
Staudinger/aza-Wittig reaction,[8] we designed a catalytic tandem
Michael addition/intramolecular Wittig reaction, for the synthesis
of N-heterocycles and polysubstituted cyclopentenones.[9] The
purification step of these processes is significantly simplified
because the silanol/siloxane waste (coming from the phosphine
oxide reduction with silane) is easily separated from the crude
mixture with a simple liquid-liquid extraction. Furthermore, in
cases involving the formation of stereogenic centers, these
catalytic processes could also unlock the development of
asymmetric transformations (Scheme 1a). While it was previously
not conceivable to use stoichiometric quantities of expensive
chiral phosphines for these transformations, it is now possible to
consider the use of substoichiometric amounts of chiral
phosphines. The generation of such PIII/PV enantioselective
processes has been considered for a long time as an arduous
task, as it is very difficult to find an enantiopure chiral phosphine
which could be at the same time nucleophilic enough at the PIII
oxidation state, and with an easily reductible phosphine oxide
O=PV under mild reaction conditions. Furthermore, in the context
of enantioselective catalysis, the product has to be isolated with
high stereoselectivity. All these prerequisites explain the difficulty
of the present task for the development of new PIII/PV catalytic and
asymmetric redox transformations. In 2014, Werner described the
first enantioselective catalytic Wittig transformation, via the
desymmetrization of prochiral diketones.[10] After these initial
results, it was not until 2019 that Kwon and our group
simultaneously developed highly efficient catalytic and
also developed
a
straightforward phosphine-catalyzed
methodology for the synthesis of many nitrogen-containing
heterocycles, including 2,3-dihydro-1,3,4-oxadiazole, 9H-
pyrrolo[1,2-a]indoles, pyrrolizines, 1,2-dihydroquinolines and
others, with preliminary results in asymmetric catalysis.[9b]
Scheme 1. (a) General strategy for a catalytic and asymmetric PIII/PV process.
(b) and (c) Representative examples. (d) Proposed work for the synthesis of
dihydropyrrole and tetrahydropyridine derivatives.
1
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10.1002/ejoc.202100404
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Following our previous studies, we propose in the present work to
use N-substituted 2-amino-1-phenylethan-1-one (I) and 3-
aminopropanal (II) derivatives as substrates, in the presence of
dialkyl acetylenedicarboxylate (DAAD) and trivalent phosphine, to
furnish the corresponding 2,5-dihydro-1H-pyrrole (III)[13a-c] and
tetrahydropyridine (IV)[9b, 13d] backbones (Scheme 1d). These N-
heterocycles are present in numerous natural products and
bioactive compounds, and can also be useful as synthetic
intermediates in more complex scaffolds.[14] After validation of the
proposed syntheses using stoichiometric amounts of
triphenylphosphine, the catalytic processes have been
implemented. Finally, the use of enantiopure chiral phosphines,
in line with an optimized reducing system, allowed to achieve
honorable levels of enantioselectivity in the targeted reactions.
At the outset of this study, we first tested the reactivity of five
different N-substituted 2-amino-1-phenylethan-1-one substrates
1a-e, in the presence of dimethyl but-2-ynedioate 2a and
stoichiometric amounts of triphenylphosphine (Condition A in
Table 1). The reaction produced the desired 1,4-diphenyl-2,5-
dihydro-1H-pyrrole product 3a in 62% yield, with the simultaneous
formation of the corresponding pyrrole derivative 4a (entry 1).
Surprisingly, the N-para-chloro-phenyl substrate furnished mostly
the achiral pyrrole product 4b (entry 2). Fortunately, the desired
dihydro-1H-pyrrole products 3c-e were formed in 75-85% yields,
The initial protocol for this reaction was the use of 4-methyl-1-
phenyl-2,3-dihydrophosphole 1-oxide as precatalyst (10 mol%)
and bis(p-nitrophenyl)phosphate (10 mol%) as additive, in the
presence of phenylsilane (1.5 equivalents), in refluxing toluene.
Previous results have already proved the chemoselectivity of this
system combining phenylsilane and phosphate, to efficiently
reduce the phosphine oxide.[15] Unfortunately, the first attempts
failed (entries 1-3, right column). Indeed, either the conversion
was not good, or the isolated major product was the pyrrole
derivative 4a and 4c. It is noteworthy that with the use of N-tosyl
substrate, 3d was isolated in 34% yield (entry 4). The modification
of the reaction conditions did not improve this result. Finally, using
2.5 equivalents of silane with the same reaction conditions
resulted in a 99% yield with N-Cbz substrate 1e (entry 6), thereby
validating the development of efficient catalytic PIII/PV process for
the synthesis of N-Cbz-phenyl-2,5-dihydro-1H-pyrrole-2,3-
dicarboxylate 3e. Microwave heating condition can be used in this
transformation, decreasing the reaction time to only two hours
(80% yield, entry 7).
