Catalytic Asymmetric Arylation of α-Aryl-α-diazoacetates with Aniline Derivatives

Article abstract of DOI:10.1021/jacs.5b05086

The asymmetric arylation of diazo compounds with aniline derivatives cooperatively catalyzed by an achiral dirhodium complex and a chiral spiro phosphoric acid is reported. The reaction provides a new method for the facile synthesis of α-diarylacetates, v

Full text of DOI:10.1021/jacs.5b05086

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Communication
Catalytic Asymmetric Arylation of #-Aryl-
-diazoacetates with Aniline Derivatives
#
Bin Xu, Mao-Lin Li, Xiao-Dong Zuo, Shou-Fei Zhu, and Qi-Lin Zhou
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Jun 2015
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Bin Xu , Mao-Lin Li , Xiao-Dong Zuo , Shou-Fei Zhu *, and Qi-Lin Zhou
1
2
State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science
and Engineering (Tianjin), Nankai University, Tianjin 300071, China
Supporting Information Placeholder
ABSTRACT: The asymmetric arylation of diazo compounds with
aniline derivatives cooperatively catalyzed by an achiral dirhodium
complex and a chiral spiro phosphoric acid is reported. The reaction
provides a new method for the facile synthesis of α-diarylacetates,
versatile building blocks with a diaryl tertiary chiral center, in good
yields (up to 95%) with high enantioselectivities (up to 97% ee).
Preliminary mechanistic studies suggest that the arylation reaction
proceeds via a stepwise process, in which the enantioselectivity is
controlled by a chiral spiro phosphoric acid–promoted proton shift
in a zwitterionic intermediate. This work represents the first asym-
2
metric intermolecular C(sp )–H bond insertion reaction with arenes.
Diaryl tertiary chiral centers are ubiquitous substructures in nat-
Figure 1. Selected bioactive compounds containing a chiral diaryl
tertiary center.
1
ural products and pharmaceuticals, such as (+)-sertraline
1
b
1c
1d
(Zoloft), (R)-tolterodine (Detrol), podofilox (Condylox),
1
e
1f
CDP-840, and nomifensine (Figure 1). Therefore, the develop-
ment of methods for enantioselective synthesis of compounds with
Scheme 1. Enantioselective Catalytic Arylation of α-Aryl α-
Diazoacetates
2
this substructure has attracted considerable attention. One possible
method is the arylation (formal C(sp )–H insertion) of α-aryl-α-di-
azoacetates with benzene derivatives, which is a straightforward,
efficient route to α-diaryl acetates. Although remarkable progress
has been made on the nonasymmetric version of the reaction, the
asymmetric version remains unknown. Davies and co-workers in-
2
3
4
vestigated the arylation reaction of methyl 2-(4-bromophenyl)-2-
diazoacetate with N,N-dimethylaniline using chiral dirhodium cat-
alysts but obtained only the racemic product. We herein report the
enantioselective arylation of α-aryl-α-diazoacetates with aniline
derivatives cooperatively catalyzed by dirhodium(II) trifluoroace-
tate and chiral spiro phosphoric acids (SPAs). This new reaction
directly and efficiently provides chiral α-diaryl acetates in good
yields (up to 95%) with high enantioselectivities (up to 97% ee)
(Scheme 1). Although transition-metal-catalyzed C–H insertion of
carbenoids is a powerful method for C–H functionalization, and
significant progress has been made in the development of asym-
We optimized the reaction conditions for the arylation by using
methyl 2-diazo-2-phenylacetate (2a) and 1-phenylpyrrolidine (3a)
as substrates (Table 1). The reaction was complete in 30 min when
it was conducted at room temperature in the presence of 1 mol%
Rh (OAc) and 1 mol% (R)-1a as catalysts, and the desired aryla-
2 4
tion product (4a) was obtained in 52% yield with 17% ee, along
3
5
metric C(sp )–H insertion reactions, reports of asymmetric
2
C(sp )–H insertion reactions are scarce and focus on intramolecular
6
7
reactions and reactions with indoles, a typical heteroarenes. To
the best of our knowledge, the reaction reported herein represents
3
with the C(sp )‒H insertion product, methyl 2-phenyl-2-(1-phe-
nylpyrrolidin-2-yl)acetate (20% yield, 0% ee, entry 1). Evaluation
2
the first asymmetric intermolecular C(sp )–H insertion reaction
with arenes.
of various chiral SPAs revealed that (R)-1g, which has two 6,6-di-
(2,4,6-trimethylphenyl) moieties, gave the highest enantioselectiv-
ity (51% ee, entries 2‒8). The use of a bulkier dirhodium catalyst,
Rh (piv) or Rh (TPA) , reduced the enantioselectivity to 10% ee
and 16% ee, respectively (entries 9 and 10). Remarkably, the use
of Rh (TFA) , a strong Lewis acid, improved the enantioselectivity
2
4
2
4
2
4
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to 92% ee (entry 11). When the reaction temperature was increased
to 45 °C, the enantioselectivity increased to 95% ee (entry 12). Fur-
ther heating the reaction to reflux, the desired arylation product was
obtained with retained enantioselectivity but lower yield (entry 13).
