A Versatile, Traceless C-H Activation-Based Approach for the Synthesis of Heterocycles

Article abstract of DOI:10.1021/acs.orglett.6b00949

A versatile, traceless C-H activation-based approach for the synthesis of diversified heterocycles is reported. Rh(III)-catalyzed, N-amino-directed C-H alkenylation generates either olefination products or indoles (in situ annulation) in an atom- and step-economic manner at room temperature. The remarkable reactivity endowed by this directing group enables scale-up of the reaction to a 10 g scale at a very low catalyst loading (0.01 mol %/0.1 mol %). Ex situ annulation of olefination product provides entry into an array of heterocycles.

Full text of DOI:10.1021/acs.orglett.6b00949

Letter
pubs.acs.org/OrgLett
A Versatile, Traceless C−H Activation-Based Approach for the
Synthesis of Heterocycles
Shuguang Zhou, Jinhu Wang, Feifei Zhang, Chao Song, and Jin 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, China
S
* Supporting Information
ABSTRACT: A versatile, traceless C−H activation-based approach
for the synthesis of diversified heterocycles is reported. Rh(III)-
catalyzed, N-amino-directed C−H alkenylation generates either
olefination products or indoles (in situ annulation) in an atom- and
step-economic manner at room temperature. The remarkable
reactivity endowed by this directing group enables scale-up of the
reaction to a 10 g scale at a very low catalyst loading (0.01 mol %/0.1
mol %). Ex situ annulation of olefination product provides entry into
an array of heterocycles.
ransition-metal-catalyzed C−H activation (CHA) has
We expected that the high lability would allow the exposure
of the reactive linkage for both ex situ and in situ annulation. In
particular, we disclose herein diversified heterocycle synthesis
based on an initial Rh(III)-catalyzed C−H alkenylation process,
with alkene (bearing an ester group) and alkyne as the coupling
partner (Scheme 1). The N-amino group exhibits a remarkable
directing reactivity at a very low catalyst loading (0.01 mol
%/0.1 mol %). In addition, the alkenylation step features a mild
reaction condition (room temperature), atom economy
(release of a small fragment), step economy (internal
oxidation), and functional group tolerance. The alkenylated
scaffold contains plentiful reactive sites9 on the CHA-installed
T
emerged as an important synthetic tool for the
construction of heterocycles.1 The key annulation step, which
involves the participation of directing group (with reaction at
either the linkage unit site2 or directing unit site3) and CHA-
installed structure, can proceed only through the matching of
reactivity. Depending on the reactivity profiles of annulation
partners, two distinct synthetic manifolds can be envisioned, in
situ annulation (either on-cycle4 or off-cycle,5 one-pot) and ex
situ annulation (off-cycle, stepwise6). The in situ method
provides a facile step-economic way of generating a target
product, but its associated efficiency and convenience come at
the cost of limited structural diversity under CHA-compatible
conditions. Indeed, the original reactive sites are typically all
sequestered into a single type of molecular framework. The ex
situ method takes advantage of separate steps for annulation,
thus allowing the potential of reactive sites to be fully harnessed
and generation of diversified frameworks. Despite the appealing
features associated with ex situ annulation, virtually all
documented heterocycle synthesis protocols6 thus far require
additional synthetic manipulation, generally in an ad hoc
fashion, to expose the reactive sites for annulation. Herein, we
report on a versatile, traceless CHA-based approach for both ex
situ and in situ synthesis of heterocycles.
Scheme 1. Schematic of CHA-Based, ex Situ, and in Situ
Synthesis of Heterocycles
We have recently launched a CHA synthetic program by
using a labile N−N bond-containing functionality as the
directing group.7 A traceless, in situ synthesis of the indole
framework has been achieved with the N-nitroso group. In the
search for a more labile N−N bond (lowered lability in the N-
nitroso group because of partial double bond character), we
have turned our attention to the N-amino, or hydrazine, group
(a N-alkyl group as the reactive linkage and substituent-free
amino group as the directing unit, which is different from
previous systems that rely on an amide bond for the increase of
proton acidity on the amino group8) in view of the weak nature
of this single bond.
Received: April 2, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00949
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Letter
structure (Scheme 1: sites 1, 2, 3) for annulation with the
reactive linkage (ex situ for sites 1, 2, 3 with an olefin, in situ for
site 2 with an alkyne). The ex situ annulation is enabled by
either polarity relay (PORE), through the participation of an
additional coupling partner, or configuration inversion
(CONIN) at the original CC bond (from trans to cis).
The in situ annulation occurs through an on-cycle annulation
and N−N bond cleavage process.