Having shown that the reaction can be made catalytic in
phosphine, we then used enantiopure chiral phosphines to
develop the first asymmetric synthesis of such molecules
(Scheme 2a). The really important point in this study is to find the
right balance between reactivity, enantioselectivity and facility to
reduce the corresponding phosphine oxide. First, we screened
HypPhos phosphines P1-P9, which have previously
demonstrated their effectiveness in phosphine organocatalysis.[11,
12, 16] If as a general trend, the isolated yields were moderate (up
to 55% yield in 3e with the use of P2), the enantioselectivity
reached 82% ee with chiral phosphine exo-1-naphthyl-P9. This
catalytic reaction condition was also used with N-Cbz ethyl
glycinate substrate 5, in the presence of DAAD 2b (Scheme 2b).
Results remained moderate in terms of conversion and
enantioselectivity (up to 60% ee). This result however
outperforms our previous endeavours on the same reaction (30%
ee).[9b]
with
para-methoxyphenyl,[13b] tosyl and carboxybenzyl
substituents (entries 3-5). We next attempted to develop a
catalytic version of this tandem transformation (Table 1, Condition
B).
Table 1. Variation of the nitrogen-substituent for selective formation of
dihydropyrroles 3.
Entry
R
Condition A
Condition B
3/4
ratio[a]
Yield
3 [%][b]
3/4
ratio[a]
Yield
3 [%][b]
1
2
3
4
5
6
7
1a, Ph
3/1
1/4
8/1
5/1
>20/1
-
3a, 62
3b, <5
3c, 85
3d, 75
3e, 84
-
1/3
3a, 6
<5
1b, pCl-C6H4
1c, pMeO-C6H4
1d,Ts
3/1
<1/20
>20/1
>20/1
>20/1
>20/1
<5
3d, 34
3e, 35
3e, 99[c]
3e, 80[d]
1e,Cbz
1e,Cbz
1e,Cbz
-
-
Scheme 2. Screening of chiral phosphines for the formation of dihydropyrrole
derivatives 3e and 6.
[a] Determined according to 1H NMR of the crude mixture. [b] Isolated yield. [c]
2.5 equiv of PhSiH3 instead of 1.5 equiv. [d] PhSiH3 (2 equiv), 120 °C, microwave
heating, 2 h.
2
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10.1002/ejoc.202100404
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COMMUNICATION
We next turned our attention to the synthesis of chiral
tetrahydropyridines 8 from 3-aminopropanal substrates 7a-i
(Table 2). First, five carbamate derivatives (N-CO2-R’) were
prepared with R’ = benzyl, tert-butyl, allyl, 9-fluorenylmethyl and
2,2,2-trichloroethyl substituents (substrates 7a-e). 2,2,2-trifluoro-
N-(3-oxopropyl)acetamide 7f was also prepared, featuring a
strong electron-withdrawing group. Finally, three sulfonamides
7g-i were synthesized in good yield (see SI for the procedures).
Using 1.2 equivalents of triphenylphosphine in toluene, 16 h at
60 °C (condition C), all N-protected 1,2,3,6-tetrahydropyridines
were isolated in moderate to good yields (56-94% yields), with the
exception of N-Boc- and m-Tosyl-substrates (entries 2 and 8,
Table 2) leading to low conversions. Before screening different
chiral phosphines, we verified that optimized conditions for the
development of phosphine-catalyzed transformations, i.e.
Condition D, Table 2 (10 mol% of phospholene oxide and bis(p-
nitrophenyl)phosphate, with 2.0 equivalents of phenylsilane in
toluene at 60°C) gave isolated yields similar to those obtained
with stoichiometric amounts of phosphine. Indeed, products 8a,
8c-e and 8g-i were obtained in 57-92% yields (Table 2, right
column). Again, Boc-protected 8b has not been isolated though.
Similarly, “Conditions D” did not give the expected cyclized
product 8f either (entry 6). As previously demonstrated,[9c] in this
case a diethyl 2-(3-aminopropylidene)succinate product was
instead isolated as an E/Z isomeric mixture. Next, the use of
enantiopure HypPhos phosphine P9 gave products 8a, 8c-e and
8g-i in up to 62% ee (Table 3, entries 1 and 3).
As a general trend, these first results showcased the difficulty to
obtain both decent yields and enantiomeric excesses. The best
compromise between yield and enantioselectivity was obtained
with substrate 7e (R1 = Troc = 2,2,2-trichloroethyl, 73% yield, 41%
ee, entry 4). Other chiral phosphines P10-P12 were screened with
this substrate. The enantioselectivity of 8e increased to 63% ee,
at the expense of a lower yield (entries 5-7). Variation of the
DAAD substrate has been then studied, with the use of dimethyl
and di-tert-butyl acetylenedicarboxylates 2b-c. Yields remained
acceptable, but enantiomeric excesses have not increased
significantly (up to 48% ee, entries 8-9). Finally, for sulfonamide-
derived substrates 7g-i, better results were reached using of Me-
Ferrocelane phosphine P13 (up to 48% ee, entries 10-12).