Table 2. Enantioselective Arylation of α-Aryl-α-diazoace-
tates with 1-Phenylpyrrolidine
a
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o
However, the reaction performed at 0 C became sluggish with sig-
nificantly lowered yield and enantioselectivity (entry 14). The
yield and enantioselectivity were further increased to 79% and 97%
ee, respectively, when 2 mol% catalyst (R)-1g and 2.0 equiv of sub-
strate 3a were used (entry 15). Note that the arylation reaction oc-
curred specifically at the para position of the 1-phenylpyrrolidine.
The reaction is sensitive to water and the addition of water into the
reaction mixture leads to the decrease of yield and enantioseletivity
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(Table S1).
Table 1. Enantioselective Arylation of Methyl 2-Diazo-2-
phenylacetate with 1-Phenylpyrrolidine: Optimization of
Reaction Conditions
entrya Rh
L
SPAs
yield (%)b
52
ee (%)c
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Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
Rh
(OAc)
(OAc)
(OAc)
(OAc)
(OAc)
(OAc)
(OAc)
(OAc)
4
4
4
4
4
4
4
4
(R)-1a
(R)-1b
(R)-1c
(R)-1d
(R)-1e
(R)-1f
(R)-1g
(R)-1h
(R)-1g
(R)-1g
(R)-1g
(R)-1g
(R)-1g
(R)-1g
(R)-1g
The reaction conditions and analysis method were the same as
those described in Table 1, entry 15.
34
48
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46
11
10
51
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45
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Figure 2. X-ray structure of (R)-4i. H atoms, except the one at the
chiral center, have been omitted for clarity.
(piv)
4
20
10
16
92
95
95
49
97
0
(TPA)
(TFA)
(TFA)
(TFA)
(TFA)
(TFA)
4
4
4
4
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4
66
Table 3. Enantioselective Arylation of Methyl 2-Phenyl-2-
a
1
64
diazoacetate with Aniline Derivatives
2d
3e
4f
66
55
43
15d,g
79
a
Reaction conditions: Rh
at 25 °C. Isolated yield. Determined
by supercritical fluid chromatography using a Chiralcel OJ-H col-
2 4
L /SPA/2a/3a = 0.002:0.002:0.2:0.2
b
c
(
mmol) in 3 mL of CHCl
3
d
e
f
o
umn. At 45 °C. At reflux; reaction time: 5 min. At 0 C; reaction
time: 1 h. Using 2 mol% (R)-1g and 2.0 equiv 3a.
g
Using the optimal reaction conditions, we evaluated the reactions
of various α-aryl-α-diazoacetates 2 with 1-phenylpyrrolidine (3a)
(Table 2). Substituents at the para and meta positions of the aryl
ring of the α-aryl-α-diazoacetates had a negligible impact on the
yield and enantioselectivity of the reaction; substrates with this type
of substitution underwent arylation in 30 min and afforded the cor-
responding chiral α-diarylacetates (4a–4i and 4k) in good yields
(66–95%) with excellent enantioselectivities (93–97% ee). Diazo-
acetate 2j, which has an ortho fluoro substituent, gave a relatively
low yield (54%). Diazoacetates with a fused ring, such as
benzo[d][1,3]dioxol-5-yl (2l) and 2-naphthyl (2m), were also suit-
able substrates for the reaction and afforded the corresponding
products (4l and 4m) in satisfactory yields and enantioselectivities.
The phenyldiazoacetates with bulkier ester moieties exhibited
lower yields and enantioselectivities (4n and 4o). Arylation product
a
The reaction conditions and analysis method were the same as
those described in Table 1, entry 15.
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i was determined to have the (R)-configuration by means of X-ray
mechanism (Scheme 4). First, Rh carbene A generated from the α-
aryl α-diazoacetate reacts with the electron-rich aromatic ring of
the aniline to form zwitterion B. Dissociation of rhodium from B
generates metal-free zwitterion C, which undergoes a 1,2-proton
shift to give the arylation product. The 1,2-proton shift is mediated
by the SPA and occurs via a proton shuttle model (TS), and it is at
this step that the chiral induction occurs. Water present in trace
amounts in the reaction medium may exchange a proton with inter-
mediate B or C and may even be present in the transition state (TS)
as a bridge, which could explain the deuterium distribution ob-
served in the reactions shown in Scheme 3a,c. Investigation of the
details of the reaction mechanism is underway in our laboratory.
