Rhodium(III)-catalyzed N-nitroso-directed C-H addition to ethyl 2-oxoacetate for cycloaddition/fragmentation synthesis of indazoles

Article abstract of DOI:10.1002/chem.201404506

RhI^II-catalyzed N-nitroso-directed C-H addition to ethyl 2-oxoacetate allows subsequent construction of indazoles, a privileged heterocycle scaffold in synthetic chemistry, through the exploitation of reactivity between the directing group and installed group. The formal [2+2] cycloaddition/fragmentation reaction pathway identified herein, a unique reactivity pattern hitherto elusive for the N-nitroso group, emphasizes the importance of forward reactivity analysis in the development of useful C-H functionalization-based synthetic tools. The synthetic utility of the protocol is demonstrated with the synthesis of a tri-cyclic-fused ring system. The diversity of covalent linkages available for the nitroso group should enable the extension of the genre of reactivity reported herein to the synthesis of other types of heterocycles.

Full text of DOI:10.1002/chem.201404506

DOI: 10.1002/chem.201404506
Communication
&
Organic Chemistry
Rhodium(III)-Catalyzed N-Nitroso-Directed CÀH Addition to Ethyl
2-Oxoacetate for Cycloaddition/Fragmentation Synthesis of
Indazoles
Jinsen Chen, Pei Chen, Chao Song, and Jin Zhu*[a]
skeleton generation approach comes at the price of limited
Abstract: RhIII-catalyzed N-nitroso-directed CÀH addition
available experimental parameter space and therefore dimin-
to ethyl 2-oxoacetate allows subsequent construction of
indazoles, a privileged heterocycle scaffold in synthetic
chemistry, through the exploitation of reactivity between
the directing group and installed group. The formal [2+2]
cycloaddition/fragmentation reaction pathway identified
herein, a unique reactivity pattern hitherto elusive for the
N-nitroso group, emphasizes the importance of forward
reactivity analysis in the development of useful CÀH func-
tionalization-based synthetic tools. The synthetic utility of
the protocol is demonstrated with the synthesis of a tri-
cyclic-fused ring system. The diversity of covalent linkages
available for the nitroso group should enable the exten-
sion of the genre of reactivity reported herein to the syn-
thesis of other types of heterocycles.
ished chance for success because of the requirement for the
robustness of catalytic species under subsequent cyclization
conditions.
We are interested in the creation of distinct molecular skele-
tons after the CÀH functionalization step. In particular, we an-
ticipate that such a directed intermolecular CÀH functionaliza-
tion for the intramolecular cyclization strategy allows for the
exploration of synergy between a directing group and an in-
stalled group at an expanded experimental parameter space
and should therefore increase the likelihood of discovering
new reactivity patterns. Intramolecular cyclization has been
routinely used for the construction of heterocycles (e.g.,
indole)[5] but frequently involves cumbersome preassembly of
substrate frameworks. The CÀH functionalization-based strat-
egy offers a handy tool for expeditious heterocycle synthesis,
and forward reactivity analysis[6] is essential to the success of
this integrated approach.
Transition-metal-catalyzed CÀH functionalization represents
a promising strategy for expediting the synthesis of sophisti-
cated chemical architectures. The functionalization typically
relies on a directing group for the streamlining of a target re-
action course.[1,2] Indeed, an effective directing group can pro-
vide proximity-driven high reactivity and selectivity. However,
a high-efficiency reaction does not automatically translate to
a synthetically useful tool. An equally important requirement is
the ability to elaborate the directing groups and/or installed
groups into desired functionalities. In this regard, transform-
able groups have been vigorously pursued for the improve-
ment of versatility and practicality of CÀH functionalization re-
actions.[3,4] The majority of transformations reported thus far
are individually targeted at either the directing groups or in-
stalled groups for the generation of distinct appendages.[3] The
creation of distinct molecular skeletons is synthetically more
demanding and typically proceeds at the CÀH functionalization
stage.[4] The convenience of such a cascade reaction-based
We have recently launched a program on the utilization of
nitroso (C-, N-, O-, or S-linked) groups for directed CÀH func-
tionalization.[7] The initially explored N-nitroso group system
