Enantioselective base-free electrophilic amination of benzofuran-2(3H)- ones: Catalysis by binol-derived P-spiro quaternary phosphonium salts

Article abstract of DOI:10.1002/anie.201100283

A spiroing reactivity: A series of novel binol-derived P-spiro quaternary phosphonium salts were designed, prepared, and used for the first highly enantioselective amination of benzofuranones (see scheme; binol=1,1-2- binaphthol, Bn=benzyl). An unprecedented mechanism involving the π-π interactions between the substrate and the catalyst was proposed as the primary binding mode on the basis of molecular modelling and DFT calculations.

Full text of DOI:10.1002/anie.201100283

DOI: 10.1002/anie.201100283
Asymmetric Synthesis
Enantioselective Base-Free Electrophilic Amination of Benzofuran-
2(3H)-ones: Catalysis by Binol-Derived P-Spiro Quaternary
Phosphonium Salts**
Chuan-Le Zhu, Fa-Guang Zhang, Wei Meng, Jing Nie, Dominique Cahard, and Jun-An Ma*
Benzofuran-2(3H)-ones are important building blocks that
are found in a large variety of natural products,[1] potential
medicines,[2] and other highly functionalized compounds.[3]
Many of them feature a chiral quaternary stereocenter at
the C3 position of the heterocyclic ring (Figure 1).[1c–f]
ureas and amines were used as catalysts.[6] Enantioselective
introduction of a heteroatom group at the C3 position would
substantially broaden the benzofuranone chemistry and offer
more functionalized chiral products. Herein, we present a
hitherto unknown catalytic enantioselective amination of
benzofuranones by employing a new class of rigid chiral P-
spiro quaternary phosphonium salts as organocatalysts.
Over the past decades, organocatalysis that exploits the
use of chiral quaternary ammonium salts has emerged as an
area of intense interest in asymmetric synthesis owing to its
operational simplicity and mild reaction conditions.[7,8]
A
number of quaternary ammonium salt catalysts have demon-
strated useful levels of enantioselectivity in a wide range of
asymmetric reactions. Furthermore, a recent breakthrough in
this field involved the design and application of chiral
quaternary phosphonium salts in catalytic asymmetric syn-
thesis.[9] For examples, the group of Ooi developed a series of
P-spiro tetraaminophosphonium salts as chiral Brønsted acids
for substrate recognition and functional-group activation
through hydrogen bonding.[9e–j] Maruoka and co-workers
reported other chiral quaternary tetraalkylphosphonium
salts and their use in asymmetric phase-transfer catalysis.[9m–o]
Despite the above mentioned progress, this field is still in its
infancy and the construction of new phosphonium catalysts is
still in great demand to meet the need of many challenging
asymmetric reactions.
Since 1,1’-binaphthyl-based enantiopure chiral materials
are among the most readily available privileged sources of
chirality, chemical modification of binaphthyls resulting in the
formation of new modular structures for catalytic application
has been a proven strategy for the development of novel
chiral catalysts. We envisioned that the introduction of two
chiral 2,2’-bis(methylene)-1,1’-binaphthyl moieties onto a
phosphorus center would form a rigid P-spiro tetraalkylphos-
phonium framework, thus enabling a high level of asymmetric
induction. A series of novel homochiral tetraalkylphospho-
nium bromides 1 possessing a [7.7] spirocyclic core were
readily prepared by the reaction of (S)-4,5-dihydro-3H-
dinaphtho[2,1-c:1’,2’-e]phosphepine[10] with (S)-3,3’-disubsti-
tuted 2,2’-bis(bromomethyl)-1,1’-binaphthyls and purified in
analytically pure form after one simple recrystallization.
Crystals suitable for X-ray diffraction analysis were obtained
for the quaternary phosphonium salt 1a.[11] The ORTEP view
of this structure is shown in Figure 2. As expected, the two
binaphthylmethylene units are twisted at the phosphorus
center. The dihedral angle between the planes of the two
naphthyl units is 69.18. It was expected that the conforma-
tional rigidity imposed by the P-spiro scaffold could poten-
Figure 1. Examples of chiral benzofuran-2(3H)-ones.
However, enantioselective synthesis of such significant
chiral benzofuran-2(3H)-ones remains a considerable chal-
lenge. Catalytic enantioselective introduction of substituents
at the C3 position represents the most direct approach to
chiral benzofuranones. For instance, Vedejs et al. and Hill and
Fu have presented the asymmetric Black rearrangement of O-
acylated benzofuranones by means of chiral derivatives of 4-
dimethylaminopyridine (DMAP) to afford enantioenriched
C-acylated isomers with up to 98% enantiomeric excess.[4,5]
Very recently, two other groups reported the enantioselective
conjugate addition reactions of benzofuran-2(3H)-ones to
a,b-unsaturated carbonyl compounds, in which chiral thio-
[*] C.-L. Zhu, F.-G. Zhang, W. Meng, J. Nie, Prof. J.-A. Ma
Department of Chemistry, Tianjin University
Tianjin 300072 (China)
Fax: (+86)22-2740-3475
E-mail: majun_an68@tju.edu.cn
Dr. D. Cahard
UMR 6014 CNRS, laboratoire COBRA de l’IRCOF
Universitꢀ et INSA de Rouen, Mont Saint Aignan (France)
[**] This work was supported financially by the NSFC (20972110 and
21002068). We thank the NSCC-TJ and Aiping Fu (Qingdao
University) for help with the computational studies. binol=1,1’-bi-
2-naphthol.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100283.
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5869

