Rhodium(III)-catalyzed c-h activation and indole synthesis with hydrazone as an auto-formed and auto-cleavable directing group

Article abstract of DOI:10.1002/chem.201304302

An efficient, practical, and external-oxidant-free indole synthesis from readily available aryl hydrazines was developed, by using hydrazone as a directing group for Rh^III-catalyzed C-H activation and alkyne annulation. The hydrazone group was formed by in situ condensation of hydrazines and Ci￡O source, whereas its N-N bond was served as an internal oxidant, for which we termed it as an auto-formed and auto-cleavable directing group (DG^auto). This method needs no step for pre-installation and post-cleavage of the directing group, making it a quite easily scalable approach to access unprotected indoles with high step economy. The DG^auto strategy was also applicable for isoquinoline synthesis. In addition, synthetic utilities of this chemistry for rapid assembly of π-extended nitrogen-doped polyheterocycles and bioactive molecules were demonstrated. Copyright

Full text of DOI:10.1002/chem.201304302

DOI: 10.1002/chem.201304302
Full Paper
&
Indole Synthesis
Rhodium(III)-Catalyzed CÀH Activation and Indole Synthesis With
Hydrazone as an Auto-Formed and Auto-Cleavable Directing
Group
Liyao Zheng and Ruimao Hua*[a]
Abstract: An efficient, practical, and external-oxidant-free
indole synthesis from readily available aryl hydrazines was
developed, by using hydrazone as a directing group for RhIII-
catalyzed CÀH activation and alkyne annulation. The hydra-
zone group was formed by in situ condensation of hydra-
zines and C=O source, whereas its NÀN bond was served as
an internal oxidant, for which we termed it as an auto-
formed and auto-cleavable directing group (DGauto). This
method needs no step for pre-installation and post-cleavage
of the directing group, making it a quite easily scalable ap-
proach to access unprotected indoles with high step econo-
my. The DGauto strategy was also applicable for isoquinoline
synthesis. In addition, synthetic utilities of this chemistry for
rapid assembly of p-extended nitrogen-doped polyhetero-
cycles and bioactive molecules were demonstrated.
Introduction
Recently, CÀH activation has emerged as a robust toolkit for
rapid assembly of heterocycles,[1] including indole, a ubiquitous
structural component in natural products and pharmaceuti-
cals.[2–4] Since 2008, several synthetic strategies have been de-
veloped for indole synthesis by CÀH activation using external
oxidants.[5–8] In 2010, Hartwig reported a unique indole synthe-
sis by Pd-catalyzed intramolecular amination, in which the NÀ
O bond served as an internal oxidant (Scheme 1).[9] Afterwards,
this strategy was widely extended to RhIII- or RuII-catalyzed in-
termolecular cyclization, by using an N-O containing oxidizing
directing group (DGox).[10–12] Nevertheless, design of an NÀN
containing DGox is still challenging.[13]
In 1883, E. Fischer discovered an indole synthesis by the
acid-mediated rearrangement of arylhydrazone, with NÀN
cleavage and elimination of NH3.[14] After that, hydrazones
became a widely used class of compounds, and the NÀN bond
was tamed by chemists as a useful synthetic handle. Inspired
by this, we designed two modes of hydrazone as multifunc-
tional DGox, in which the two nitrogen atoms serve as the di-
recting atom and the nitrogen source for heterocycle synthe-
sis, whereas the NÀN bond serves as a linkage as well as an in-
ternal oxidant (Scheme 1). Though nitrogen-containing groups
such as pyridines and amides are well studied as directing
Scheme 1. CÀH activation with internal oxidants.
groups or CÀH activation, hydrazone, especially in mode I is
rarely exploited.[15]
In pioneering work, Fagnou and Stuart developed an ele-
gant indole synthesis by RhIII-catalyzed oxidative coupling of
acetanilides and alkynes (Scheme 2).[6] Afterwards, Pd- and Ru-
catalyzed indole syntheses were also developed by using 2-
pyridyl, acetyl or 2-pyrimidyl as a directing group (DG).[7] In
these methods, the DGs are pre-installed and removed after
the synthesis, resulting in very low step economy. Recently,
Huang developed a unique triazene DG for alkyne annulation
to access unprotected indoles, in which the N=N bond of tri-
azene DG is cleaved in the reaction.[8] However, the N=N bond
does not serve as an internal oxidant for CÀH activation, and
stoichiometric Cu(OAc)2 is needed as an external oxidant.
In the Fischer indole synthesis, hydrazones are usually
formed by in situ condensation of hydrazines and aldehydes/
[a] L. Zheng, Prof. Dr. R. Hua
Key Laboratory of Organic Optoelectronics and
Molecular Engineering of Ministry of Education
Department of Chemistry, Tsinghua University
Beijing 100084 (P.R. China)
E-mail: ruimao@mail.tsinghua.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304302.
