Phosphine-Catalyzed Reaction between 2-Aminobenzaldehydes and Dialkyl Acetylenedicarboxylates: Synthesis of 1,2-Dihydroquinoline Derivatives and Toward the Development of an Olefination Reaction

Article abstract of DOI:10.1021/acs.orglett.8b01870

A series of 1,2-dihydroquinolines were synthesized in good to excellent yields by reacting 2-aminobenzaldehyde derivatives and dialkyl acetylenedicarboxylates with catalytic amounts of phosphine. This reaction was rendered catalytic by the selective in situ phosphine oxide reduction with the use of phenylsilane. Furthermore, with the same starting materials and with an additional role of the reducing agent, a new olefination reaction was discovered. Hydrogen/deuterium (H/D) exchange experiments revealed the possible mechanism of this reaction.

Full text of DOI:10.1021/acs.orglett.8b01870

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Phosphine-Catalyzed Reaction between 2‑Aminobenzaldehydes
and Dialkyl Acetylenedicarboxylates: Synthesis of 1,2-
Dihydroquinoline Derivatives and Toward the Development of an
Olefination Reaction
Xu Han, Nidal Saleh, Pascal Retailleau, and Arnaud Voituriez*
́
́
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Universite Paris-Sud, Universite Paris-Saclay, 1 av. de la Terrasse,
91198 Gif-sur-Yvette, France
S
* Supporting Information
ABSTRACT: A series of 1,2-dihydroquinolines were synthe-
sized in good to excellent yields by reacting 2-amino-
benzaldehyde derivatives and dialkyl acetylenedicarboxylates
with catalytic amounts of phosphine. This reaction was
rendered catalytic by the selective in situ phosphine oxide
reduction with the use of phenylsilane. Furthermore, with the
same starting materials and with an additional role of the
reducing agent, a new olefination reaction was discovered.
Hydrogen/deuterium (H/D) exchange experiments revealed
the possible mechanism of this reaction.
Scheme 1. Synthesis of 1,2-DHQ or Succinate Derivatives
hosphines play a key role as stoichiometric reagents in a
variety of transformations such as the Wittig, Staudinger,
P
and Mitsunobu reactions and many others.1 Even if they are
widely used today, big quantities of waste are generated in
these processes, especially phosphine oxides, and the
purifications are sometimes difficult. In view of an ideal
synthesis, it was envisaged to simplify the purification of these
reactions in several ways: (1) immobilization of the trivalent
phosphine reagent,2 (2) the use of water-soluble phosphines,3
(3) fluorous-containing phosphine and rapid fluorous solid
phase extraction,4 (4) a catalytic strategy involving activation
of phosphine oxide with isocyanates or oxalyl chloride,5 and
(5) the use of catalytic amounts of phosphine via in situ
phosphine oxide reduction.6 Recently, the latter strategy was
used by several research groups, and consequently it is now
possible to render catalytic in phosphine many different
phosphine-promoted reactions with the use of silanes as
reducing agents.7 In this field, we developed the first
phosphine-catalyzed Michael addition/intramolecular Wittig
reaction for the synthesis of 9H-pyrrolo[1,2-a]indole and 3H-
pyrrolizine derivatives.8a This catalytic protocol was used for
the synthesis of numerous polycyclic nitrogen-containing
heterocycles.8b
which phenylsilane plays a dual role as a reducing agent for the
in situ reduction of phosphine oxide and as a reagent for a
novel olefination reaction, leading to succinates (Scheme 1, eq
2). Such products were usually synthesized via a Stobbe
condensation or a Horner−Wadsworth−Emmons reaction and
served as key building blocks in numerous total syntheses.10
Thus, the discovery of new pathways for their synthesis is
highly relevant.11
The phosphine-catalyzed reaction between tert-butoxycar-
bonyl-protected aminobenzaldehyde 1a and diethyl acetylene-
dicarboxylate 2a is detailed in Table 1. The catalytic system
was optimized with the use of P-phenylphospholene as the
catalyst and [PhSiH3/(pNO2C6H4O)2PO2H]8,12 as the re-
ducing system to selectively reduce in situ the phosphine oxide.
First, we investigated the effect of the silane stoichiometry on
The initial goal of the present study was to generalize the
reactivity of 2-aminobenzaldehydes with dialkyl acetylenedi-
carboxylate (DAAD) to synthesize highly functionalized 1,2-
dihydroquinoline (1,2-DHQ) derivatives (Scheme 1, eq 1).
