Sc(OTf)3-catalyzed transfer diazenylation of 1,3-dicarbonyls with triazenes via N-N bond cleavage

Article abstract of DOI:10.1021/ol5027014

A new and efficient method for diazenylation reactions was developed with a Sc(OTf)₃-catalyzed nitrogen-nitrogen bond cleavage process with triazenes. The transfer diazenylation reactions accommodate a diverse range of active methylene substrat

Full text of DOI:10.1021/ol5027014

Letter
pubs.acs.org/OrgLett
Sc(OTf)3‑Catalyzed Transfer Diazenylation of 1,3-Dicarbonyls with
Triazenes via N−N Bond Cleavage
Cong Liu,†,‡,§ Jian Lv,†,‡ Sanzhong Luo,*,†,‡ and Jin-Pei Cheng†,‡,§
†Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory for Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
§Stake Key Laboratory of Elemento-Organic Chemistry, Department of Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A new and efficient method for diazenylation
reactions was developed with a Sc(OTf)3-catalyzed nitrogen−
nitrogen bond cleavage process with triazenes. The transfer
diazenylation reactions accommodate a diverse range of active
methylene substrates including simple ketones to give aliphatic
azo compounds that are of significant potential as azo prodrugs
in high yields under mild conditions.
zo derivatives are commonly utilized in both laboratories
compounds is particularly challenging due to the lack of
Aand industry as indicators, radical reaction initiators, azo functional group tolerance of most of the available synthetic
procedures as well as the inherent instability of the aliphatic azo
moiety. Recently, aliphatic azo compounds with the general
structures ArNN-alkyl have been developed as prodrugs with
promising antibiotic and anti-inflammatory activity,7 addressing
significant demands for economic and selective synthetic
protocols. Herein, we present a conceptually distinctive azo-
transfer reaction in which an aryl azo moiety can be directly
transferred from aryl triazene and installed chemoselectively
onto aliphatic carbons under rather mild conditions.
Aryl triazenes (ArNNNR1R2), are a class of compounds
with intriguing structural and chemical properties and a long
history dating back to 1875.8,9 Recent pursuit of chemoselective
methodology has sparked new interest in the chemistry of
aryltriazenes. Accordingly, aryltriazenes have been explored as
precursors of phenylium cations or radicals in arylation and
dehydrogenation reactions.10,11 The triazene moiety can also be
utilized as a directing group in C−H functionalization12 as well
as in oxidative indole synthesis13 (Scheme 1, B). Though
typically regarded as masked diazonium ions, aryl triazenes have
seldom been employed in diazenylation reactions. In a single
instance, intramolecular coupling of triazene with alkyne has
been reported to give cinnolines under either thermal14 or Pd-
catalytic conditions.15,16 Intermolecular azo-transfer with aryl
triazenes has surprisingly not been reported so far.
ligands of metal complexes, dyes and pigments, therapeutic
agents, modern material sciences, and food additives.1,2
Reflecting on the development of azo syntheses, classic and
general methods in the formation of nitrogen−nitrogen double
bonds include electrophilic azo coupling reactions of diazonium
salts, Mills coupling of anilines with aromatic nitroso and nitro
compounds, and Wallach rearrangements of azoxy derivatives.3
Recent advances in the synthesis of azo compounds mainly
involve catalytic reductive aromatic nitro derivatives,4 oxidation
of anilines,5 as well as dehydrogenation of arylhydrazines6
(Scheme 1, A). Development of a chemoselective diazenylation
strategy is still in high demand in order to address remaining
issues such as excess use of explosive diazonium salts, harsh
reaction conditions, and invariably accompanying oxidant or
reductant waste. In this regard, the synthesis of aliphatic azo
Scheme 1. Synthetic Strategies for Azo Derivatives
Initially, we sought to develop an asymmetric α-arylation
reaction using aryl triazenes as phenyl precursors under
enamine catalysis; however, no α-arylation product was
detected in our initial experiments with our previously
developed chiral primary amines.17 Instead, we found Lewis
acid Sc(OTf)3 can promote transfer diazenylation with aryl
Received: September 12, 2014
Published: October 8, 2014
© 2014 American Chemical Society
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Letter
triazene via efficient N−N cleavage, which enables chemo-
selective aryl diazenylation of β-dicarbonyls beyond the reach
otherwise18 (Scheme 1, B), and this diazenylation reaction was
hence further explored.