proves to be effective for CÀC and CÀN couplings. The ach-
ievement of CÀN coupling is exclusively built upon the reactiv-
ity of the NÀN bond. The creation of a distinct molecular skele-
ton mandates the identification of a distinct path of reactivity
between the N-nitroso group and installed group. In line with
this, we have decided to explore the N=O bond as a synthetic
handle, inspired by a previously documented [2+2] cycloaddi-
tion of a C-nitroso group and ketene.[8] Described herein is
a RhIII-catalyzed N-nitroso-directed CÀH addition to ethyl
2-oxoacetate for the synthesis of 3-hydroxyindazoles, a privi-
leged heterocycle scaffold in synthetic chemistry.[9] Significant-
ly, 3-hydroxyindazoles are generated through a formal intramo-
lecular [2+2] cycloaddition/fragmentation pathway, a hitherto
synthetically elusive reactivity pattern for the N-nitroso
group.[10]
Reaction development was initiated with the screening of
experimental conditions for the achievement of N-nitroso-
directed CÀH addition (with N-methyl-N-nitrosoaniline, 1a, as
the model substrate) to the aldehyde carbonyl group of ethyl
2-oxoacetate (2). Although directing group (e.g., pyridinyl, qui-
nolinyl, oxime, azo, amide, carboxyl) approaches have recently
been demonstrated for such a transformation,[11] they suffer
from the requirement to use a harsh reaction conditions (e.g.,
high reaction temperature), a synthetically restrictive directing
[a] Dr. J. Chen, P. Chen, C. Song, Prof. Dr. J. Zhu
Department of Polymer Science and Engineering
School of Chemistry and Chemical Engineering
State Key Laboratory of Coordination Chemistry
Nanjing National Laboratory of Microstructures
Nanjing University, Nanjing 210093 (P. R. China)
E-mail: jinz@nju.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404506.
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group, or a pre-purified cationic metal catalyst. Our transform-
able N-nitroso group enables RhIII-catalyzed synthesis of target
molecule 3a in 96% isolated yield at 508C. An optimal catalyt-
ic system includes 2.5 mol% [RhCl2Cp*]2/10 mol% (Cp*=
1,2,3,4,5-pentamethylcyclopentadienyl) AgSbF6 as the catalyst
precursor, 10 mol% NaOAc as the base and proton shuttle,
and dichloroethane as the solvent. The reaction can be scaled
up to 10 mmol (~2.5 g 3a) level without sacrificing the prod-
uct yield.
group (1p). For
a
meta-substituted N-nitrosoaniline, the
degree of regioselectivity is governed by the substituent
(1q–u). The reaction proceeds in a regiocontrolled manner for
the two examined disubstituted N-nitrosoanilines (1v, 1w);
however, a diverged site selectivity is displayed. The critical di-
recting role of N-nitroso group is demonstrated by the ab-
sence of reaction between N-methylaniline and 2.
Mechanistic experiments indicate the intermediacy of a five-
membered rhodacycle[7] in the catalytic cycle and CÀH activa-
tion as the turnover-limiting step (kinetic isotope effect value
of 2.0). A catalytic mechanism involving N-nitroso-directed
electrophilic CÀH activation/ortho-rhodation (with the assis-
tance of OAcÀ), migratory insertion of the aldehyde carbonyl
group, and proto-demetalation for product release and catalyst
turnover, is therefore proposed.
An investigation of the reactivity of N-nitrosoaniline deriva-
tives identifies exclusive N-nitroso-directed ortho selectivity
and compatibility of a broad range of substitution patterns
(1a–w, Table 1). The existence of syn and anti isomers[7] in the
CÀH functionalization products reported herein due to thermo-
dynamically restricted NÀN bond rotation does not affect their
synthetic utility because further elaboration of the transform-
able N-nitroso group is typically mandated and allows for the
generation of identical synthetic targets. The yield is observed
to be inversely correlated with the steric bulkiness of the N-
substituent (1a–d). The ortho-substituted N-nitrosoanilines
(1e–i) generally exhibit a lower reactivity than the para-substi-
tuted counterparts (1j, 1l–o). The reaction is favored for an
electron-donating group (1j, 1l) over an electron-withdrawing
With CÀH functionalization products 3a–w in hand, we then
set out to explore the N=O bond as a synthetic handle for the
creation of a heterocycle scaffold. The [2+2] cycloaddition re-
activity of the C-nitroso N=O bond toward the ketene,[8] cou-
pled with ketene generation from an a proton-bearing ester[12]
and remarkable stability of NÀN bond[10] under basic condi-
tions, highlights a hypothetically viable mechanistic course.
