Rhodium-catalyzed direct annulation of aldehydes with alkynes leading to indenones: Proceeding through in situ directing group formation and removal

Article abstract of DOI:10.1021/ol4021145

The Rh-catalyzed direct annulation of an aldehyde with an alkyne leading to indenone was achieved. The in situ temporal installation of acetylhydrazine enables the annulation of the ortho arene C-H bond with alkynes to form ketone hydrazone. Subsequently, the in situ directing group removal takes place since ketone hydrazone is more susceptible toward hydrolysis than aldehyde hydrazone. Notably, this procedure tolerates a series of functional groups, such as methoxyl, acetylamino, fluoro, trifluoromethyl, methoxycarbonyl, chloro, and bromo groups.

Full text of DOI:10.1021/ol4021145

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rhodium-Catalyzed Direct Annulation of
Aldehydes with Alkynes Leading to
Indenones: Proceeding through in Situ
Directing Group Formation and Removal
Shuyou Chen,‡ Jintao Yu,† Yan Jiang,† Fan Chen,‡ and Jiang Cheng*,†
School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic
Materials and Technology, Changzhou University, Changzhou 213164, P. R. China, and
College of Chemistry & Engineering, Wenzhou University, Wenzhou, 325000,
P. R. China
jiangcheng@cczu.edu.cn
Received July 26, 2013
ABSTRACT
The Rh-catalyzed direct annulation of an aldehyde with an alkyne leading to indenone was achieved. The in situ temporal installation of
acetylhydrazine enables the annulation of the ortho arene CÀH bond with alkynes to form ketone hydrazone. Subsequently, the in situ directing
group removal takes place since ketone hydrazone is more susceptible toward hydrolysis than aldehyde hydrazone. Notably, this procedure
tolerates a series of functional groups, such as methoxyl, acetylamino, fluoro, trifluoromethyl, methoxycarbonyl, chloro, and bromo groups.
Indenone frameworks are ubiquitous in pharmaceutical
and material sciences.1 Yoshikai reported the cobalt-
catalyzed self-coupling of aromatic aldimines for the
synthesis of indenone.2 Kuninobu and Takai described
the ruthenium-catalyzed trimerization of aryl aldehyde for
the construction of the indenone framework.3 The annula-
tion of alkynes with ortho bifunctionalized arenes is a
powerful strategy leading to indenones (Scheme 1, eq 1).4
However, on one hand, the prefunctionalization of a sub-
strate is time and cost consuming, and on the other hand,
many polysubstitutedortho bifunctionalized arenesarenot
commercially or readily available. Alternatively, transi-
tion-metal-catalyzed annulation of the arene CÀH bond
with alkyne has been widely reported for the construction
‡ Wenzhou University.
† Changzhou University.
(1) (a) Huebner, C. F.; Donoghue, E. M.; Plummer, A. J.; Furness,
D. A. J. Med. Chem. 1966, 9, 830. (b) Jeffrey, J. L.; Sarpong, R. Org.
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(4) Annulation with ortho-ester-containing phenylboronic acids: (a)
Tsukamoto, H.; Kondo, Y. Org. Lett. 2007, 9, 4227. With 2-iodoar-
enenitriles: (b) Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem.
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Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2007, 129, 5766. With
2-bromophenylboronic acids and formaldehyde: (f) Morimoto, T.;
Yamasaki, K.; Hirano, A.; Tsutsumi, K.; Kagawa, N.; Kakiuchi, K.;
Harada, Y.; Fukumoto, Y.; Chatani, N.; Nishioka, T. Org. Lett. 2009,
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r
10.1021/ol4021145
XXXX American Chemical Society

of benzo five-membered heteroarenes.5 In 2005, Takai pio-
neered the carbocyclization of imines with alkynes toward
indenamines.6 Subsequently, Shi, Li, Zhao, Cramer, Glorius,
Cheng, Jeganmohan, Miura, and Li independently reported
the construction of indene frameworks via CÀH activation,
insertion of aryl metal to alkyne, and nucleophilic addition of
the formed alkenyl metal intermediate to a carbonyl or iminyl
group.7 However, to the best of our knowledge, only one
example was reported by Shi on the direct annulation of the
CÀH bond of benzimide with alkynes leading to indenone
(Scheme 1, eq 2).7a
2-aminopyridyl group.12 Herein, we report employing this
strategy in the annulation of the arene CÀH bond neigh-
boring a formyl group with an alkyne leading to indenone,
proceeding through in situ directing group formation and
removal.