Our investigation began with the phenyl diazenylation of 2-
methyl acetoacetate 1a, and the representative results are
summarized in Table 1. To our gratification, we found that
system (Table 1, entry 18, 85% yield over 24 h). It was
noteworthy that, in the absence of Sc(OTf)3, almost no
diazenylation product 3a was obtained (Table 1, entry 19).
Therefore, it can be concluded that the optimized reaction
should be performed under the catalysis of 10 mol % of
Sc(OTf)3 in the presence of 1.0 equiv of TMSCl in CH2Cl2.
The substrate scope with 1,3-dicarbonyls was next explored
(Scheme 2). The diazenylation all occurred at the α-position as
Table 1. Optimization for Phenyl Diazenylation Reaction of
2-Methyl Acetoacetate
a
Scheme 2. Scope of Intermolecular Diazenylation of Active
Methylene Compounds and Triazophenyl Reagent
a,b
b
time
(h)
yield
(%)
entry
Lewis acid
Sc(OTf)3
reagent
solvent
1
2
3
4
5
2a
2b
2c
2d
2e
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOH
48
48
48
48
24
48
48
48
48
48
3
75
Sc(OTf)3
48
Sc(OTf)3
66
Sc(OTf)3
69
Sc(OTf)3
N.D.
trace
N.D.
39
c
6
Sc(OTf)3
c
7
Sc(OTf)3
DMSO
CH3CN
hexane
ether
c
8
Sc(OTf)3
d
9
Sc(OTf)3
43
10
Sc(OTf)3
69
e
11
BF3·Et2O (2 equiv)
FeCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
31
12
13
14
15
16
48
48
48
48
48
24
24
24
46
Bi(OTf)3
32
CuBr2
N. D.
72
Hf(OTf)4
Sc(OTf)3 (10 mol %)
Sc(OTf)3 (10 mol %)
Sc(OTf)3 (10 mol %)
none
50
f
17
54
g
,
,
h
h
18
19
85
g
<10
a
General conditions: 1a (0.1 mmol), 2 (0.1 mmol), and Lewis acid
b
(20 mol %) at 40 °C in the solvent (0.4 mL) under Ar. Isolated yield.
c
d
e
f
80 °C. 60 °C. At room temperature. CH3COCl (0.1 mmol) as the
g
h
additive. TMSCl (0.1 mmol) as the additive. 1a (0.12 mmol). N.D.
= no product was observed by TLC.
a
Lewis acids were viable catalysts for the diazenylation reactions.
Among various Lewis acids screened (Table 1, entries 1 and
11−15), Sc(OTf)3 was eventually identified as an optimal
Lewis acid for this reaction (Table 1, entry 1). The expected
diazenylation adduct (3a) can be obtained in 75% yield. The
nature of the terminal tertiary amine substituent of triazenes
was then tested, with similar results for methyl, isopropyl,
benzyl, and cyclic morpholine groups (Table 1, entries 2−4).
Surprisingly, the use of the common diazonium salt 2e led to
no desired product (Table 1, entry 5), highlighting the
chemoselective nature of aryl triazenes. Solvent effects have
also been examined, and the reactions were found to work
poorly in other solvents such as EtOH, DMSO, CH3CN,
hexane, and ether (Table 1, entries 6−10). The choice of acidic
additives significantly influenced the yield (Table 1, entries 16−
18), especially to those inert and bulky substrates, with TMSCl
proving to be the optimal reaction additive, presumably due to
the capture of the liberating diisopropylamine in the catalytic
General conditions: 1 (0.12 mmol), 2 (0.1 mmol), TMSCl (0.1
mmol), and Sc(OTf)3 (10 mol %) at 40 °C in the CH2Cl2 (0.4 mL)
b
c
d
under Ar. Isolated yield. 2 equiv of 1 and 2 equiv of TMSCl.
equiv of ketone in 80 °C.
3
expected. The C−N bond formation proceeded in consistently
high yield for many acetoacetate derivatives in which the ester
moiety (R3) ranges in size from the ethyl group to the steric
adamantyl group (3a−e). The reaction also worked on a larger
scale (2 mmol) with comparable 79% yield (3a). The influence
of R1 and R2 groups of 1,3-dicarbonyls was also investigated.
