New electrophilic addition of α-diazoesters with ketones for enantioselective C-N bond formation

Article abstract of DOI:10.1021/ja2056159

α-Diazoesters were discovered to be good electrophiles in a catalytic asymmetric α-functionalization of ketones for the first time. This reaction also provided a direct and efficient method for C-N bond formation with excellent yields (up to 98%) and enantioselectivities (up to 99% ee) under mild conditions. The application of the electrophilicity of α-diazoesters opens up a novel way to access the diversity of diazo chemistry.

Full text of DOI:10.1021/ja2056159

COMMUNICATION
pubs.acs.org/JACS
New Electrophilic Addition of α-Diazoesters with Ketones for
Enantioselective CꢀN Bond Formation
Wei Li, Xiaohua Liu, Xiaoyu Hao, Xiaolei Hu, Yangyang Chu, Weidi Cao, Song Qin, Changwei Hu, Lili Lin,
and Xiaoming Feng*
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, P. R. China
S Supporting Information
b
Scheme 1. Observations from the Reaction between 1-Tet-
ralone (2a) and α-Benzyl-α-diazoester (1a)
ABSTRACT: α-Diazoesters were discovered to be good
electrophiles in a catalytic asymmetric α-functionalization of
ketones for the first time. This reaction also provided a
direct and efficient method for CꢀN bond formation with
excellent yields (up to 98%) and enantioselectivities (up to
99% ee) under mild conditions. The application of the
electrophilicity of α-diazoesters opens up a novel way to
access the diversity of diazo chemistry.
In the initial study, the reaction between 2a and 1a was
performed in CH2Cl2 at 20 °C with a 10 mol % loading of a
Lewis acid catalyst prepared in situ from a metal salt and the
chiral N,N0-dioxide ligand L1.10 Excellent enantioselectivity but a
very low yield of the particular alkylhydrazone compound 4a was
obtained in the presence of the L1ꢀSc(OTf)3 complex (Table 1,
entry 1). Other metal sources, including Y(OTf)3, La(OTf)3,
and Sc(OiPr)3, were evaluated and failed to catalyze the reaction
(entries 2ꢀ4). To improve the reactivity, it was envisioned that
bases might be favorable toward the enolization of 2a, thereby
enhancing its nucleophilic capability. To our delight, when 10 mol %
K2CO3 was added as a basic additive, the yield increased to 33%
while the enantioselectivity was maintained (entry 5). Better
results were obtained with Na2CO3 (entry 6), and further impro-
vement was achieved with the use of Li2CO3 (entry 7). The
structure of the N,N0-dioxide ligand was also found to influence
the yield greatly. Chiral N,N0-dioxide ligands L2 and L3 derived
from L-pipecolic acid and L-proline, respectively, gave lower
reactivities than ligand L1 derived from L-ramipril (entries 8
and 9 vs 7). No product was observed with aniline-derived N,
N0-dioxide ligand L4 instead of the bulky and electron-rich 2,
6-diisopropylaniline-derived one (entry 10). These results
showed that the subunits of the supporting ligand could fine-
tune the Lewis acidity and the spatial environment of the catalyst
in concert. When 50.0 μL of 2a was used as both the solvent and
reagent, the reaction was obviously improved, giving the product
4a in 90% yield with 95% ee within 24 h (entry 11). Changing the
ligand/metal ratio to 1:1.2 further improved the reactivity, giving
almost quantitative yield with a shorter reaction time (entry 12).
Remarkably, excellent outcomes were still obtained when
the catalyst loading was reduced to 5 mol % (entry 13).
he chemistry of α-diazocarbonyl compounds has attracted
T
great attention because of its extensive applications in
organic chemistry since the first recorded synthesis of ethyl
diazoacetate by Curtius in 1883.1 Remarkably, α-diazocarbonyl
compounds have been well-studied as metal carbene precursors,2
1,3-dipoles,3 and nucleophiles.4 Comparatively, the utility of the
electrophilic capability of α-diazocarbonyl compounds has rarely
been studied. One related reaction is the JappꢀKlingemann
reaction, in which aryldiazonium compounds are used as the
electrophiles and are attacked by β-ketoesters under basic con-
ditions to form arylhydrazone compounds.5 Another direct
nucleophilic addition to α-diazoesters using highly active orga-
nolithium reagents and Grignard reagents under rigorous con-
ditions was recently reported by Takamura and co-workers.6
In our previous study of the chiral Lewis acid-catalyzed
reaction between α-diazoesters and aromatic aldehydes, an
efficient catalytic asymmetric Roskamp reaction was accom-
plished by using the nucleophilicity of α-diazoesters.7 Contin-
uous experiments were carried out to explore the reaction
between α-diazoesters and ketones under similar reaction con-
ditions. It was rationally expected that a ring-expansion product
would be obtained from the initial nucleophilic addition of the α-
diazoester to the CdO bond of the ketone.8 To our great
surprise, the unexpected alkylhydrazone compound 4a was
obtained from the reaction between 1-tetralone (2a) and
α-benzyl-α-diazoacetate (1a), and no related ring-expansion
product 3 was observed (Scheme 1). Herein we report this
new reaction involving the electrophilic addition of α-diazoesters
to α-alkyl ketones under mild reaction conditions. Meanwhile, a
highly catalytic asymmetric α-hydrazonation of unactivated
ketones to construct homochiral CꢀN bonds with exceptional
enantioselectivities was accomplished. It is also a potential
alternative approach to α-amination of ketones.9
Received: June 21, 2011
Published: September 01, 2011
r
2011 American Chemical Society
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|

