Domino Oxidative [Pd]-Catalysis: One-Pot Synthesis of Fluorenones Starting from Simple Benzylamines and Iodo Arenes

Article abstract of DOI:10.1021/acs.orglett.5b03077

A domino [Pd]-catalysis for the efficient synthesis of fluorenones is presented. The overall reaction proceeds through the formation of a five membered Pd(II)-cycle via a highly regioselective ortho C(sp²)-H activation(s) of simple benzylamine that combines with external iodo arenes to give ortho arylated products. Significantly, the reaction further activates the C(sp³)-H and C(sp²)-H (intramolecular oxidative Heck coupling) bonds to give tricyclic imine systems. Then the usual water workup affords the fused tricyclic ketones (fluorenones). Remarkably, this one-pot operation enabled the effective construction of two C-C to three C-C bonds

Full text of DOI:10.1021/acs.orglett.5b03077

Letter
pubs.acs.org/OrgLett
Domino Oxidative [Pd]-Catalysis: One-Pot Synthesis of Fluorenones
Starting from Simple Benzylamines and Iodo Arenes
Devarapalli Ravi Kumar and Gedu Satyanarayana*
Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Telangana 502 285, India
S
* Supporting Information
ABSTRACT: A domino [Pd]-catalysis for the efficient
synthesis of fluorenones is presented. The overall reaction
proceeds through the formation of a five membered Pd(II)-
cycle via a highly regioselective ortho C(sp2)-H activation(s) of
simple benzylamine that combines with external iodo arenes to give ortho arylated products. Significantly, the reaction further
activates the C(sp3)-H and C(sp2)-H (intramolecular oxidative Heck coupling) bonds to give tricyclic imine systems. Then the
usual water workup affords the fused tricyclic ketones (fluorenones). Remarkably, this one-pot operation enabled the effective
construction of two C−C to three C−C bonds
ransition-metal-catalyzed ortho C−H activation1 of aro-
fluorenones could be achived in one-pot by coupling simple
benzylamines with iodoarenes. Herein, we present an efficient
and novel strategy for fluorenones through domino13 one-pot
highly regioselective ortho-arylation (mono- or diarylation) and
subsequent intramolecular coupling using simple benzylamines
and iodo arenes, in the presence of a [Pd]-catalyst. We
envisioned that after ortho-arylations, the reaction would further
propagate to furnish the cyclic imine intermediate that facilitates
the activation of C(sp3)−H and C(sp2)−H (intramolecular
oxidative Heck coupling) bonds. Finally, the typical water
workup would furnish fluorenones as the end products of the
reaction sequence.
We initially examined the reaction with the oxidant Ag2O and
solvent CH3COOH with 1:4 and 1:2 ratios of benzylamine14 1a
and 4-iodoanisole 2d, respectively. As expected, the diarylated
product 3ad was obtained albeit in very poor yield (Table 1,
entries 1 to 2). Since it was well established that the [Pd]-
catalysis of directing a free amine group will be retarded by the
acid medium probably through protonation, we thus thought
that loading more equivalents of benzylamine 1a would be good
to increase the yield. To our delight, as anticipated, a gradual
increase of equivalents of benzylamine 1a showed pronounced
results (Table 1, entries 3 to 5). Increasing the concentration of
reaction showed further increment of the yield (Table 1, entry 6).
Notably, longer reaction times gave the product 3ad in very good
yield (Table 1, entry 7). However, all variations such as with
different oxidizing agents and solvents or solvent mixtures were
not very effective (Table 1, entries 8 to 19).