With ethyl ketone (R1 = Et) and phenyl ketone (R1 = Ph), the
corresponding products 3f and 3g were obtained in excellent
yield. When unsubstituted ethyl benzoylacetate 1h was used as
the reactant, the product was isolated in 95% yield as a major
keto isomer (keto/enol ≈ 7:1). The cyclic 1,3-ketoester methyl
2-carboxylate indanone (1j) and tetralone (1k) also proceeded
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Letter
well, giving the products in moderate yields. Pleasingly,
propargyl (1i) and heterocyclic (1l) substituents were well-
tolerated to give the desired adducts in 88% and 75% yields,
respectively. β-Diketones possess a more acidic C−H bond and
a higher enol/keto- ratio than β-keto esters,19 and this type of
substrate worked extremely well to give the diazenylation
adducts in 94% and 91% yield (3m and 3n). Moreover, a
variety of active methylene compounds, such as the substituted
malonic ester (1o), ethyl cyanacetate (1p), β-keto amide (1q),
β-keto phosphonate (1r), and α-(phenylsulfonyl)acetophenone
(1s), were well compatible with the reaction conditions. In
particular, the reaction also worked for aryl ketones such as
propiophenone 1t, furnishing the α-azo adduct in 40% yield.
Other simple ketones such as cyclohexanone and 3-pentanone
have also been examined in the reactions, showing unfortu-
nately rather poor reactivity, likely a result of their low α-
acidity.
the silyl enol ether of an alkenyl β-keto ester might exist in view
of the effect to enhance the equilibrium of the enol/keto ratio,
since its generation in situ from the reaction of an alkenyl β-
keto ester and a silyl chloride has been well demonstrated.20
The reaction is initialize via the coordination of the pendent
triazene reagent to Sc(OTf)3 on the nitrogen−nitrogen double
bond. The marked affinity of the trimethylsilyl group toward
terminal nitrogen lone pair and the weak nucleophilic nature of
chloride ions restrain the nucleophilic attack to furnish aryl
halides in the present of TMSCl.21 Afterward, conjugate
addition of the active β-keto ester and triazene compound via
the intermediate III15,22 occurs to generate the desired product
and HN(i-Pr)2, and the latter might be trapped by TMSCl or
HCl to enhance the catalytic turnovers.
Taking the requirement for β-keto ester activation using
Lewis acids into consideration, we hypothesized that the unique
binary acid system developed by our group23 might catalyze
this new and enantioselective C−N bond formation. Indeed, we
discovered that the desired aromatic azo compound was
obtained in 57% yield and 24% ee in Sc(OTf)3/polyfluoro
chiral phosphoric acid without further optimizations (Scheme
5).
Furthermore, the scope of aromatic triazo reagents has also
been examined (Scheme 3). The phenyl ring moiety can be
Scheme 3. Scope of Intermolecular Diazenylation of β-
a,b
Diketones and Aromatic Triazenes
Scheme 5. Initial Attempt on a Catalytic Asymmetric
a
Version
a
General conditions: 1m (0.1 mmol), 2 (0.2 mmol), TMSCl (0.2
mmol), and Sc(OTf)3 (10 mol %) at 40 °C in the CH2Cl2 (0.4 mL)
a
The reaction was conducted on 0.05 mmol scale in 0.4 mL of CH2Cl2
b
at 40 °C under Ar.
under Ar. Isolated yield.
ortho-, meta-, or para-substituted, which can bear an electron-
donating or an electron-withdrawing group, including a halide
or ester group. The desired aromatic azo products can be
obtained in generally good yields.
In light of the above results and previous reports, a plausible
mechanism is described in Scheme 4. The β-ketoester is
activated usually through coordination to the Sc(III) center in a
bidentate fashion by both of the carbonyl groups. Meanwhile,
In summary, we have developed a Sc(OTf)3-catalyzed
diazenylation reaction of active methylene compounds with
triazenes via N−N cleavage. This simple transfer diazenylation
method was shown to tolerate a range of substrates to afford
aliphatic azo compounds that are beyond reach with other
methods. Further studies are currently underway to develop a
catalytic asymmetric version.
ASSOCIATED CONTENT
* Supporting Information
■
Scheme 4. Proposed Mechanism
S
1
Experimental procedures, characterization data, and H NMR,
13C NMR, and HPLC spectra for new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: luosz@iccas.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of China (21390400,
21025208, 21202170, and 21472193) and the National Basic
Research Program of China (2012CB821600) for financial
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Organic Letters
Letter
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