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Table 1. Optimization of the reaction conditions.[a]
Entry[a]
C=O source (equiv)
acetone ([d]
Base (equiv)
t [h]
Yield [%][b]
1[c]
2[c]
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19[f]
20[g]
)
KOAc (2.0)
KOAc (2.0)
KOAc (2.0)
KOAc (2.0)
KOAc (2.0)
KOAc (2.0)
KOAc (2.0)
KOAc (2.0)
KOAc (2.0)
KOAc (2.0)
NaOAc (2.0)
CsOAc (2.0)
CsOPiv (2.0)
KOAc (1.5)
KOAc (1.1)
KOAc (1.1)
KOAc (1.1)
KOAc (1.1)
KOAc (1.1)
KOAc (1.1)
24
24
24
18
18
18
18
18
18
18
18
18
18
18
18
12
12
12
12
12
11
19
28
40
51
64
73 (68)
24
0
70
72
70
69
78
85
87 (83)
70
0
85
acetone (2.0)
acetone (2.0)
cyclohexanone (2.0)
cyclopentanone (2.0)
nPrCHO (2.0)
iPrCHO (2.0)
tBuCHO (2.0)
PhCHO (2.0)
CyCHO[e] (2.0)
iPrCHO (2.0)
iPrCHO (2.0)
iPrCHO (2.0)
iPrCHO (2.0)
iPrCHO (2.0)
iPrCHO (2.0)
iPrCHO (1.2)
-
Scheme 2. RhIII-Catalyzed alkyne annulation by CÀH activation.
ketones. With this and our previous one-pot isoquinoline syn-
thesis[16] in mind, we envisioned that a hydrazone could be
formed in situ from hydrazines and serve as a DGox for RhIII-cat-
alyzed CÀH activation and alkyne annulation (Scheme 2). In
this way, the hydrazone group could be an auto-formed and
auto-cleavable directing group, which we have termed as an
auto-directing group (DGauto),[17–19] leading to a one-pot synthe-
sis with a high step economy. Herein, we disclose our design
and development of a hydrazone DGauto strategy for the rapid
assembly of unprotected indoles in a practical and external-
oxidant-free way.
iPrCHO (2.0)
iPrCHO (2.0)
<5
[a] Reaction conditions: 1a (0.20 mmol), 2a (0.24 mmol), KOAc, and
[(Cp*RhCl2)2] (2.5 mol%) in 1.0 mL MeOH at 808C under N2 atmosphere.
[b] Yield of 3aa is based on GC by using n-C24H50 as internal standard;
value in parentheses is isolated yield at 0.5 mmol scale. [c] 608C.
[d] MeOH–acetone (4:1) as solvent. [e] Cy=cyclohexyl. [f] 5 mol% [Cp*Rh-
(MeCN)3][SbF6]2 was used. [g] 2.5 mol% [{Ru(p-cymene)Cl2}2] was used.
yields (Table 1, entries 11–13). Reaction in other solvents such
as MeCN, DCE, THF, and t-AmOH led low conversion and de-
clined yield.
Results and Discussion
We initiated our study employing phenylhydrazine hydrochlo-
ride (1a) and diphenylacetylene (2a) as substrates, and
[(Cp*RhCl2)2] as a precursor of the RhIII catalyst (Table 1). Ace-
tone was used as the C=O source to generate corresponding
hydrazone from 1a. Excess KOAc was used as base to neutral-
ize the hydrochloride and facilitate the generation of [Cp*Rh-
(OAc)n] species as the active catalyst.[11,16] As expected, reaction
at 608C for 24 h gave full conversion of 1a to corresponding
acetone hydrazone, but only 11% indole product 3aa was ob-
tained (Table 1, entry 1). Reaction with 2.0 equivalents of ace-
tone in MeOH at 808C gave improved yield (Table 1, entries 2
and 3).
To our delight, simply reducing the amount of KOAc to
1.1 equiv gave a satisfactory yield (87% GC, 83% isolated)
within a shorter reaction time (Table 1, entry 16). Reducing the
amount of iPrCHO to 1.2 equiv gave a reduced yield (Table 1,
entry 17) and reducing it to a catalytic amount led to much
lower conversions. Further optimization focused on the devel-
opment of a special C=O source for metal-organic cooperative
catalysis[17] is ongoing. No 3aa was detected without a C=O
source (Table 1, entry 18), and no hydrohydrazination product
of 2a was detected in either entry, indicating the cyclization
did not proceed by an alkyne hydrohydrazination followed by
a Fischer indole synthesis.[20] The cationic Cp*RhIII complex
showed similar catalytic activity with [(Cp*RhCl2)2] (Table 1,
entry 19). The structurally analogous RuII complex,[12] which is
active in some cases with NÀO containing DGox, showed little
catalytic activity in this reaction, and only a trace of 3aa was
detected by GC-MS (Table 1, entry 20).