T
matic compounds has emerged as one of the most powerful
methods in the realm of organic synthesis. Indeed, these
activated aromatic compounds are proven to be effective and
enable the formation of various bonds [i.e., C−C, C−O, C−N,
C−S, and C−X (X = halogen)] in a highly regioselective manner,
and have also been applied in the synthesis of natural products as
well as pharmaceutically important molecules.2 Most likely, the
C−H group is the most important and abundant moiety, which
enhances the scope of synthetic transformations in the field of
organic chemistry. A range of ortho directing functional groups
has been successfully employed for C−H activation.3 Despite the
number of reports on C−H activations, ortho C−H activations
followed by cyclization catalyzed solely by the metal-catalyst are
comparatively rare. In particular, the intramolecular activation of
C(sp2/sp3)−H bonds after the usual intermolecular ortho C−H
activations, in a domino one-pot fashion to accomplish cyclic
products, is quite a challenging task, particularly for those with β-
hydrogen to the [Pd]-species.
Fluorenones4 belong to an important class of organic
compounds, as they are present in some natural products and
compounds of biological relevance5 and also found in electronic
and optical materials.6 Their initial synthesis was based on
classical methods.7−9 Notably, the Larock research group
disclosed the synthesis of fluorenones via [Pd]-catalyzed C−H
bond activation.10 Recently, the Cheng report deals with oxime
directed [Pd]-catalyzed dual C−H activation,4a while Shi et al.
revealed a different protocol.5 The Daugulis research group
developed a sequential one-pot process.4c
Although [Pd]-catalyzed ortho C−H activation of N,N-
dialkylbenzylamines is well established, the ortho palladation of
benzylamines containing a free NH-group is uncommon. This
may be because the ortho palladation of benzylamines in strong
acid is retarded due to deactivation (protonation) of the directing
amino group. Significantly, Daugulis et al. reported [Pd]-
catalyzed direct ortho arylations of benzylamines.11 In con-
tinuation of our ongoing research interest in transition-metal
catalyzed one-pot transformations,12 we anticipated that
With the optimized reaction conditions in hand (Table 1,
entry 7), to check the scope and generality of the method, we
explored the reaction with other (simple or para substituted)
benzylamines 1a−e and iodo arenes 2a−f. Most importantly the
reaction showed a broad substrate scope and furnished the
fluorenones 3aa−df in moderate to very good yields (Table 2).
Received: October 23, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03077
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization Studies for the Formation of
Fluorenone 3ad
Table 2. Scope and Generality of Formation of Aryl
a,b,c
a
Fluorenones 3aa−df
1a/2d
yield
b
entry
oxidant
Ag2O
solvent (mL)
AcOH (1.0)
ratio
time (h) 3ad (%)
1
1/4
1/2
1/1
3/1
5/1
5/1
5/1
5/1
5/1
5/1
5/1
5/1
5/1
5/1
5/1
5/1
24
24
24
24
40
24
40
24
24
24
40
24
40
24
24
40
11
17
24
36
59
52
80
26
34
43
g
2
Ag2O
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (0.5)
AcOH (0.5)
AcOH (1.0)
AcOH (1.0)
AcOH (0.5)
AcOH (0.5)
TFA (0.5)
3
Ag2O
4
Ag2O
5
Ag2O
6
Ag2O
7
Ag2O
8
Ag2CO3
AgOAc
AgOAc
K2S2O8
Ag2O
9
10
11
12
g
c
13
d
AcOH (0.5)
AcOH (0.5)
DMF (0.5)
g
14
Ag2O
Ag2O
Ag2O
g
15
g
e
16
DMF (0.25) +
AcOH (0.25)
40
f
17
Ag2O
BQ
5/1
5/1
5/1
24
24
24
5%
g
18
19
AcOH (0.5)
Cu(OAc)2 AcOH (0.5)
10
a
a
Unless otherwise mentioned, all the reactions were carried out by
Aryl iodides 2a−f (0.43 mmol), benzylamines 1a−e (2.15 mmol, 5.0
equiv), Ag2O (199.5 mg, 2.0 equiv), acetic acid (0.5 mL), 140 °C, 36
using 100 mg (0.43 mmol) of aryl iodide 2d and 5 mol % of
b
b
Pd(OAc)2. Isolated yields of chromatographically pure products.
to 48 h. Yields in the parentheses are isolated yields of
c
d
c
Reaction was carried out without oxidant. Reaction carried out
chromatographically pure products. The first alphabet letter for the
e
without palladium acetate. Reaction carried out in mixture of acetic
compounds 3 refers to the benzylamine, while the second letter
indicates the iodo arene.
f
acid and DMF in 1:1 ratio. Reaction was carried out without solvent.
g
No significant spot was observed on TLC for isolation; neither the
starting material was recovered nor any product was isolated.