The use of tBuOK (2 equiv) in dichloromethane proved effec-
tive in delivering 1-methyl-1H-indazol-3-ol (4a, as confirmed by
single-crystal analysis, Table 2) from 3a at RT, through a formal
[2+2] cycloaddition/fragmentation process. The synthetic po-
tential of such a distinct enabling methodology is illustrated
by a broad substrate scope (3a–w, Table 2), regardless of ste-
rics and electronics. This represents a significant advantage
over previously documented methodologies that involve either
the preinstallation of synthetically demanding groups (e.g.,
halogens)[9b–h] or imposition of undesired auxiliaries (aryl sub-
stituents at N2)[9i,11a] on the products.
Table 1. Substrate scope for RhIII-catalyzed N-nitroso-directed CÀH addi-
tion to ethyl 2-oxoacetate.[a,b]
Initial attempted 1H NMR spectroscopic characterization of
the 3a to 4a reaction course directly under basic conditions
provides no informative signals, as a result of the low solubility
of ionic species involved in the transformation. Acidification
with HOAc (with inevitable presence of adventitious H2O), a re-
agent that 3a does not react with (Scheme 1, middle left, top
panel), allows the conversion process to be monitored
(Scheme 1, top panel) and, together with other pertinent ob-
servations, suggests a ketene as a key intermediate for the
[2+2] cycloaddition/fragmentation process: 1) the transforma-
tion features a fast detachment of the EtOÀ fragment from de-
1
protonated 3a (no H NMR spectroscopic signals observed for
3a after merely 20 min; detachment of EtOÀ, as confirmed by
1
a change in the H NMR spectroscopic chemical shift and split-
ting pattern of its methylene protons), presumably to generate
ketene 3a-K (as revealed by the observation of its nucleophilic
addition-afforded hydration product,[12a] 3a-det), and a slow
conversion of 3a-K to 3a-CA-FO (decrease of 3a-det and in-
crease of 4a with the elapse of time, but with their combined
amount approximately constant and equivalent to that of EtOÀ
(Scheme 1, bottom left, top panel); consistent with the initial
production of 3a-K and EtOÀ and subsequent exclusive trans-
formation of 3a-K to 3a-CA-FO). 2) Only a trace amount of 4a
can be generated from 3a-det (ruling out hydrolyzed species,
[a] Reaction conditions: N-nitrosamine 1a–w (0.4 mmol), ethyl 2-oxoace-
tate 2 (0.8 mmol), dichloroethane (DCE; 2 mL). [b] Isolated yields. [c] Iso-
mers due to restricted NÀN bond rotation; syn: N-alkyl (except for 3d, N-
phenyl) cis to nitroso oxygen atom; anti: N-alkyl (except for 3d, N-
phenyl) trans to the nitroso oxygen atom. [d] Further splitting of NMR
spectroscopic signals observed for anti-like isomers due to, presumably,
additional restricted bond rotation. [e] syn isomer.
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Table 2. Substrate scope for the synthesis of 3-hydroxyindazoles.[a,b]
Scheme 1. Evidence for ketene as a reactive intermediate and entrapment
of ring fragmentation to afford the side product CO2.
[a] Reaction conditions: 3a–w (0.2 mmol), tBuOK (0.4 mmol), dichloro-
ethane (2 mL), HOAC (0.2 mL). [b] Isolated yields. [c] CCDC-1015964 (ther-
mal ellipsoid plot drawn at the 30% probability level and hydrogen
atoms omitted for clarity) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
if any, due to the presence of adventitious water, as a viable
participant in the transformation) (Scheme 1, middle left
panel). 3) Alkoxy enediolate,[13] 3a-AED, is unlikely to be
a direct participant in the [2+2] cycloaddition (from orbital
symmetry, sterics, and electronics perspectives)[12a] and indeed,
no cycloaddition reactivity has been documented for such
a type of species (Scheme 1, middle right panel).
Scheme 2. Proposed formal [2+2] cycloaddition/fragmentation mechanism.
The following mechanism can therefore be envisioned for
the transformation (Scheme 2): double deprotonation of 3a
(consistent with the optimal condition, 2 equiv of tBuOK) to
afford alkoxy enediolate (3a-AED),[13] elimination of EtOÀ to
generate ketene (3a-K), intramolecular cycloaddition of ketene
and N=O bond with the formation of 3a-CA (rate-determining
tween EtOCO2K and HOAc)[17] (as probed by gas chromatogra-
phy, or GC, mass spectrometry, or MS, and bromothymol blue
test (Scheme 1, bottom right panel).