We commenced our investigation by screening experimental
conditions for N-amino-directed C−H olefination reactions.
Arylhydrazine substrate 1a and alkene substrate 2a were used as
the model reactants, and [RhCp*Cl2]2/4AgSbF6 was used as
the catalyst precursor. A variety of conditions can lead to the
traceless synthesis of 3a. The basic conditions are not as ideal as
acidic conditions, and with the replacement of KOAc by HOAc
as the proton shuttle, an improvement in yield from <60% to
89% was observed. Importantly, room temperature proves to be
suitable for the transformation. The standard reaction system
includes 2 mol % [RhCp*Cl2]2, 8 mol % AgSbF6, 1.2 equiv of
HOAc, and MeOH as the solvent. An external oxidant is not
necessary for the reaction. In fact, the addition of AgOAc
resulted in the generation of undesired side products and a
substantially lowered yield (20%). This example nicely
illustrates the advantage of using an internal oxidant system
for C−H functionalization.
electron-withdrawing CN (1k) and COOMe (1l) groups. The
reaction is high-yielding for meta substitution (Me, 1m;
halogen, 1n, 1o), but the regioselectivity was observed only
for 1m. This is most likely caused by the steric effect. We next
examined the olefin scope using 1a as the coupling partner.
Olefins bearing an electron-withdrawing group can participate
in the reaction effectively. The yield is not negatively impacted
by the variation of substituent on ester from Me (2a) to a
bulkier group (Et, 2p; Bu, 2q, 2r; (CH2)2OMe, 2s). A change
from the ester group to either CN (2t) or PO(OMe)2 (2u)
leads to a slightly diminished yield. In addition, styrene (2v)
and p-methoxystyrene (2w) are appropriate substrates. The
reaction with unactivated olefins (1-octene) yielded virtually no
product under current standard conditions.
The remarkable reactivity offered by the N-amino directing
group is demonstrated by the ability to scale-up the reaction to
10 g scale (Scheme 3) at a very low catalyst loading (0.01 mol
%/0.1 mol %).
Scheme 3. Gram-Scale Olefination Reaction at a Very Low
Catalyst Loading
The scope of the reaction was then examined under standard
reaction conditions. Substitution patterns on arylhydrazine
were systematically altered to test the reaction outcome, with
2a as the coupling partner (Scheme 2). The reaction proceeds
efficiently for a substrate bearing either an N-Et (1b) or a cyclic
N-alkyl substituent (1e). Both electron-rich (Me, 1c, 1f; OMe,
1g) and electron-poor (halogen, 1d, 1h, 1i, 1j) groups at a
variety of ortho and para positions of arylhydrazines are
tolerated. Especially notable is the compatibility of highly
With olefination products in hand, we next performed
heterocycle synthesis using 3a as the model substrate. Analysis
of the functional groups reveals the matching of polarity and
therefore reactivity. The amino group is nucleophilic (NP), and
C atoms next to the phenyl ring and on the ester group are
both electrophilic (EP), but the reactions between polarity-
matched centers are energetically disfavored under CHA
conditions because of the requirement for either the formation
of a four-membered ring or a change from the trans to cis
configuration. With the use of CS2, EtO2CCH2COCl, and
PhNCS10 as the PORE reagents, six-membered rings can be
formed through an NP−EP−NP−EP system, thus leading to
the synthesis of 6, 7, and 8 (Scheme 4). A trans to cis change of
the configuration can be effected by a suitable CONIN
a b c
, ,
Scheme 2. Synthetic Scope of Olefination Reaction
Scheme 4. Ex Situ Formation of Heterocycles
a
a
b
c
Conditions: arylhydrazine (0.5 mmol), alkene (1.5 equiv), MeOH (2
1,4-Diazabicyclo[2.2.2]octane. Ethyl malonyl chloride. Ethylene
d
b
c
mL). Isolated yields. Reaction time: 12 h.
glycol. Tosylmethyl isocyanide.
B
DOI: 10.1021/acs.orglett.6b00949
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condition or reagent. An elevated temperature can directly
facilitate such a change. Also, Michael addition at the CC
double bond can lead to the temporary formation of a single
bond, its subsequent free rotation, and further fixing of
configuration with the formation of a ring structure. Indeed,
under these two CONIN conditions,11 ester−amide exchange
allows the formation of six-membered rings, furnishing 9 and
10 as the products.