Scheme 1. Plausible Mechanism for the Formation of
Fluorenones 3
Interestingly, this method was amenable to different benzyl-
amines 1a−e and iodo arenes 2a−f ranging from electron
deactivating to electron rich functional groups on the aromatic
rings (Table 2). However, the reaction was unsuccessful either
with iodo arenes or benzylamines having strong electron
withdrawing groups such as esters and nitro groups; even after
many trials under several conditions (i.e., neither the starting
materials nor the products were isolated). In fact, these
observations were in good agreement with that reported by
Daugulis and co-workers. This may be probably due to the more
nucleophilic nature of the free amine functionality unlike the
work with directing the oxime group by the research group of
Cheng. Also, the reaction was unsuccessful with 1-bromo-2-iodo
benzene. This might be due to the ortho bromo substituent that
would exert steric hindrance to the flat tricyclic product. Though,
use of excess of benzylamine did not furnish the expected mono-
arylation product. Only in two cases (3de, 3df) was the
formation of mono-arylated fluorenones identified, albeit in
negligible yields (4 to 5%). This may occur because the [Pd]-
species might not depart from the system after the mono-
arylation and still be intact with the nitrogen atom via chelation
(see the plausible mechanism of Scheme 1). Subsequently, it
would prefer to form a second five-membered cycle in order to
establish the second arylation. Presumably, the second five-
membered palladacycle formations would be more feasible
owing to favorable steric repulsions caused by the first mono-
arylated ring on the adjacent [Pd]-moiety.
B
DOI: 10.1021/acs.orglett.5b03077
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Further to check the scope and limitations of the method, we
employed the reaction with other sterically constrained benzyl-
amines 1f−i as well. As anticipated, the reaction was impeded
after mono ortho C(sp2)-H activation for ortho and meta-
substituted benzylamines 1f−i. In the case of ortho-substituted
benzylamines 1f−g, there is only one ortho C(sp2)-H group
available for arylation, hence, mono-arylated fluorenones were
formed 3fa−ge. Though, in the case of meta-substituted
benzylamines 1h−i, two ortho C(sp2)-H groups are available,
the reaction stopped at mono ortho arylation because of steric
thwart and gave the corresponding mono arylated fluorenones
3hd−hg (Table 3). As discussed in the section related to Table 2,
Figure 1. X-ray crystal structure of aryl fluorenone 3ad. Thermal
ellipsoids are drawn at the 50% probability level.
via the intermediates 9, 10 and 11. Finally, the water workup16 of
12 gives fluorenones 3 (Scheme 1). For simplicity, the
mechanism is shown on a restricted mono-arylation between
the ortho substituted benzylamines 1 and simple iodo benzene 2a
(Scheme 1). We presume that the reaction sequence would
proceed through biarylation followed oxidation to imine and
oxidative Heck coupling. This could be clearly realized based on
the Daugulis report, wherein only biraylation was observed
without oxidation of the amine group.11
Table 3. Scope and Generality of Formation of Fluorenones
a,b,c
3fa−hg
The possible formation of a palladacycle through the directing
group assistance was further demonstrated by the isolation of
dimeric five-membered Pd(II)-cycle 5 by direct treatment of
Pd(OAc)2 with benzylamine 1a in CH3COOH (yield 88%). The
1
structure was established from H- and 13C NMR data. It was
further confirmed by the single crystal X-ray diffraction analysis.
In addition, treatment of 5 with iodo arene 2d, gave the
fluorenone 3ad in 89% yield (Scheme 2).