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diffraction analysis of a single crystal (Figure 2).
We also investigated the arylation reactions of various aniline
derivatives with diazoacetate 2a (Table 3). The electronic proper-
ties of meta substituents on the aryl ring of the 1-arylpyrrolidines
had a negligible effect on the enantioselectivity (4p‒4r). In contrast,
the effects of ortho substituents differed depending on their steric
and electronic characteristics: relatively small electron-withdraw-
ing groups such as Br or F gave excellent enantioselectivities (4t,
1
2
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4% ee; 4u, 91% ee), whereas relatively bulky groups and the elec-
tron-donating methyl group afforded low enantioselectivity (4s, 58%
ee). Like the 1-arylpyrrolidines, 4-phenylmorpholine also under-
went the arylation reaction, producing corresponding product 4v in
good yield (81%) with excellent enantioselectivity (97% ee). 1-
Phenylpiperidine and N,N-dimethylaniline reacted with 2a to af-
ford arylation products in good yields, but the enantioselectivities
were only moderate (4w, 64% ee; 4x, 59% ee). When other benzene
derivatives, such as anisole and toluene, were tested in the reaction
with 2a, only carbene dimerization products were obtained.
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Scheme 3. Deuterium-Labeling Experiments
Scheme 2. Applications of the Chiral α-Diarylacetates
Scheme 4. Proposed Mechanism and Chiral Induction
Model
This arylation reaction could easily be scaled up to a 1-g scale
without reduction of the yield or enantioselectivity; the reaction of
2
m (1.13 g) and 3a afforded 4m in 78% yield with 94% ee (Scheme
2
a). The amino and carboxylic groups of the arylation products
8
could serve as handles for various transformations. For example,
the pyrrolidinyl group of 4m was converted to a phenyl group by
means of a palladium-catalyzed cross coupling with a Grignard re-
agent in the presence of methyl trifluoromethanesulfonate (Scheme
8
e
2
b). Reduction of the ester group of 4m produced chiral β-diaryl
alcohol 6 (Scheme 2c), a structural unit found in many bioactive
9
compounds.
To investigate the mechanism of the arylation reaction, we per-
formed deuterium-labeling experiments. When 1-(pentadeutero-
phenyl)pyrrolidine 3a was used, arylation product 4a was obtained
with 67% deuterium incorporation at the chiral center (Scheme 3a).
This result indicates that the hydrogen atom on the chiral center
In conclusion, asymmetric arylation reaction of α-aryl-α-diazo-
acetates with aniline derivatives was achieved with an achiral dir-
hodium complex and a chiral SPA as cocatalysts. The reaction pro-
vides a new approach to the synthesis of chiral α-diarylacetates in
good yields with high enantioselectivities. Our results demonstrate
that chiral proton shuttle catalysts can be used for otherwise diffi-
cult to accomplish transition-metal-catalyzed asymmetric reactions
in which chiral induction occurs at the proton shift step.
was not derived exclusively from the para position of 3a-d
5
. The
reaction performed in CDCl gave a product without deuterium,
3
which rules out the possibility that the hydrogen atom came from
the solvent (Scheme 3b). The addition of a stoichiometric amount
of deuterium oxide to the system resulted in the formation of an
arylation product with 75% deuterium incorporation at the chiral
center, indicating that the hydrogen atom could be derived partly
from water present in the reaction medium (Scheme 3c). Taken to-
gether, the results of these experiments support a stepwise mecha-
ASSOCIATED CONTENT
Supporting Information
Full experimental and characterization data, including H and 13C
NMR spectra for all the new compounds, chiral HPLC spectra for
the products, and crystallographic data (CIF). This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
1
1
0
nism.
On the basis of the deuterium labeling experiments and previous
4
11
studies reported by Davies and Hu , we propose the following
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D.; Jing, C.; Zhou, J.; Wang, C.; Wang, D.; Hu, W. Org. Lett. 2014, 16,
AUTHOR INFORMATION
2
934.
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(
(
Corresponding Author
*sfzhu@nankai.edu.cn
2
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Rev. 2009, 38, 3242. (d) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L.
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Notes
The authors declare no competing financial interests.
(6) (a) Watanabe, N.; Ohtake, Y.; Hashimoto, S.; Shiro, M.; Ikegami, S.
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We thank the National Natural Science Foundation of China, the
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Catalytic Asymmetric Arylation of α-Aryl-α-diazoacetates with Aniline Derivatives
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