This heterocycle is present in numerous natural products and
biologically active molecules, which led to the development of
numerous methods to synthesize this skeleton of interest.7k,9
Working on this project, we have discovered a new reactivity in
Received: June 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01870
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Letter
with 2 equiv of PhSiH3 (Table 1, entry 16) (87% yield of 4e).
Classical heating could be employed, but with a lengthened
reaction time (Table 1, entry 17) (80% yield). Finally, we
verified that both the phosphine and the phosphoric acid
catalysts are required for the reactivity (Table 1, entries 18−
19).
Table 1. Optimization of the Reaction Conditions
To explore the reaction scope of the formation of 1,2-
dihydroquinoline-2,3-dicarboxylates 3, we carried out a series
of tandem addition/Wittig reactions using the optimized
conditions (Table 2). The use of alkyl acetylenedicarboxylate
Table 2. Scope of the Catalytic Cyclization Reaction for the
Formation of 1,2-Dihydroquinoline-2,3-dicarboxylate
Derivatives
a
b
Ratios were determined by 1H NMR of the crude mixture. Isolated
c
yield at a 0.10 mmol scale of the major product. 20 h reaction time.
d
e
X-ray crystal structure of 3e is available. CCDC 1836703. 40 h
reaction time. Reaction conditions of entry 16, without phosphine
catalystf and without phosphoric acid.g
a
b
Ratios were determined by 1H NMR of the crude mixture. Isolated
c
yield at a 0.10 mmol scale. 1 mmol scale (341 mg).
the reaction outcome (Table 1, entries 1−3). With 1.2 equiv of
PhSiH3, we observed the formation of two products, namely,
the 1,2-DHQ 3a and the cinnamic ester derivative 4a in a 4.3:1
ratio (60% isolated yield of 3a).13 Increasing the quantity of
the reducing agent to 2 equiv did not improve the yield of 3. In
comparison with the classical heating, the use of microwave
heating improved the reaction rate (2.5 h reaction time instead
of 20 h) (Table 1, entries 4−5). Finally, further improvement
of the reaction yield was achieved using a more concentrated
reaction solution (Table 1, entries 6 and 7) (up to 67%
isolated yield of 3). Subsequently, we studied the influence of
the aniline protecting group on the reaction selectivity.
The use of the carboxybenzyl (Cbz) group gave a 1.3:1
mixture (Table 1, entry 8) (47% yield of 3b). Unprotected
aniline, benzyl-, or methyl-nitrogen substituted substrates gave
disappointing results (Table 1, entries 9−11). Finally, the use
of nosyl- or tosyl-protecting groups furnished the olefins 4d−e
as the major products (Table 1, entries 12−13) (72% yield).
Increasing the quantity of silane and decreasing the reaction
concentration had a beneficial effect on the selectivity (Table
1, entries 14−15). The optimized catalytic system was
obtained with the use of microwave heating (2 h at 80 °C)
derivatives 2a−c exhibited an excellent 3/4 selectivity, in favor
of compound 3 (Table 2, entries 1−3) (63−70% yields).
When electron-donating methoxy groups were introduced in
different positions on aniline substrate 1, the corresponding
products 3h−l were obtained with high selectivities and up to
98% yield (Table 2, entries 4−8). On the contrary, the
introduction of fluorine as an electron-withdrawing group has a
detrimental effect on the reaction selectivity and the yields
(products 3m,n) (Table 2, entries 9−10). Finally, this method
could be extended toward the use of a Boc-protected 3-amino-
2-naphthaldehyde substrate (Table 2, entry 11).
Furthermore, we extended the microwave-assisted catalytic
olefination reaction between tosyl- and nosyl-protected amino-
benzaldehydes and DAAD using 5 mol % of phospholene
oxide catalyst and phenylsilane, at 80 °C (Scheme 2). We first
investigated the influence of the alkyl group of the DAAD
substrate. Ethyl, t-butyl, or methyl groups gave the desired
products 4e−g in 64−87% yields. Next, diethyl (E)-2-((3-
aminonaphthalen-2-yl)methylene)succinates 4h−i were iso-
lated in good yields. Fluorinated substrates furnished the
corresponding olefinic products 4j−k in 54−60% yields.