Scheme 1. Previous Pathways and Our Design Plan Leading to
Indenone
Undoubtedly, the direct annulation of an aryl aldehyde
as commercially available starting material with alkynes is
the most straightforward and atom-economical pathway
toward indenones (Scheme 1, eq 3). However, aldehydes
arecharacterized by their pooreffectasadirecting group in
CÀH bond functionalization.8 To solve this problem, the
introduction of proper directing groups, suchasiminyland
hydrazonyl, is required. However, except for the intro-
duced directing groups being part of the final product, the
subsequent removal of the directing groups is required.9
To circumvent it, the introduction of a temporal directing
group may solve this drawback.10 Indeed, the Rh-catalyzed
annulation of aromatic imines with alkynes leading to
indenone imine was achieved in Miura’s group.7i We
envisaged the inherent difference between the equilibrium
constant of aldimine (before the annulation) and ketimine
(after the annulation) could enable the in situ directing
group formation and removal (Scheme 1, eq 3).11 Jun
developed a new strategy of metalÀorganic cooperative
catalysis (MOCC) in the functionalization of CÀH adja-
cent to a carbonyl group by temporal installation of a
With this in mind, initially, we tested the reaction of
benzaldehyde 1a with diphenyl ethyne 2a with the combina-
tion of [Cp*Rh(MeCN)3](SbF6)2 (5 mol %), NH2NHAc
(1.1 equiv), and AgSbF6 (0.2 equiv) in HOAc under air at
120 °C. Pleasingly, the indenone was obtained in 45% yield
(Table 1, entry 2). The reaction efficiency was slightly
decreased by adding 2 equiv of Cu(OAc)2 as an additive
(Table 1, entry 3). However, replacing Cu(OAc)2 with
AgOAc increased the yield to 71% (Table 1, entry 4). To
our delight, the reaction efficiency was further increased to
73% by using 1 equiv of Ag2CO3 under air. The yield
increased to 80% under N2 and dramatically decreased to
50% under O2 (Table 1, entry 6). Other protic solvents
such as CF3COOH and HCOOH inhibited the reaction
(Table 1, entries 7 and 8). Replacing NH2NHAc with
NH2NHPh, NH2Ts, or NH2Ac resulted in no reaction or
low yield (Table 1, entries 9À11). Further studies revealed
other Rh catalysts, such as [RhCl(cod)]2, [RhOH(cod)]2,
RhCl(Ph3P)3, and Rh(acac)3, were totally ineffective for
this annulation reaction (Table 1, entries 12À15). In the
absence of AgSbF6, the yield dramatically decreased to
37% (Table 1, entry 6).
With the optimized reaction conditions in hand, the
substrate scope of benzaldehyde for this cyclization was
studied, as shown in Figure 1. As expected, both electron-
donating and -withdrawing groups such as methoxycar-
bonyl, methoxyl, fluoro, chloro, bromo, acetyl amino, and
trifluoromethyl on the aromatic moiety of benzaldehyde
were tolerated well under this procedure. Moreover, the
ortho groups on the phenyl of 1a had almost no effect on
the annulation. For example, 3da was isolated in 68%
yield. Notably, the chloro and bromo functional groups
survived well under the standard procedure, offering
(7) Li, B.-J.; Wang, H.-Y.; Zhu, Q.-L.; Shi, Z.-J. Angew. Chem., Int.