Considering that structure of the hydrazone group may
have a great influence on the generation of the rhodacycle in-
termediate and reactivity of the NÀN bond, we then focused
on screening various C=O sources. Cyclic ketones gave im-
proved yields (Table 1, entries 4 and 5), whereas benzaldehyde
gave no desired product (Table 1, entry 9). For alkyl aldehydes
RnCH3-nCHO, those with a 28 carbon connected to CHO (n=2,
Table 1, entries 7 and 10) proved to be better C=O sources
than those with a 18 carbon (n=1, Table 1, entry 6) or a 38
carbon (n=3, Table 1, entry 8).With isobutyraldehyde (iPrCHO)
as a C=O source, other carboxylates such as NaOAc, CsOAc
and CsOPiv were tested and gave similar or slightly lower
With the optimized reaction conditions in hand, the general-
ity of the one-pot synthesis of indoles was examined. By em-
ploying 2a as the alkyne partner, various substituted aryl hy-
drazines were surveyed (Table 2). o-Methylphenylhydrazine
gave an improved yield (3ba, 90%) and m-methylphenylhydra-
zine afforded 3ca as a single regioisomer. Aryl hydrazines with
an electron-donating group (EDG) as para-substituent showed
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Table 2. Substrate scope of aryl hydrazines.[a]
Table 3. Substrate scope of alkynes.[a]
[a] Reaction conditions: 1 (0.50 mmol), 2 (0.60 mmol), KOAc (0.55 mmol),
and [(Cp*RhCl2)2] (2.5 mol%) in 2.5 mL MeOH at 808C under N2 atmos-
phere. [b] 1.4 equiv alkyne (0.70 mmol). [c] 6 mmol scale. [d] 2.0 equiv
alkyne (1.0 mmol).
tions of these products to valuable molecules (Scheme 3).
Under Miura’s conditions[21] with a modification, a fused prod-
uct 4aa was obtained by RhIII-catalyzed alkyne annulation of
3aa in 93% yield. 3aa could also be converted to 5aa by de-
hydrogenative coupling.[22] 4aa and 5aa are polyheterocycles
with p-extended and nitrogen-doped conjugated systems,
[a] Reaction conditions:
(0.55 mmol), and [(Cp*RhCl2)2] (2.5 mol%) in 2.5 mL MeOH at 808C under
N2 atmosphere. [b] 6 mmol scale.
1
(0.50 mmol), 2a (0.60 mmol), KOAc
higher reactivity than those with an electron with-
drawing group (EWG). Products with p-Me (3da) or
p-OMe (3ea) were obtained in excellent yields (>
90%), whereas those with halogens (3ga–ia) were
obtained in moderate yield. Notably, substrates with
two substitutes reacted smoothly, giving rapid access
to multiply substituted indoles (3 fa, 3ja–la).
The scope of alkynes was next investigated
(Table 3). Diaryl alkynes with either EDGs (Me, OMe)
or EWGs (F, Br) were tolerated to afford 3ab–ae. Aryl-
alkyl asymmetric alkynes reacted regioselectively to
afford 3af–ah. The regioselectivity was in accordance
with other RhIII-catalyzed alkyne annulations[6,11,16]
and contrary to the Fischer indole synthesis.[20] Signif-
Scheme 3. Derivatization of products to valuable molecules.
icantly, alkynes with a free hydroxyl group were toler-
ated for synthesis of 3ag and 3ah, whereas the hy-
droxyl group needs protection in the Fagnou indole synthe-
sis.[6] This type of product (2-aryl tryptophol) are also quite
challenging in the traditional Fischer indole synthesis.[14] Termi-
nal alkyne tBuꢀH was also compatible to afford the 2-substitut-
ed indole 3ai. It should be noted that terminal alkynes in RhIII-
catalyzed reactions are rare, expecially with CuII as an external
oxidant, due to severe side reactions such as alkyne dimeriza-
tion and oxidative homocoupling.[6,11]
which are promising for organic semiconductors. 2-Aryl indole
is a privileged structure for drug discovery.[3] Especially, 2-aryl
tryptamines such as 6ag are high-affinity selective h5-HT2A an-
tagonists.[23] We converted 2-phenyl tryptophol 3ag to 6ag by
a simple tosylation-amination on a 4 mmol scale in excellent
yield (1.10 g, 90%), which is much more efficient and scalable
than previous method.[23] 3ag could also be converted to 7ag
with a naturally occurring furoindoline skeleton.[24]
To probe the practical synthetic utility of our method, large
scale reactions were carried out for 3aa (1.30 g, 80%) and 3ag
(1.07 g, 75%) up to gram scale, facilitating further transforma-
To test the versatility of DGauto with NÀN bond as an internal
oxidant, we extended this strategy to isoquinoline synthesis
with hydrazone mode II (Scheme 1). With benzophenone hy-
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Scheme 4. Isoquinoline synthesis by hydrazone DGauto
.
drazone (8a) and 2a as substrates, isoquinoline 9aa was
formed, as expected (Scheme 4), though the yield was only
moderate (53%) due to low conversion (approx. 60%) of the
alkyne annulation step. Interestingly, iPrCHO gave a much
lower yield, indicating that the C=O source should be selected
specifically for each type of substrates.