Scheme 2. Formation of Fluorenone 3ah via the Isolation of
a
Five-Membered Palladacycle
a
Aryl iodides 2a−g (0.43 mmol), benzylamines 1f−j (4.3 mmol, 10
equiv), Ag2O (199.5 mg, 2.0 equiv), acetic acid (0.5 mL), 140 °C, 36
b
to 48 h. Yields in the parentheses are isolated yields of
c
chromatographically pure products. The first alphabet letter for the
compounds 3 refers to the benzylamine, while the second letter
indicates the iodo arene.
a
the reaction was still unsuccessful with iodo arenes or
benzylamines with strong electron withdrawing groups (esters
and nitro groups). On the other hand, we also attempted to
isolate the tricyclic imine intermediate by direct loading of the
concentrated crude reaction mixture to the short silicagel column
purged with triethylamine. Even then, we were able to isolate
solely the fluorenone, but not the imine, showing the high
reactive nature to form stable ketones.
In addition to the spectroscopic evidence, the structure of
fluorenones 3 was confirmed by the single crystal X-ray
diffraction analysis of 3ad and 3hd (see Supporting Informa-
tion).
To account for the catalytic path of the reaction, the possible
mechanism would proceeded via the formation of five-
membered palladacycle15 5 through directing group assistance.
Now the palladacycle 5 combines with the external iodo arene 2
to give ortho arylated products 7 via the insertion intermediate 6.
Further, the arylated product 7 continues through C(sp3)-H
activation to give the imine intermediate 8. The subsequent
C(sp2)-H activations lead to the formation of tricyclic imine 12
Thermal ellipsoids are drawn at the 50% probability level for the
crystal structure of intermediate palladium complex 5.
Besides the reaction on palladacycle 5, to confirm the final
cyclization from amine through imine followed by fluorenone
formation, the [Pd]-catalyzed cyclization was conducted on
amine 1j and imine 13. As anticipated, the reaction afforded the
fluorenone 4a (Scheme 3). On the one hand, the reaction with
aryl aldimine without Pd(OAc)2 gave back the biphenyl aldehyde
without any Friedel−Crafts cyclization, presumably due to the
intervening effect of the acetic acid medium. This proves the
importance of the [Pd]-catalyst for oxidative cyclization. On the
Scheme 3. Formation of Fluorenone 4a from 1j and 13
C
DOI: 10.1021/acs.orglett.5b03077
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) (a) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 4156.
(b) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 7330. (c) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am.
Chem. Soc. 2004, 126, 2300. (d) Giri, R.; Chen, X.; Yu, J.-Q. Angew.
Chem. 2005, 117, 2150. (e) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami,
K. J. Am. Chem. Soc. 2006, 128, 11748.
(4) (a) Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C. H.
Angew. Chem., Int. Ed. 2008, 47, 9462. (b) Pletnev, A. A.; Larock, R. C. J.
Org. Chem. 2002, 67, 9428. (c) Shabashov, D.; Daugulis, O.; Cheme, S. J.
Org. Chem. 2008, 73, 7818. (d) Li, H.; Zhu, R. Y.; Shi, W. J.; He, K. H.;
Shi, Z. J. Org. Lett. 2012, 14, 4850−4853. (e) Gandeepan, P.; Hung, C.
H.; Cheng, C. H. Chem. Commun. 2012, 48, 9379. (f) Yang, G. Y.;
Zhang, Q. H.; Miao, H.; Tong, X. L.; Xu, J. Org. Lett. 2005, 7, 263.
(g) Shi, Z.; Glorius, F. Chem. Sci. 2013, 4, 829. (h) Wan, J.; Huang, J.;
Jhan, Y.; Hsieh, J. Org. Lett. 2013, 15, 2742. (i) Zhao, J.; Yue, D.; Campo,
M. A.; Larock, R. C. J. Am. Chem. Soc. 2007, 129, 5288−5295. (j) Yang,
G.; Zhang, Q.; Miao, H.; Tong, X.; Xu, J. Org. Lett. 2005, 7, 263.