B
DOI: 10.1021/acs.orglett.8b01870
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Organic Letters
Letter
Scheme 2. Scope of the Catalytic Olefination Reaction
Scheme 3. Proposed Mechanism for the Formation of 3 and
4
However, with different substitution patterns, other groups
isolated such molecules.14 Finally, we can point out the
influence of the aniline protecting group in the reaction
outcome. The most nucleophilic deprotonated substrate 1a
(PG = Boc) gave the cyclic product 3a, whereas the substrates
substituted with a more electron-withdrawing tosyl group gave
the olefinic product 4e.
Moreover, the proposed mechanism for the formation of 4
was investigated using deuterium-labeled substrates and
reagents (Scheme 4). Because a proton exchange could come
a
Isolated yield of product 4. The E-olefin was always obtained as the
major product, in mixture with product 3; see the experimental
section, Table S1, for details. CCDC 1836706. CCDC 1836704.
b
c
Scheme 4. H/D Exchange Experiments
Finally, nosyl-protected substrates gave the olefinic products
4d and 4l in decent yields. The major olefinic product was
always the E-isomer, and the E/Z ratio varied from 77:23 to
>98:2. The structure of the products and the geometry of the
double bonds were ascertained by X-ray diffraction studies of
compounds 4d and 4h.
Concerning the different mechanisms for the formation of
either 3 or 4, the two postulated pathways are shown in
Scheme 3. For the formation of the 1,2-dihydroquinoline-2,3-
dicarboxylate 3 (Scheme 3, Path A) and according to the
accepted mechanism,9h,i the phosphine adds to DAAD 2, and
the zwitterionic species I is formed. The latter deprotonates
the aniline 1a to obtain the vinylphosphonium salt II.
After addition of the conjugate base of 1a to II, the
phosphorus ylide III is formed and undergoes a Wittig reaction
to furnish the compound 3a. Finally, the phenylsilane reduces
the phosphine oxide to the corresponding trivalent phosphine.
For the formation of the olefinic product 4e, the addition of
the zwitterion I to the aldehyde function of 1e can be proposed
(Scheme 3, Path B), and the corresponding oxaphosphole IV
would be formed. The latter could then react in the presence of
silane to form the intermediate V. After opening of the
oxaphosphole ring, intermediate VI could be obtained
concurrently with the release of the phosphine oxide which
will be reduced by silane to complete the catalytic cycle. The
desired product 4e might be subsequently formed via
protonation with traces of water present in the solvent. In
our hands, we did not succeed to isolate and characterize IV.
from the substrate and additives, we paid attention to using
deuterated aniline and phosphoric acid (see the Supporting
Information for additional deuterated experiments). Our
mechanistic investigation started with the use of deuterated
silane. The H/D exchange was conducted, and >95%
deuterium incorporation at the allylic position was observed
(product 5). This seems to prove that the silane acts as a
hydride donor to open the oxaphosphole cycle. Second, since
the final protonation of the intermediate VI could be achieved
with water, a reaction in dry toluene and with D2O was
launched. We observed the formation of the monodeuterated
product 5.
C
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Furthermore, when the deuterated silane and the D2O were
used together, we observed the formation of the bis-deuterated
product 6. In the latter case, the formation of the
monodeuterated product 5 was also observed, which can be
attributed to the difficulty in having strictly anhydrous reaction
conditions. The H/D exchange of the aniline proton in the
final products 5 and 6 might take place during the purification.
Finally, we were interested by the role of the aniline function
in the formation of products 4. As recently pointed out in the
literature for the synthesis of pyrrolidine derivatives, some
phosphine-catalyzed reactions should be hydroxy-assisted via
the use of o-hydroxyaryl substrates.15 In our case, no products
were formed with the use of N-methylaniline and 3- and 4-
hydroxybenzaldehydes (Scheme 5, eq 1). The olefinic product
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: arnaud.voituriez@cnrs.fr.
ORCID
Arnaud Voituriez: 0000-0002-7330-0819
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
Scheme 5. Reaction Scope and Limitation
ACKNOWLEDGMENTS
■
The authors acknowledge the support of the “Centre National
de la Recherche Scientifique” (CNRS) and the French “Agence
Nationale de la Recherche” (ANR) for funding (HUISPHOS
project: ANR-13-JS07-0008). We warmly thank the CSC
(China Scholarship Council) for a Ph.D. grant to X.H.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01870.
■
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all new compounds (PDF)
Accession Codes
CCDC 1836703−1836706 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
D
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E
DOI: 10.1021/acs.orglett.8b01870
Org. Lett. XXXX, XXX, XXX−XXX