To gain a better understanding of the reaction mechanism,
several experiments were carried out (Scheme 5). First, parallel
reactions were performed under standard conditions for
45 min with or without adding alkynes. Remarkable HRMS sig-
Scheme 6. Proposed mechanism.
affords a seven-membered rhodacycle M2, which rearranges to
a more stable six-membered rhodacycle M3.[8] Reductive elimi-
nation of M3 formed M4,[11b] which undergoes HOAc promot-
ed NÀN cleavage to form M5. Protonation of M5 yields the
indole product 3 and turnover of the RhIII catalyst. For another
possible pathway, M3 might undergo NÀN cleavage to afford
RhV nitrene intermediate M6,[26,27] which could undergo reduc-
tive elimination to form 3.
Conclusions
Scheme 5. Mechanistic studies. Conditions: [(Cp*RhCl2)2] (2.5 mol%), KOAc
(1.1 equiv), iPrCHO (2.0 equiv), 808C, N2.
In summary, we have developed a novel CÀH activation and
annulation strategy with hydrazone as an auto-formed and
auto-cleavable directing group (DGauto) and its NÀN bond as in-
ternal oxidant, which enables efficient and external-oxidant-
free synthesis of unprotected indoles from readily available
aryl hydrazines and alkynes. The synthetic utilities of this
chemistry and extension of the strategy for isoquinoline syn-
thesis were also demonstrated. We expect that more diverse
transformations can be developed through rational design of
nals fitted with [C20H28N2Rh]+ and [C30H29NRh]+ were observed,
indicating the formation of complex A and B, respectively. In
addition, 1a gave >90% conversion to the hydrazone 10a
within 2 min, indicating that hydrazone is formed rapidly and
can serve as an efficient DG. When these reactions were per-
formed in deuterated methanol, deuteration at the ortho posi-
tions of 10a was observed, indicating the cyclorhodation was
reversible even with an alkyne.[6b] A modest kinetic isotope
effect (KIE) of 2.0 was observed in the early stage by compari-
son of parallel reactions with 1a and [D5]-1a, indicating the CÀ
H cleavage should be involved in turnover-controlling steps
but may not be an exclusive step.[5d,25]
DGauto
.
Experimental Section
Typical procedure for synthesis of indole 3: To a 25 mL tube
equipped with a magnetic stirrer, phenylhydrazine hydrochloride
(1a, 72.3 mg, 0.50 mmol), 1,2-diphenylacetylene (2a, 106.9 mg,
0.60 mmol, 1.2 equiv), [(Cp*RhCl2)2] (7.7 mg, 0.0125 mmol,
2.5 mmol%) and KOAc (54.0 mg, 0.55 mmol, 1.1 equiv) were added
sequentially. The tube was evacuated and backfilled with nitrogen
three times. Isobutyraldehyde (72.1 mg, 1.0 mmol, 2.0 equiv) was
dissolved in MeOH (2.5 mL), and added under nitrogen atmos-
Based on these facts and previous mechanistic studies of NÀ
O bond containing DGox,[11,26] we propose the mechanism
shown in Scheme 6. First, hydrazone 10a was formed in situ
from 1a and iPrCHO rapidly, with the generation of 1 eqiuv
HOAc. To initiate the catalytic cycle, 10a undergoes reversible
CÀH activation to form rhodacycle M1. Alkyne insertion of M1
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phere and the tube was sealed. The tube was immersed in an oil
bath (808C) and stirred for 12 h. After removal of the solvent under
reduced pressure, purification was performed by flash column
chromatography on silica gel with petroleum ether/acetone (gradi-
ent mixture ratio from 100:0 to 80:20) as eluant to afford 3aa
(111.4 mg, 83%). For detailed reaction procedures for other com-
pounds, see the Supporting Information.
Acknowledgements
We thank the National Natural Science Foundation of China
(21032004, 20972084) for support of this research. Liyao Zheng
thanks Miss Yuan Chen and Mr. Xiaoyun Gong for their helpful
discussions.
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Keywords: CÀH activation · hydrazones · indoles · NÀN
cleavage · rhodium catalysis
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Received: November 3, 2013
Published online on January 23, 2014
Chem. Eur. J. 2014, 20, 2352 – 2356
www.chemeurj.org
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