Ed. 2012, 51, 3948. (b) Yang, L.; Correia, C. A.; Li, C.-J. Adv. Synth.
Catal. 2011, 353, 1269. (c) Sun, Z.-M.; Chen, S.-P.; Zhao, P. Chem.;
Eur. J. 2010, 16, 2619. (d) Tran, D. N.; Cramer, N. Angew. Chem., Int.
Ed. 2010, 49, 8181. (e) Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed.
2011, 50, 11098. (f) Patureau, F. W.; Besset, T.; Kuhl, N.; Glorius, F.
J. Am. Chem. Soc. 2011, 133, 2154. (g) Jayakumar, J.; Parthasarathy, K.;
Cheng, C.-H. Angew. Chem., Int. Ed. 2012, 51, 197. (h) Chinnagolla,
R. K.; Jeganmohan, M. Eur. J. Org. Chem. 2012, 417. (i) Fukutani, T.;
Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem. Commun. 2009,
5141. (j) Zhao, P.; Wang, F.; Han, K.; Li, X. Org. Lett. 2012, 14, 5506.
(8) Dubost, E.; Fossey, C.; Cailly, T.; Rault, S.; Fabis, F. J. Org.
Chem. 2011, 76, 6414.
(9) For reviews, see: (a) Mousseau, J. J.; Charette, A. B. Acc. Chem.
Res. 2013, 46, 412. (b) Wang, C.; Huang, Y. Synlett 2013, 24, 145. (c)
Engle, K. M.; Mei, T.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45,
788. (d) Rousseau, G.; Breit, B. Angew. Chem., Int. Ed. 2011, 50, 2450.
(10) Examples on the CÀH bond functionalization involving in situ
directing group formation and removal: (a) Bedford, R. B.; Betham, M.;
Caffyn, A. J. M.; Charmant, J. P. H.; Lewis-Alleyne, L. C.; Long, P. D.;
Polo-Ceron, D.; Prashar, S. Chem. Commun. 2008, 990. (b) Bedford,
R. B.; Haddow, M. F.; Webster, R. L.; Mitchell, C. J. Org. Biomol.
Chem. 2009, 7, 3119. (c) Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.;
Limmert, M. E. Angew. Chem,. Int. Ed. 2003, 42, 112. (d) Bedford, R. B.;
Limmert, M. E. J. Org. Chem. 2003, 68, 8669.
(11) For the direct annulation of an aromatic aldehyde with an
alkyne leading to indenone in the presence of a free radical initiator in
low yield, please see: Monahan, A.; Campbell, P.; Cheh, S.; Fong, J.;
Grossman, S.; Miller, J.; Rankin, P.; Vallee, J. Synth. Commun. 1977, 7,
553.
(12) (a) Jun, C.-H.; Jo, E.-A.; Park, J.-W. Eur. J. Org. Chem. 2007,
1869. (b) Jun, C.-H.; Lee, D.-Y.; Lee, H.; Hong, J. B. Angew. Chem., Int.
Ed. 2000, 39, 3070. (c) Jun, C.-H.; Lee, H.; Hong, J. B.; Kwon, B.-I.
Angew. Chem., Int. Ed. 2002, 41, 2146. (d) Jun, C.-H.; Lee, H. J. Am.
Chem. Soc. 1999, 121, 880. (e) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc.