(h) Zhang, X.; Larock, R. C. Org. Lett. 2005, 7, 3973.
other hand, it is noteworthy that the reaction with aldimine
derived from simple benzaldehyde gave back simple benzalde-
hyde with or without the [Pd]-catalyst. This might occur because
the sp3-hybridized nitrogen atom is more nucleophilic, chelating
[Pd]-catalyst better than the sp2-hybridized imine nitrogen.
In summary, we have disclosed a novel domino [Pd]-catalysis
for the efficient synthesis of fluorenones. The overall reaction
proceeds through the formation of a five-membered Pd(II)-cycle
and subsequent ortho C(sp2)-H activation(s) with external iodo
arenes in a highly regioselective manner. Significantly, the
reaction was not stopped after the usual ortho arylation(s);
instead, it further continued to C(sp3)-H and C(sp2)-H
activations to give the fused tricyclic ketones after a normal
water workup procedure, and enabled the effective construction
of two C−C to three C−C bonds.
ASSOCIATED CONTENT
(5) Waldo, J. P.; Zhang, X.; Shi, F.; Larock, R. C. J. Org. Chem. 2008, 73,
6679.
■
S
* Supporting Information
(6) Venkatesan, K.; Dhivya, S.; Rethavathi, J.; Narasimhan, S. J. Chem.
Pharm. Res. 2012, 4, 4477.
(7) (a) Kingston, D. G. I.; Bursey, J. T.; Bursey, M. M.; Ionization, B. C.
Chem. Rev. 1974, 74, 215. (b) Sartori, G.; Maggi, R. Chem. Rev. 2006,
106, 1077.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03077.
Characterization of 7-methoxy-1-(4-methoxyphenyl)-9H-
fluoren-9-one (CIF)
Characterization of 2,7-dimethoxy-9H-fluoren-9-one
(8) Pschorr, R. Ber. Dtsch. Chem. Ges. 1896, 29, 496.
(9) (a) Sauer, J.; Sustmann, R. Angew. Chem., Int. Ed. Engl. 1980, 19,
779. (b) Ahrendt, K. A.; Borths, C. J.; Macmillan, D. W. C.; January, R.
V. J. Am. Chem. Soc. 2000, 122, 4243.
(10) (a) Campo, M. A.; Larock, R. C. J. Org. Chem. 2002, 67, 5616.
(b) Zhang, X.; Larock, R. C. Org. Lett. 2005, 7, 3973.
(CIF)
Experimental details, characterization data for new
compounds PDF
(11) Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211.
AUTHOR INFORMATION
(12) (a) Mahendar, L.; Krishna, J.; Reddy, A. G. K.; Ramulu, B. V.;
Satyanarayana, G. Org. Lett. 2012, 14, 628. (b) Mahendar, L.;
Satyanarayana, G. J. Org. Chem. 2014, 79, 2059. (c) Mahendar, L.;
Satyanarayana, G. J. Org. Chem. 2015, 80, 7089. (d) Mahendar, L.;
Reddy, A. G. K.; Krishna, J.; Satyanarayana, G. J. Org. Chem. 2014, 79,
8566. (e) Krishna, J.; Niharika, P.; Satyanarayana, G. RSC Adv. 2015, 5,
26749. (f) Krishna, J.; Reddy, A. G. K.; Satyanarayana, G. Tetrahedron
Lett. 2014, 55, 861. (g) Reddy, A. G. K.; Krishna, J.; Satyanarayana, G.
Tetrahedron Lett. 2012, 53, 5635. (h) Reddy, A. G. K.; Satyanarayana, G.
Tetrahedron 2012, 68, 8003. (i) Krishna, J.; Reddy, A. G. K.;
Satyanarayana, G. Synlett 2013, 24, 967.