Communications
the binaphthyl units could improve the ee value to up to 95%
(entries 2–4) and the addition of another tier of aryl rings
could further improve the ee value to up to 98% (entries 5
and 6). Among them, catalyst 1e gave excellent yield and the
highest enantioselectivity. A comparison of the results
obtained in different solvents showed that this asymmetric
transformation is highly sensitive to the solvent used
(entries 7–11). Polar solvents generally gave lower ee values
and toluene was found to be the best solvent for this reaction.
Decreasing the amount of catalyst to 1 mol% caused only a
slight decrease in the yield and the ee value of the product
(entry 12).
Under the optimized reaction conditions, the scope of this
unprecedented enantioselective amination of benzofuranone
was further examined in the presence of catalyst 1e and the
results are listed in Scheme 1. Substrates with electron-
donating and electron-neutral groups on the benzofuranone
gave the desired products in high yields and enantioselectiv-
ities (90–98% ee; 3a–c). Halogen substitution at the 5-
position of the benzofuranone had no impact on the activity
of the amination, but a lower enantioselectivity was observed
(3d and 3e). The adduct 3d was crystallized from CH2Cl2/
petroleum ether, and its structure, including its absolute
configuration, was determined by Rꢀntgen diffraction stud-
ies.[11] 3-Arylbenzofuranones gave high yields and excellent
enantioselectivities (3 f–i). In addition, 3-isopropyl benzofur-
Figure 2. Synthesis of new quaternary phosphonium salts 1. An
ORTEP view (ellipsoids shown at 50% probability) of 1a is provided
(counter anion, calculated hydrogen atoms, and solvent molecules are
omitted for clarity).
tially translate into a positive attribute in achieving a high
level of asymmetric induction in the catalyzed reaction.
With these novel quaternary phosphonium catalysts in
hand, we set out to examine their activity in the reaction of 3-
phenylbenzofuran-2(3H)-one (2a) and (E)-dibenzyl diazene-
1,2-dicarboxylate to identify the best catalyst and the optimal
reaction conditions (Table 1). Gratifyingly, in the absence of
any base, the simplest catalyst, 1a, catalyzed this amination
reaction in toluene at room temperature for 48 hours to give
product 3a in 39% yield with a 66% ee (entry 1). We were
pleased to find that the introduction of bulky substituents on
the catalyst had a remarkably beneficial effect on both the
reactivity and the stereoselectivity. Thus, the presence of
substituted phenyl groups on the 3,3’-positions of only one of
Table 1: Screening of novel quaternary phosphonium catalysts and
optimization of reaction conditions.[a]
Entry
1 (mol%)
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a (2)
1b (2)
1c (2)
1d (2)
1e (2)
1 f (2)
1e (2)
1e (2)
1e (2)
1e (2)
1e (2)
1e (1)
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
Et2O
39
85
80
80
99
87
38
99
60
65
98
94
66
65
95
90
98
95
65
90
59
27
35
96
9
THF
10
11
12
1,4-dioxane
CH3CN
toluene
Scheme 1. Selected examples of catalytic enantioselective amination of
3-substituted benzofuran-2(3H)-ones. For the X-ray crystal structure
the thermal ellipsoids are shown at 50% probability and the hydrogen
atoms are omitted for clarity.
[a] See the Supporting Information for details concerning the reaction
conditions. [b] Yields are of isolated pure products. [c] Determined by
HPLC analysis using a chiral stationary phase. Bn=benzyl.
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Figure 3. a) MS (ESI) spectrum of substrate 2a. b) The new species detected by HPLC/MS (ESI) analysis of the reaction mixture of 2a and
dibenzyl diazene-1,2-dicarboxylate in the presence of catalyst 1e.
anone also afforded the desired product 3j in good yield but
with only a moderate ee value.[12]
enol is bound to the catalyst through p–p interactions.
Gratifyingly, the binding mode with the lowest energy was
found to be one that leads to effective shielding of the Si face
of the enol, thereby leaving its Re face open to the electro-
philic attack by the azodicarboxylate. The enol form of 2a is
sandwiched between the catalyst and the azodicarboxylate.