A salient feature of the cycloaddition/fragmentation mecha-
nism formulated above is predicted nucleophilic reactivity for
N2 driven by the ring fragmentation. In corroboration of this
proposal, MeI can serve as an electrophilic trap and furnishes
an N2-methylated product. Significantly, this represents an um-
polung reactivity as compared to the original nitroso nitrogen
atom[10] and this reactivity is not experimentally observed for
4a under the tBuOK conditions employed herein.
1
step, as indicated by the lack of cyclic adduct by H NMR spec-
trosopy, vide supra), ring-strain-release fragmentation[8,12a,14,15]
furnishing 3a-CA-FN/3a-CA-FO (as a resonance-stabilized spe-
cies) with the concomitant loss of CO2 (CO2 entrapped by
EtOÀ, with EtOCO2K as the product, as characterized by
13C NMR spectroscopy (Scheme 1, bottom left panel)).[16] The
entrapment of CO2 is also evidenced by the absence of CO2 in
the gas phase of the reaction mixture, and its appearance
upon the addition of HOAc (release of CO2 by the reaction be-
The synthetic utility of the CÀH functionalization based pro-
tocol developed herein is demonstrated on the synthesis of
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Scheme 3. Synthesis of a tricyclic fused ring system. Reaction conditions:
i) ref. [18a], 1-iodo-4-methylbenzene (1 mmol), 4-aminobutan-1-ol
(1.5 mmol), CuI (0.05 mmol) Cs2CO3 (2 mmol), 2-isobutyrylcyclohexanone
(0.2 mmol), DMF (0.5 mmol), RT, 16 h; 99%; ii) t1 (0.025 mmol), NaNO2
(0.025 mmol), HCl (conc., 3.7 mL, 0.12 mol), ice (10 g), 08C, 2 h; 96%; iii) t2
(0.4 mmol), ethyl 2-oxoacetate (0.8 mmol), [RuCl2Cp*] (0.01 mmol), AgSbF6
(0.04 mmol), NaOAc (0.04 mmol), dichloroethane (2 mL), 508C, 24 h; 88%;
iv) t3 (0.4 mmol), tBuOK (1.2 mmol), dichloromethane (2 mL), RT, 18 h,
workup with HOAc (0.4 mL); 32%; v) ref. [18a], t3 (1.56 mmol), CBr4
(1.72 mmol), PPh3 (1.72 mmol), dichloromethane (6 mL), RT, 6 h; 77%; vi) t5
(1 mmol), tBuOK (2 mmol) THF (6 mL), 608C, 4 h; 25%.
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a tricyclic fused ring system (Scheme 3), a natural product ana-
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to t6) stages and features a one-step generation of two rings
through a cascade sequence (t5 to t6).
In summary, a directed intermolecular CÀH functionalization
for intramolecular cycloaddition/fragmentation synthesis of
heterocycle strategy has been developed. RhIII-catalyzed
N-nitroso-directed CÀH addition to ethyl 2-oxoacetate has en-
abled access to indazoles through the exploitation of a distinct
path of reactivity between the directing group and installed
group. The unique reaction pathway identified herein empha-
sizes forward reactivity analysis as an essential guide to the
CÀH functionalization-based synthetic strategy. Given the di-
versity of covalent linkages available for the nitroso group, we
anticipate that this genre of reactivity can be extended to the
synthesis of other types of heterocycles.
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Keywords: CÀH
functionalization
·
cycloaddition/
fragmentation · directing groups · installed groups · rhodium
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Received: July 22, 2014
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Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Organic Chemistry
J. Chen, P. Chen, C. Song, J. Zhu*
&& – &&
Go cyclo! Herein RhIII-catalyzed N-ni-
troso-directed CÀH addition to ethyl 2-
oxoacetate for the formal [2+2] cyclo-
addition/fragmentation synthesis of in-
dazoles is reported (see scheme;
dienyl). The unique reactivity pattern
identified herein emphasizes the impor-
tance of forward reactivity analysis in
the development of useful CÀH func-
tionalization-based synthetic tools.
Rhodium(III)-Catalyzed N-Nitroso-
Directed CÀH Addition to Ethyl 2-
Oxoacetate for Cycloaddition/
Fragmentation Synthesis of Indazoles
Cp*=1,2,3,4,5-pentamethylcyclopenta-
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!