We then examined if the standard reaction conditions for
alkenes could be applied to the alkyne settings. Satisfactorily,
the reaction proceeds equally well and provides indole
derivatives in a traceless fashion (Scheme 5). Tolerance of a
substantially different environment (amide-like and imine-like,
respectively) as compared to our N-amino group system. The
substituent-free structural environment for our coordination N
atom translates to a superior reactivity for the C−H
functionalization reactions reported herein (Scheme 1).
Taken together, the combination of so many desired features
in a single transition-metal-catalyzed directed C−H function-
alization system (Scheme 1) should be able to instill confidence
in the organic community that CHA is not only an academic
curiosity but also a synthetically useful tool.
The high efficiency of the alkenylation reaction prompted us
to investigate the reaction mechanism. A competition experi-
ment revealed preferred conversion for a substrate bearing an
electron-donating group. A kinetic isotope effect of 2.85 was
observed using a parallel reaction method. These data suggest
an electrophilic, rate-limiting CHA step.
a b c
, ,
Scheme 5. In Situ Formation of Indoles
Thus, far, no five-membered rhodacycle has been isolated
relevant to a substituent-free amino group-directed CHA
process. We were able to obtain two such complexes (1a-Rh-
1
Cl and 1l-Rh-Cl) and characterize their structures with H
NMR, 13C NMR, HRMS, elemental analysis, and X-ray single
crystal diffraction (Scheme 7). Important structural features are
Scheme 7. Olefination and Indole Synthesis Catalyzed by a
Rhodacycle
the substantial shortening of the original N−N bond (bond
length: 126 and 128 pm, respectively; the elasticity of the N−N
bond is due to, most likely, its weak bond strength) and
coplanarity of five atoms comprising the rhodacycle. These
complexes, when activated with AgSbF6, could not only react
stoichiometrically with 2a and 4a but also catalyze the reactions
between 1a, 1l and 2a, 4a, to generate the desired products 3a,
3l, 5a, and 5l. These observations are consistent with the
intermediacy of a five-membered rhodacycle in the catalytic
cycle.
The reaction system was further probed by the identification
of a side product. A 15N-labeled substrate (1a-15N) was allowed
to react with either 2a or 4a, respectively, and in both cases, a
single, clean 15N NMR signal consistent with the formation of a
15NH4OAc (with commercially available 15NH4OAc as the
reference) was observed (Scheme 8). This provides evidence
for an internal oxidation mechanism through the cleavage of the
N−N bond (formation and subsequent sequestration of NH3
by HOAc).
a
Conditions: arylhydrazine (0.5 mmol), alkyne (1.5 equiv), MeOH (2
b
c
mL). Isolated yields. The structure of the alkyne substrate is placed
in the parentheses.
broad range of functional groups on arylhydrazine is observed.
The substituents on the alkyne can be Ph/alkyl, alkyl/alkyl, or,
in the case of synthesis with a terminal alkyne equivalent, Ph/
silyl.
Notably, the room temperature reaction conditions reported
herein are unprecedented for a CHA-based, traceless indole
synthetic protocol.8,12 In addition, the remarkable directing
reactivity of the N-amino group is likewise evidenced by the
scale-up reaction (Scheme 6).
Although acetyl-modified hydrazines and in situ generated
hydrazones have been previously used in the synthesis of
indoles,8,12 the exact coordination site, the N atom, is in a
Scheme 6. Gram-Scale Indole Synthesis at a Very Low
Catalyst Loading
Scheme 8. Characterization of a Side Product
C
DOI: 10.1021/acs.orglett.6b00949
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In summary, we have developed a versatile, traceless CHA-
based approach for the synthesis of heterocycles. Arylhydrazine
can undergo Rh(III)-catalyzed alkenylation with both alkenes
and alkynes at room temperature at a very low catalyst loading
(0.01 mol %/0.1 mol %). Mechanistic investigation revealed the
intermediacy of a five-membered rhodacycle and NH3 as the
N−N bond cleavage side product. Further ex situ and in situ
annulation has allowed the synthesis of a diversity of
heterocycles.
ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge on the
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Experimental procedure, characterization of the products
(PDF)
1
Copies of the H and 13C NMR spectra of selected
products (PDF)
Crystallographic data for complex 3g (CIF)
Crystallographic data for complex 5a (CIF)
Crystallographic data for complex 5e (CIF)
Crystallographic data for complex 1a-Rh-Cl (CIF)
Crystallographic data for complex 1l-Rh-Cl (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jinz@nju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the National Natural
Science Foundation of China (21425415, 21274058) and the
National Basic Research Program of China (2015CB856303).
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DOI: 10.1021/acs.orglett.6b00949
Org. Lett. XXXX, XXX, XXX−XXX