■
Corresponding Author
*Tel.: (040) 2301 6033. Fax: (040) 2301 6003/32. E-mail:
gvsatya@iith.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Department of Science and Technology-
Science and Engineering Research Board (DST-SERB)
[NO.:SB/S1/OC-39/2014], New Delhi, for the financial
support. D.R.K. thanks UGC, New Delhi, for the award of a
research fellowship. We are thankful to Dr. G. Prabusankar and
Dr. T. K. Panda, Department of Chemistry, Indian Institute of
Technology, Hyderabad, for their inputs on the X-ray crystal
structures.
(13) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Satyanarayana, G.;
Maier, M. E. Org. Lett. 2008, 10, 2361. (c) Satyanarayana, G.; Maichle-
Mossmer, C.; Maier, M. E. Chem. Commun. 2009, 1571. (d) Satyanar-
̈
ayana, G.; Maier, M. E. Eur. J. Org. Chem. 2008, 2008, 5543.
(14) (a) Yadav, A. K.; Yadav, L. D. S. RSC Adv. 2014, 4, 34764.
(b) Ahrendt, K. A.; Borths, C. J.; Macmillan, D. W. C. J. Am. Chem. Soc.
2000, 122, 4243.
(15) (a) Saura-llamas, I.; Palin, M. G.; Jones, P. G.; Ramı, M. C.
Organometallics 1997, 16, 826. (b) Gandeepan, P.; Cheng, C. H. J. Am.
Chem. Soc. 2010, 132, 8569. (c) Dupont, J.; Consorti, C. S.; Spencer, J.
Chem. Rev. 2005, 105, 2527.
(16) (a) Kwon, M. S.; Kim, S.; Park, S.; Bosco, W.; Chidrala, R. K.;
Park, J. J. Org. Chem. 2009, 1, 2877. (b) Maimone, T. J.; Buchwald. J. Am.
Chem. Soc. 2010, 132, 9990.
(17) (a) Kefalidis, C. E.; Holstein, P. M.; Clot, E.; Baudoin, O. J. Org.
Chem. 2014, 79, 11903. (b) Janody, S.; Jazzar, R.; Comte, A.; Holstein, P.
M.; Vors, J.-P.; Ford, M. J.; Baudoin, O. Chem. - Eur. J. 2014, 20, 11084.
(c) Ratnikov, M. O.; Xu, X.; Doyle, M. P. J. Am. Chem. Soc. 2013, 135,
9475.
REFERENCES
■
(1) (a) Kakiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077.
(b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731.
(c) Jun, C.-H.; Moon, C. W.; Lee, D.-Y. Chem. - Eur. J. 2002, 8, 2423.
(d) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. (e) Stuart, D.
R.; Fagnou, K. Science 2007, 316, 1172−1175. (f) Castro, L. C. M.;
Chatani, N. Chem. - Eur. J. 2014, 20, 4548. (g) Tobisu, M.; Ano, Y.;
Chatani, N. Org. Lett. 2009, 11, 3250. (h) Daugulis, O.; Zaitsev, V. G.
Angew. Chem., Int. Ed. 2005, 44, 4046. (i) Warratz, S.; Kornhaaß, C.;
Cajaraville, A.; Niepotter, B.; Stalke, D.; Ackermann, L. Angew. Chem.,
̈
Int. Ed. 2015, 54, 5513. (j) Chinnagolla, R. K.; Jeganmohan, M. Chem.
Commun. 2014, 50, 2442. (k) Wang, G.-W.; Yuan, T.-T.; Li, D.-D.
Angew. Chem., Int. Ed. 2011, 50, 1380. (l) Xu, X.; Deng, Y.; Yim, D. N.;
Zavalij, P. Y.; Doyle, M. P. Chem. Sci. 2015, 6, 2196.
(2) (a) Wang, X.; Lu, Y.; Dai, H. X.; Yu, J.-Q. J. Am. Chem. Soc. 2010,
132, 12203. (b) Apers, S.; Vlietinck, A.; Pieters, L. Phytochem. Rev. 2003,
2, 201.
D
DOI: 10.1021/acs.orglett.5b03077
Org. Lett. XXXX, XXX, XXX−XXX