Crucial for the reactivity, is the catalytic electrophilic
activation of the nitrogen donor reagent by the phosphonium
group. Other stacking combinations on different faces of the
catalyst that would move the azodicarboxylate away from the
phosphonium are not reactive since the electrophilic activa-
tion of the azodicarboxylate is not permitted. Although the
true mechanism of this reaction requires further detailed
Mechanistically, the reactions that are conducted under
homogeneous reaction conditions in the absence of any base
are clearly distinct from phase-transfer catalysis. The lack of
the possibility for the formation of hydrogen bonds as well as
other interactions such as ionic attraction between the
catalyst and the substrate present a rather intriguing case
for mechanistic interpretation. While a pure sample substrate
1
of 2a was shown to be homogeneous by H NMR analysis
([D8]toluene) and its enol form undetectable on the timescale
of the NMR experiment,[13] trace amounts of a new species
were detected with the help of HPLC/MS methods during its
reaction with dibenzyl diazene-1,2-dicar-
boxylate in the presence of catalyst 1e. As
shown in Figure 3, this new species exhibits
a distinct mass spectrum (Figure 3b) when
compared with that of 2a (Figure 3a) and
is characterized by a base peak at m/z
209.0. The structure of this species was
assigned as 2a-E, that is, the enol form of
2a.[14] This observation led us to propose
that the highly enantioselective electro-
philic amination of 2a stems from the
efficient formation of the enol in a dynamic
process whereby a strong p–p interaction
between the enol form of 2a and the axially
chiral binaphthylene moiety of 1e ensures
a favorable reversal in the equilibration
between the lactone and the enol
(Figure 4), which is reminiscent of the
induced fit in enzymatic reactions. DFT
calculations[15] based on catalyst 1a and
lactone 2a indicate that the formation of
the catalyst–enol complex (C·E) is approx-
imately 3.4 kcalmolÀ1 more favorable than
that of the catalyst–lactone complex (C·L).
With the help of the X-ray structure of 1a
and DFT structure optimization, we were
Figure 4. Proposed transition-state assembly for the catalytic enantioselective amination of
able to qualitatively emulate the way the 3-substituted benzofuran-2(3H)-one.
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Communications
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In summary, a new class of rigid binol-derived P-spiro
quaternary phosphonium salts were designed and synthe-
sized. Their catalytic activity and stereoselectivity have been
clearly demonstrated in the development of the first highly
enantioselective amination of benzofuranones. These studies
also offer valuable insights into the rational design of novel
catalyst systems that have alternative mechanisms for asym-
metric induction. Further investigation of the reaction
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Experimental Section
A mixture of substituted benzofuran-2(3H)-one (0.1 mmol), (E)-
dibenzyl diazene-1,2-dicarboxylate (35.8 mg, 0.12 mmol), and (S,S)-
1e (2.7 mg, 2 mol%) in toluene (2 mL) was stirred vigorously at 258C
for the stated time. After the reaction was complete (determined by
TLC), the resulting mixture was concentrated. The residue was
purified by column chromatography on silica gel (ethyl acetate/
petroleum ether= 1/10 as eluent) to afford the desired adduct 3. The
product was identified by NMR spectroscopy. The enantiomeric
excess of the product was determined by HPLC using a chiral column.
Received: January 13, 2011
Revised: April 6, 2011
Published online: May 10, 2011
Keywords: amination · asymmetric synthesis ·
.
enantioselectivity · heterocycles · p–p interactions
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[13] The signal corresponding to the enol form was not detected by
either UV or IR spectrometers possibly owing to the fact that
there were only trace amounts of enol. We thank one of the
reviewers for suggesting that we examine the reaction process by
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