Chem. Res. 2008, 41, 222.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Screening the Optimized Reaction Conditionsa
additive
yield
(%)
entry
1
(equiv)
NH2R
rhodium
solvent
À
À
À
[Cp*Rh(MeCN)3]- CH3COOH <5
(SbF6)2
2
3
4
5
6
7
8
9
NH2NHAc [Cp*Rh(MeCN)3]- CH3COOH 45
(SbF6)2
Cu(OAc)2 H2O NH2NHAc [Cp*Rh(MeCN)3]- CH3COOH 38
3
(2.0)
(SbF6)2
AgOAc (2.0)
NH2NHAc [Cp*Rh(MeCN)3]- CH3COOH 71
(SbF6)2
Ag2O (1.0)
NH2NHAc [Cp*Rh(MeCN)3]- CH3COOH 68
(SbF6)2
NH2NHAc [Cp*Rh(MeCN)3]- CH3COOH 73(80)b
Ag2CO3 (1.0)
Ag2CO3 (1.0)
Ag2CO3 (1.0)
Ag2CO3 (1.0)
(SbF6)2
(50)c (37)d
NH2NHAc [Cp*Rh(MeCN)3]- CF3COOH <5
(SbF6)2
NH2NHAc [Cp*Rh(MeCN)3]- HCOOH
(SbF6)2
<5
NH2NHPh [Cp*Rh(MeCN)3]- CH3COOH <5
(SbF6)2
Figure 1. Substrate scope of aldehydes. Reaction conditions:
1 (0.2 mmol), diphenyl acethyne 2a (0.3 mmol), NH2NHAc
(0.22 mmol), [Cp*Rh(MeCN)3](SbF6)2 (5 mol %), AgSbF6
(20 mol %), Ag2CO3 (0.2 mmol), and 2 mL of HOAc, N2,
120 °C, sealed tube, 14 h.
10 Ag2CO3 (1.0)
11 Ag2CO3 (1.0)
NH2Ts
[Cp*Rh(MeCN)3]- CH3COOH 15
(SbF6)2
NH2Ac
[Cp*Rh(MeCN)3]- CH3COOH
(SbF6)2
5
12 Ag2CO3 (1.0)
13 Ag2CO3 (1.0)
14 Ag2CO3 (1.0)
15 Ag2CO3 (1.0)
NH2NHAc [RhCl(cod)]2
NH2NHAc [RhOH(cod)]2
NH2NHAc RhCl(Ph3P)3
NH2NHAc Rh(acac)3
CH3COOH <5
CH3COOH <5
CH3COOH <5
CH3COOH <5
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), NH2R
(0.22 mmol), [Cp*Rh(MeCN)3](SbF6)2 (5 mol %), AgSbF6 (20 mol %),
additive with indicated equivalent, and 2 mL of indicated solvent, air,
120 °C, sealed tube, 14 h. Cp* = pentamethylcyclopentadiene. b N2.
c O2. d No AgSbF6, N2.
handles for further functionalization (3fa, 3ga, and 3ia).
Importantly, thecyclization tookplace on the lesshindered
ortho position for the meta-substituted substrate 1f, and no
regioisomeric product of 3fa was observed by GC-MS.
Disappointingly, the salicylaldehyde derivative possessing
a free phenolic hydroxyl did not work using the procedure.
Next, the substrate scope and the limitation of alkynes
for this annulation were studied, as shown in Figure 2.
Once again, the diaryl alkynes ran smoothly under the
procedure, providing the indenones in good to excellent
yields. The chloro and bromo groups in the phenyl ring of
the alkynes remained untouched during this transforma-
tion. Notably, 4-octyne was applicable to the procedure,
providing the annulation product 3ah in moderate yield.
1,2-Di(thiophen-3-yl)ethyne provided the annulation pro-
duct 3ai in 32% yield. Particularly, methyl phenyl alkyne
afforded 3-methyl-2-phenyl-1H-inden-1-one in 61% yield
along with 9% of isomer. Unfortunately, dimethylacety-
lenedicarboxylate did not work under this procedure.
To gain a preliminary understanding of the mechanism,
the kinetic isotope effects of benzaldehyde were studied.
However, during the intramolecular kinetic isotope
effect study, 88% of H on the C-7 position of indenone
Figure 2. Substrate scope of alkynes. Reaction conditions: 1a
(0.2 mmol),
[Cp*Rh(MeCN)3](SbF6)2 (5 mol %), AgSbF6 (20 mol %),
Ag2CO3 (0.2 mmol), and 2 mL of HOAc, N2, 120 °C, sealed
tube, 14 h.