Table 3. Towards a catalytic and asymmetric synthesis of tetrahydropyridines
8.
Entry
R1
R2
*PR3
yield [%][a]
ee [%][b]
1
7a, Cbz
7c, Alloc
7d, Fmoc
7e, Troc
7e, Troc
7e, Troc
7e, Troc
7e, Troc
7e, Troc
7g, pTs
7h, mTs
Et
Et
Et
Et
Et
Et
Et
Me
tBu
Et
Et
Et
P9
8a, 11 (23)[c]
8c, <5
8d, 5
62 (63)[c]
24
Table 2. Synthesis of different N-substituted tetrahydropyridines 8a-i.
2
P9
3
P9
62
4
P9
8e, 73
8e, 7
41
5
P10
P11
P12
P9
63
6
8e, 18
8e, 20
8ea, 56
8ec, 58
8g, 27
8h, 30
8i, 32
50
7
38
8
48
9
P9
31
Entry
R
Condition C
yield [%][a]
Condition D
yield [%][a]
10
11
12
P13
P13
P13
41
1
2
3
4
7a, CO2Bn (Cbz)
8a, 64
8b, <5
8c, 83
8d, 68
90[b]
<5
33
7b, CO2tBu (Boc)
7i,
SO2-
48
pOMe-C6H4
7c, CO2CH2CHCH2 (Alloc)
60
[a] Isolated yield. [b] Determined by HPLC on a chiral stationary phase. [c] P9
7d, Fluorenylmethoxycarbo-
nyl (Fmoc)
67
(20 mol%).
5
6
7
8
9
7e, CO2CH2CCl3 (Troc)
7f, COCF3 (TFA)
8e, 94
8f, 91
8g, 72
8h, 18
8i, 56
92
<5
7g, SO2-pMe-C6H4 (pTs)
7h, SO2-mMe-C6H4 (mTs)
7i, SO2-pOMe-C6H4
79[b]
70
57
A postulated mechanism is presented in Scheme 3. The reaction
starts with the formation of zwitterionic species A, after the
addition of the trivalent phosphine to DAAD substrate 2. With its
protonation by substrates 1 or 7, the resulting nitrogen nucleophile
[a] Isolated yield. [b] Result from ref. [9b]
3
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COMMUNICATION
Appl. Chem. 2019, 91, 95-102; e) J. M. Lipshultz, G. Li, A. T. Radosevich,
J. Am. Chem. Soc. 2021, 143, 1699-1721.
B adds on the vinylphosphonium salt C to generate ylide D. This
is the enantiodetermining step of this transformation. Following
the intramolecular Wittig reaction, chiral N-heterocycles 3 or 8 are
delivered and the phosphine oxide is reduced in situ by the
phenylsilane to regenerate the trivalent phosphine catalyst. To
facilitate this reduction, both the addition of catalytic amounts of
phosphate and the use of cyclic phosphines have a positive
impact on the reaction outcome. Indeed, chiral bicyclic
phosphines often represent the ideal balance between
nucleophilicity and facility of performing the PIII/PV redox cycling,
while having a congested chiral structure that can achieve good
stereoselectivity.[8b] The direct formation of N-aryl-pyrroles 4a-c
can be explained by the direct addition of the nitrogen atom of 1
to DAAD substrate 2, following a cyclization/dehydration process,
without the use of phosphine.[17a-c,18] Indeed, with more
nucleophilic substrate 1c and using “Condition B” without
phosphine, pyrrole 4c was isolated. Fortunately, with N-Cbz
substrate 1e, this non-desired reactivity was suppressed.
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Scheme 3. Proposed mechanism for the formation of 3 and 8.
In conclusion, we have demonstrated that the two catalytic
approaches described in this study provided a facile and efficient
route for the isolation of substitued dihydropyrroles and
tetrahydropyridines. The use of enantiopure bicyclic HypPhos
phosphines furnished five- and six-membered nitrogen
heterocyles in moderate yields and promising enantioselectivities.
Further studies will be oriented toward the development of other
transformations via P(III)/P(V) redox cycling and the development
of specifically designed chiral phosphines.
[8]
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Acknowledgements
The authors acknowledge the support of the Centre National de
la Recherche Scientifique (CNRS). C.L. thanks MESRI (Paris-
Saclay University) for a Ph.D. fellowship.
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Keywords: Phosphine • organocatalysis • asymmetric • dihydro-
1H-pyrrole • tetrahydropyridine
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10.1002/ejoc.202100404
European Journal of Organic Chemistry
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Entry for the Table of Contents
An access to chiral 2,5-dihydro-1H-pyrroles and tetrahydropyridines has been elaborated through a phosphine-catalyzed Michael
addition/Wittig reaction. The use of catalytic amounts of chiral phosphines affords these nitrogen heterocycles with promising
enantioselectivities.
Institute and/or researcher Twitter usernames: @ArnaudVoituriez
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This article is protected by copyright. All rights reserved.