Journal of the American Chemical Society
COMMUNICATION
Table 1. Optimization of the Reaction Conditionsa
Table 2. Scope of the α-Diazoester in the Catalytic Asym-
metric CꢀN Bond Formationa
entry
R1
Et
R2
t (h)
yield (%)b
ee (%)c
1d
2
Bn
24
30
27
24
24
27
25
26
24
35
26
20
26
56
98 (95) (4a) 95 (95) (S,E)
Me Bn
81 (4b)
95 (4c)
93 (4d)
95 (4e)
92 (4f)
98 (4g)
95 (4h)
92 (4i)
80 (4j)
89 (4k)
90 (4l)
92 (4m)
85 (4n)
93
93
92
95
96
97
96
97
93
93
91
95
97
3
i-Pr Bn
4
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
2-MeC6H4CH2
3-MeC6H4CH2
4-MeC6H4CH2
4-BrC6H4CH2
4-NO2C6H4CH2
2-NpCH2
Et
entry
L
metal
base
t (h)
yield (%)b
ee (%)c
5
6
1
2
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L1
L1
L1
Sc(OTf)3
Y(OTf)3
La(OTf)3
Sc(OiPr)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
ꢀ
ꢀ
ꢀ
ꢀ
72
72
72
72
72
72
72
72
72
72
24
15
24
24
21
0
95
ꢀ
7
8
3
0
ꢀ
9
4
0
ꢀ
10
11
12
13e
14
5
K2CO3
Na2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
33
68
85
42
6
95
95
95
95
80
ꢀ
n-Bu
6
allyl
7
propargyl
8
Ph
9
a Unless otherwise noted, reactions were performed with 1:1.2
10
11d
12e
13e,f
0
L1/Sc(OTf)3 (5 mol %), Li2CO3 (10 mol %), 1 (0.1 mmol), and 50.0 μL
90
99
98
45
95
95
95
95
c
of 2a at 20 °C for the indicated times. b Isolated yields. Determined by
chiral HPLC. d The configuration of 4a was determined to be (S,E) by X-ray
crystallographic analysis. The results in parentheses were obtained when the
model reaction was run on a gram scale: 1a (1.03 g, 5.0 mmol) and 2a
(2.50 mL) yielded 4a (1.37 g, 95% yield, 95% ee). e Using 2 mol % catalyst.
14e,g L1
a Unless otherwise noted, reactions were performed with 1:1 L/metal
(10 mol %), base (0 or 10 mol %), 1a (0.1 mmol), and 2a (0.1 mmol) in
CH2Cl2 (0.2 mL) at 20 °C. b Isolated yields. c Determined by chiral HPLC.
d Using 50.0 μL of 2a without CH2Cl2. e Using 50.0 μL of 2a without
CH2Cl2; 1:1.2 L/Sc(OTf)3. f Using 5 mol % catalyst. g Using 2 mol %
catalyst.
moderate reactivity (entries 1ꢀ6). In addition, chroman-4-one
(2h) and thiochroman-4-one (2i) were good candidates and
yielded the products with 98% ee in yields of 75 and 90%,
respectively (entries 7 and 8). Next, other benzo cyclic ketones
were applied in the current system. 1-Indanone (2j) incorporat-
ing a five-membered ring was compatible with this method,
giving a moderate yield with good enantioselectivity (entry 9),
whereas a higher yield (98%) and enantioselectivity (99% ee)
were obtained using 1- benzosuberone (2k) as the nucleophile
(entry 10). Non-benzo cycloalkanones such as cyclohexanone
(2l) and 4-thiacyclohexanone (2m), were used in this process,
giving the enantioenriched products in good yields (entries 11
and 12). Moreover, seven-, eight-, and ten-membered aliphatic
cyclic ketones were tolerated in this transformation, delivering
the corresponding products with modest enantioselectivities,
although cyclooctanone exhibited relatively lower reactivity (entries
13ꢀ15). It should be noted that this strategy could also be extended
to the use of propiophenone (2q), which afforded the desired
product with moderate enantioselectivity and yield (entry 16).
The issue of concern is how the α-diazoester emerges as the
electrophile attacked by the inactive ketone under such mild
conditions. Some control experiments were performed to probe
the mechanism (Scheme 2). Neither the aryldiazonium salt used
in the JappꢀKlingemann reaction nor diphenyldiazomethane
showed reactivity under the current reaction conditions (eq 1 in
Scheme 2). The effect of the ester group of the diazoester was
further investigated. Only a trace amount of product was obtained
when the highly sterically hindered tert-butyl ester instead of the
The enantioselectivity was maintainedevenwhenthecatalystloading
was decreased to 2 mol %, albeit with a loss of reactivity (entry 14).
With the optimized conditions in hand (Table 1, entry 13),
we explored the scope of the reaction. The ester group of the
α-diazoester and the position and electronic nature of the substi-
tuents on the α-benzyl group of the α-diazoester had no obvious
influence on the results (Table 2, entries 1ꢀ8). Also, 2-naphthyl-
methyl-substituted α-diazoester could be employed in this reac-
tion with excellent enantioselectivity and yield (entry 9).
α-Diazoesters bearing an aliphatic side chain were applicable in
the process (entries 10 and 11). Moreover, allyl and alkynyl
groups were well-tolerated in this system (entries 12 and 13).
Notably, the α-aryl-substituted α-diazoester was found to be a
suitable substrate, providing the adduct in 85% yield with 97% ee
after a prolonged reaction time (entry 14). Gram-scale quantities
of α-diazoester 1a (1.03 g, 5.0 mmol) could be used successfully,
yielding the product 4a in 95% yield with 95% ee (values in
parentheses in entry 1).
Subsequently, the broad spectrum of α-alkyl ketones as
nucleophiles was probed (Table 3). Regardless of the positions
and electronic properties of the substituents on the benzene ring
of 1-tetralone derivatives 2bꢀg, excellent yields and ee values
were obtained, except that 6-methoxy-1-tetralone (2c) displayed
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Journal of the American Chemical Society
COMMUNICATION
Table 3. Scope of the Ketone in the Catalytic Asymmetric
Scheme 2. Control Experiments
CꢀN Bond Formationa,b,c
Scheme 3. Natural Bond Orbital Charges of Free 1a and the
1aꢀSc(OTf)3 Complex Computed at the B3LYP/6-31G*
Level
neighboring nitrogen (0.083) (Scheme 3A). However, when
the carbonyl oxygen of the diazoester combines with the strong
Lewis acid Sc(OTf)3, the positive charge on the terminal
nitrogen atom greatly increases (from 0.039 to 0.118) and
exceeds that on the neighboring nitrogen atom (Scheme 3B).
On the contrary, the C-nucleophilicity of the α-diazoester
changes little after the activation (from ꢀ0.104 to ꢀ0.106).
These results indicate that the electrophilicity oftheα-diazoester is
greatly increased through activation of the scandium complex and
thus promotes this unusual reaction.11
In summary, we have described for the first time the electro-
philic capability of α-diazoesters in a unique catalytic asymmetric
CꢀN bond formation reaction via α-hydrazonation of unactive
ketones. Remarkably, in the presence of an N,N0-dioxideꢀ
scandium complex, a wide range of α-diazoesters and ketones
underwent the reaction smoothly, providing the chiral nitrogen-
containing products in excellent yields (up to 98%) and enantio-
selectivities (up to 99% ee) under mild conditions. Preliminary
experiments and theoretical calculations were carried out to
explain the unusual process. Application of the electrophilic
capability of α-diazoesters will open up a novel way to access
the diversity of diazo chemistry. Extension of this work to other
related systems and studies of further reactions of the products,
especially cleavage of the NꢀN bond,12 are currently underway.
a Unless otherwise noted, for substrates 2bꢀ2g, 2j, 2l, and 2m, 1a
(0.1 mmol), 2 (0.2 mmol, 2.0 equiv), 1:1.2 L1/Sc(OTf)3 (5 mol %),
Li2CO3 (10 mol %) and CH2Cl2 (50.0 μL) at 20 °C; for others, 1a (0.1
mmol), 2 (50.0 μL), 1:1.2 L1/Sc(OTf)3 (5ꢀ10 mol %), and Li2CO3
(10 mol %) at 20 °C. b Isolated yields are shown. c The ee's were deter-
mined by chiral HPLC. d Using 10 mol % catalyst.
ethyl ester was used (eq 2 in Scheme 2). These results imply that
the ester group may be necessary for the activation of the
diazoester by coordinating to the Sc catalyst to promote the
reaction. The base Li2CO3 by itself could not initiate the reaction
(eq 3 in Scheme 2), which further confirmed that the activation
of the scandium complex to the substrates was crucial for the
reaction to occur. In view of the much lower nucleophilicity of
ketone 2 than the organolithium reagents used in the previous
work,6 the change of the α-diazoester in the system should be
considered as the key factor for the occurrence of the reaction.
Primary theoretical calculations were also performed to give
useful information for this uncommon reaction. The results
showed that the C2 atom in free α-alkyl-α-diazoester 1a has
strongly negative charge (ꢀ0.104) and that the terminal nitrogen
of the diazo has a less positive charge (0.039) than the
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and ana-
b
lytic data (NMR, HPLC and ESI-HRMS). This material is
available free of charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
xmfeng@scu.edu.cn
’ ACKNOWLEDGMENT
We appreciate the National Natural Science Foundation of
China (Nos. 20732003, and 21021001), and National Basic
Research Program of China (973 Program: No. 2010CB833300)
for financial support. We also thank Sichuan University Analytical &
Testing Center for NMR analysis.
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