2 (0.3 mmol), NH2NHAc (0.22 mmol),
maintained retention (Scheme 2, eq 1), indicating an H/D
exchange may be involved during the procedure. Indeed,
by replacing HOAc with CD3COOD, the reaction of 1a
and 2a resulted in 89% deuteration of the H atom on the
C-7 position (Scheme 2, eq 2). However, only 23% of the
deuterium atom was incorporated when indenone was
subjected to the standard reaction conditions in CD3COOD
(Scheme 2, eq 3). The H/D exchange suggested a cyclorho-
dation step was involved in the reaction.
Org. Lett., Vol. XX, No. XX, XXXX
C

acetylhydrazone and aldehyde.13 First, coordination of Rh
species with benzaldehyde acetylhydrazone facilitated the
ortho aromatic CÀH bond cleavage to form intermediate
4. This step is reversible supported by the observed H/D
exchange in Scheme 2. Second, the insertion of intermedi-
ate 4 to a CÀC triple bond produces the alkenyl rhodium
species 5. Subsequently, the nucleophilic addition of inter-
mediate 5 to the CdN bond forms intermediate 6.14 Third,
the β-H elimination of intermediate 6 delivers HRhX2
species along with the intermediate 7,15 which transforms
to indenone by protonation.16 Finally, the reductive elim-
ination of HRhX2 followed by the oxidation by Ag(I)
regenerates the Rh(III) species.
Scheme 2. Isotopic Labelling Study
In conclusion, we have developed a Rh-catalyzed annu-
lation of benzaldehyde with alkynes in the presence of 1.1
equiv of acetic hydrazide leading to indenones with good
functional group tolerance. The important feature of the
present catalytic system is the application of the strategy of
in situ directing group formation and removal. Thus, it
might open up an expedient synthetic pathway for the
formyl-directing arene CÀH bond functionalization. Efforts
to expand the strategy to new reactions and to elucidate the
mechanism in detail are underway in our laboratory.
Scheme 3. A Tentative Mechanism
Acknowledgment. We thank the National Natural Science
Foundation of China (Nos. 21272028, 21272178, and
21202013), Jiangsu Key Laboratory of Advanced Catalytic
Materials &Technology (BM2012110), Jiangsu Province
Key Laboratory of Fine Petrochemical Engineering, and
the Priority Academic Program Development of Jiangsu
Higher Education Institutions for financial support.
Supporting Information Available. Experimental pro-
cedures along with copies of spectra. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Although the mechanism in detail remains unclear at
this current stage, based on the well documented annula-
tion of an arene CÀH bond with an alkyne,5À7 a proposed
mechanism was outlined in Scheme 3. In the reaction proce-
dure, there is an equilibrium reaction between benzaldehyde
(15) The intermolecular Heck-type reaction of imine, for Rh, please
see: (a) Ishiyama, T.; Hartwig, J. J. Am. Chem. Soc. 2000, 122, 12043.
For Pd, please see: (b) Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 14800. (c) Ohno, H.; Aso, A.; Kadoh, Y.; Fujii, N.; Tanaka, T.
Angew. Chem., Int. Ed. 2007, 46, 6325. For the Heck-type intramolecular
alkenylation of imine, please see ref 7i.
(13) The 1H NMR of the mixture of benzaldehyde and NH2NHAc in
CD3COOD confirmed the benzaldehyde acetylhydrazone was the main
species. For details, see Supporting Information.
(14) For reviews in the nucleophilic addition of a CdN bond, please
see: (a) Schmidt, F.; Stemmler, R.; Rudolph, J.; Bolm, C. Chem. Soc.
Rev. 2006, 35, 454. (b) Robert, B. Chem. Rev. 1998, 98, 1407–1438. (c)
Shu, K.; Haruro, I. Chem. Rev. 1999, 99, 1069.
(16) The 1H NMR of the mixture of indenone and NH2NHAc in
CD3COOD confirmed the indenone was the dominant species. For
details, see Supporting Information.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX