Rhodium(III)-amine dual catalysis for the oxidative coupling of aldehydes by directed C-H activation: Synthesis of phthalides

Article abstract of DOI:10.1021/ol402145m

A novel oxidative coupling of aldehydes to form C3-substituted phthalides facilitated by co-operative dual catalysis of a Rh(III) complex and an aryl amine is reported. The reaction involves a cascade ortho C-H activation-insertion-annulation sequence. This methodology is efficient and applicable for the homo- and heterocoupling of various functionalized aldehydes generating the corresponding phthalides in moderate to high yields.

Full text of DOI:10.1021/ol402145m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rhodium(III)-Amine Dual Catalysis for
the Oxidative Coupling of Aldehydes by
Directed CꢀH Activation: Synthesis
of Phthalides
Peng Wen Tan, Nur Asyikin Binte Juwaini, and Jayasree Seayad*
Organic Chemistry, Institute of Chemical and Engineering Sciences, 8 Biomedical Grove,
Neuros, #07-01, Singapore 138665
jayasree_seayad@ices.a-star.edu.sg
Received July 29, 2013
ABSTRACT
A novel oxidative coupling of aldehydes to form C3-substituted phthalides facilitated by co-operative dual catalysis of a Rh(III) complex and an aryl
amine is reported. The reaction involves a cascade ortho CꢀH activationꢀinsertionꢀannulation sequence. This methodology is efficient and
applicable for the homo- and heterocoupling of various functionalized aldehydes generating the corresponding phthalides in moderate to high yields.
Phthalide scaffolds, particularly C3-substituted phthalides,
are prevalent in many natural products as well as biologically
active compounds and are also useful as synthetic intermedi-
ates for complex organic molecules.1 They are traditionally
synthesized by multistep synthetic pathways using stoichio-
metric organic and organometallic reagents.2 Recently, alter-
native transition metal catalyzed methods for the synthesis of
phthalides were developed such as Rh-, Pd-, and Co-cata-
lyzed cascade arylationꢀlactonization of phthalaldehyde3 or
iodo benzoates4 using boron reagents and zinc respec-
tively, Rh- and Ru-catalyzed intramolecular ketone
hydroacylation,5 and Ru-catalyzed reductive cyclization
of 2-arylacylcarboxylates.6 Lately, further elegant methods
based on CꢀH activation have been reported. Synthetic
methods by means of direct CꢀH activation are attractive
from a green chemistry perspective, as they minimize
the necessity of prefunctionalization and thus improve
the overall atom economy of the process in addition to
reducing the use of environmentally hazardous reagents
and generation of wastes.7 For instance, a Ru-catalyzed
oxidative ortho CꢀH bond alkenylation of benzoic acid
(1) (a) Beck, J. J.; Chou, S.-C. J. Nat. Prod. 2007, 70, 891. (b)
Yoganathan, K.; Rossant, C.; Ng, S.; Huang, Y.; Butler, M. S.; Buss,
A. D. J. Nat. Prod. 2003, 66, 1116. (c) Zhou, J.; Gupta, K.; Yao, J.; Ye,
K.; Panda, D.; Giannakakaou, P.; Joshi, H. C. J. Biol. Chem. 2002, 277,
39777. (d) Witulski, B.; Zimmermann, A.; Gowans, N. D. Chem.
Commun. 2002, 2984. (e) Holler, U.; Gloer, J. B.; Wicklow, D. T.
J. Nat. Prod. 2002, 65, 876. (f) Puder, C.; Zeeck, A.; Beil, W. J. Antibiot.
2000, 53, 329. (g) Kobayashi, K.; Maeda, K.; Uneda, T.; Morikawa, O.;
Konishi, H. J. Chem. Soc., Perkin Trans. 1 1997, 443.
(4) Chang, H. T.; Jeganmohan, M.; Cheng, C. H. Chem.;Eur. J.
2007, 13, 4356.
(5) (a) Phan, D. H. T.; Kim, B.; Dong, V. M. J. Am. Chem. Soc. 2009,
131, 15608. (b) Willis, M. C. Angew. Chem., Int. Ed. 2010, 49, 6026. (c)
Omura, S.; Fukuyama, T.; Murakami, Y.; Okamoto, H.; Ryu, I. Chem.
Commun. 2009, 6741.
(2) (a) Hayat, S.; Rahman, A.; Choudhary, M. I.; Khan, K. M.;
Bayer, E. Tetrahedron Lett. 2001, 42, 1647. (b) Hall, J. D.; Duncan-
Gould, N. W.; Siddiqi, N. A.; Kelly, J. N.; Hoeferlin, L. A.; Morrisonb,
S. J.; Wyatt, J. K. Bioorg. Med. Chem. 2005, 13, 1409. (c) Pedrosa, R.;
Sayalero, S.; Vicente, M. Tetrahedron 2006, 62, 10400.
(3) Kuriyama, M.; Ishiyama, N.;Shimazawa, R.; Shirai, R.;Onomura,
O. J. Org. Chem. 2009, 74, 9210.
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r
10.1021/ol402145m
XXXX American Chemical Society

derivatives followed by an oxa-Michael reaction to form
3-alkyl phthalides was reported by Ackermann and
Pospech.8 In 2012, Shi and Li9 demonstrated a Rh-catalyzed
ortho functionalization of essentially electron rich benzoic
acids with aldehydes to form aryl and alkyl substituted
phthalides albeit the reaction required harsh conditions
(48 h at 150 °C). Similarly, with the use of a Rh(III) catalyst,
Ellmann et al.10 developed a method that involves a cascade
ortho CꢀH bond activation and addition of benzimidates to
aldehydes to form various aryl and alkyl substituted phtha-
lides at 110 °C (20 h). Although the reaction was efficient,
presynthesis of the benzimidates was necessary and that
involved multistep protocols using harmful reagents. We
report herein the synthesis of C-3 substituted phthalides
directly by the oxidative homo- and heterocoupling of
readily available aldehydes via dual catalysis using a Rh(III)
complex and an aryl amine under relatively mild conditions.
In our initial studies using benzaldehyde (1a) with
Table 1. Screening of Amine Catalysts for the Oxidative
Homocoupling of Benzaldehyde to 3-Phenyl-1,3-dihydro-2-
benzofuran-1-one
entry
amine catalyst
yield (%)a
1
2
3
4
5
6
7
ꢀ
trace
trace
trace
10
pyrrolidine
cyclohexylamine
N-methylaniline
aniline
28
p-anisidine
trace
69
4-trifluoromethylaniline
11
catalytic [RhCp*Cl2]2 and AgBF4 in the presence of
a NMR yield determined by using CH2Br2 as the internal standard.
Ag2CO3 as the oxidant at 130 °C, we observed the forma-
tion of traces of the phthalide, 3-phenyl-1,3-dihydro-2-
benzofuran-1-one (2a). We envisaged that the presence of
catalytic amounts of amines will be able to enhance the
reactivity by forming imine, iminium, or aminal intermedi-
ates in situ which could act as better directing groups for
the Rh-catalyzed ortho CꢀH activation compared to the
aldehyde functionality itself.12
indeed catalyzed the reaction efficiently giving up to 69%
NMR yield of the phthalide in 1.5 h at130 °C. Tracesofside
products such as N-benzylidene-4-(trifluoromethyl)aniline
(4a) and benzyl alcohol (5a) were also detected by GC-MS
and 1H NMR.
Relatively more nucleophilic amines such as p-anisidine,
pyrrolidine, and cyclohexyl amine gave only traces of
the product. Consequently, further screening and optimi-
zation of reaction parameters were carried out using
4-trifluoromethylaniline as the amine catalyst (Table 2).
The presence of the Rh catalyst particularly [RhCp*Cl2]2
was necessary for the reaction to occur. Reactions without
any rhodium catalyst or by using other Rh(I) and Rh(III)
precursors such as [Rh(cod)Cl]2, Rh(acac)3, and RhCl3
(entries 1ꢀ3, Table 2) did not generate any products. Silver
additives with weakly co-ordinating counterions were also
essential, among which AgOTf and AgSbF6 were found to
work reasonably well, but AgBF4 was the best (entries
4ꢀ6, Table 2). The addition of an oxidant was necessary,
as in the absence of any oxidant only traces of the product
weregenerated. Amongthe oxidantsstudied(entries 8ꢀ10,
Table 2), Ag2CO3 was the most suitable. When molecular
oxygen was used as the oxidant only 15% yield of the
phthalide was obtained while a significant amount of
benzaldehyde was found to be converted to benzoic acid.
The use of simple bases such as KOAc and Cs2CO3 (entries
11 and 12, Table 2), instead of the oxidant, resulted only in
the formation of the corresponding imine, N-benzylidene-
4-(trifluoromethyl) aniline (4a). Diglyme was the best
solvent for this reaction followed by ethyl lactate while
the reaction was also effective under neat conditions. The
yield increased to 78% by lowering the temperature to
90 °C and prolonging the reaction time to 16 h. The
reaction was also found to occur at 70 °C under these
conditions, albeit with a slight drop in the yield (76%).
After attaining the optimized conditions, we explored
the scope of this methodology for the homocoupling of dif-
ferent functionalized aryl aldehydes to form C3-substituted
Accordingly, after screening various primary and sec-
ondary amines (Table 1), we were delighted to discover that
primary aryl amines particularly 4-trifluoromethylaniline
(7) For selected reviews on CꢀH activation: (a) Yamaguchi, J.;
Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960.
(b) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew.
Chem., Int. Ed. 2012, 51, 2. (c) Ackermann, L. Chem. Rev. 2011, 111,
1315. (d) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (e)
€
Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011,
40, 4740T. (f) Lyons, W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (g)
Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O.
Chem.;Eur. J. 2010, 16, 2654. (h) Chen, X.; Engle, K. M.; Wang, D.-H.;
Yu, J. Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (i) Daugulis, O.; Do,
H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (j) Li, C.-J. Acc.
Chem. Res. 2009, 42, 335. (k) Stuart, D. R.; Fagnou, K. Science 2007,
317, 1172. (l) Godula, K.; Sames, D. Science 2006, 312, 67. (m) Kakiuchi,
F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (n) Jia, C.; Kitamura, T.;
Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633. (o) Arndtsen, B. A.;
Bergman, R. G.; Mobley, T. A.; Peterson, T. H. Acc. Chem. Res.
1995, 28, 154.
(8) Ackermann, L.; Pospech, J. Org. Lett. 2011, 13, 4153.
(9) Shi, X.; Li, C.-J. Adv. Synth. Catal. 2012, 16, 2933.
(10) Lian, Y.; Bergman, R. G.; Ellman, J. A. Chem. Sci 2012, 3, 3088.
(11) For selected reports on Rh-catalyzed CꢀH activation: (a)
ꢀ
Brasse, M.; Campora, J.; Ellman, J. A.; Bergman, R. G. J. Am. Chem.
Soc. 2013, 135, 6427. (b) Shi, Z.; Grohmann, C.; Glorius, F. Angew.
Chem., Int. Ed. 2013, 52, 1. (c) Song, G.; Wang, F.; Li, X. Chem. Soc.
Rev. 2012, 41, 3651. (d) Sharma, S.; Park, E.; Park, J.; Kim, I. S. Org.
Lett. 2012, 14, 906. (e) Satoh, T.; Miura, M. Chem.;Eur. J. 2010, 16,
11212. (f) Muralirajan, K.; Parthasarathy, K.; Cheng, C.-H. Angew.
Chem., Int. Ed. 2011, 50, 4169. (g) Patureau, F. W.; Besset, T.; Kuhl, N.;
Glorius, F. J. Am. Chem. Soc. 2011, 133, 2154. (h) Besset, T.; Kuhl, N.;
Patureau, F. W.; Glorius, F. Chem.;Eur. J. 2011, 17, 7167. (i) Park, J.;
Park, E.; Kim, A.; Lee, Y.; Chi, K.-W.; Kwak, J. H.; Jung, Y. H.; Kim,
I. S. Org. Lett. 2011, 13, 4390. (j) Colby, D. A.; Bergman, R. G.; Ellman,
J. A. Chem. Rev. 2010, 110, 624.
(12) (a) Lian, Y.; Hummel, J. R.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2013, 135, 12548. (b) Park, S. H.; Kim, J. Y.; Chang, S.
Org. Lett. 2011, 13, 2372. (c) Kuninobu, Y.; Matsuki, T.; Takai, K. Org.
Lett. 2010, 12, 2948. (d) Fukutani, T.; Umeda, N.; Hirano, K.; Satoh, T.;
Miura, M. Chem. Commun. 2009, 5141.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Optimization Studies on the Homocoupling of Benzaldehyde to 3-Phenyl 1,3-dihydro-2-benzofuran-1-one
rhodium
catalyst
silver
temp
time
(h)
yielda,b
(%)
entry
additive
oxidant
Ag2CO3
solvent
diglyme
(°C)
1
Rh(cod)2Cl2
Rh(acac)3
AgBF4
AgBF4
AgBF4
ꢀ
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
90
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
16
ꢀ
2
Ag2CO3
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
p-xylene
ethyl lactate
DMF
ꢀ
3
RhCl3
Ag2CO3
ꢀ
4
(RhCp*Cl2)2
(RhCp*Cl2)2
(RhCp*Cl2)2
(RhCp*Cl2)2
(RhCp*Cl2)2
(RhCp*Cl2)2
(RhCp*Cl2)2
(RhCp*Cl2)2
(RhCp*Cl2)2
(RhCp*Cl2)2
(RhCp*Cl2)2
(RhCp*Cl2)2
(RhCp*Cl2)2
(RhCp*Cl2)2
(RhCp*Cl2)2
(RhCp*Cl2)2
Ag2CO3
ꢀ
5
AgBF4
AgSbF6
AgOTf
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
Ag2CO3
69
52
62
41
ꢀ
6
Ag2CO3
7
Ag2CO3
8
AgOAc
9
benzoquinone
O2 (1 atm)
10
11
12
13
14
15
16
17
18
19
15
ꢀ
c
ꢀ
d
ꢀ
ꢀ
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
41
57
18
44e
78
76
14
ꢀ
diglyme
diglyme
diglyme
16
70
16
50
16
a Reaction conditions: benzaldehyde (2 mmol), [Rh] (2.5 mol %), silver additive (5 mol %), 4-trifluoromethyl amine (10 mol %), oxidant (1 mmol),
solvent (0.2 mL). b NMR yield, determined by using CH2Br2 as the internal standard. c In the presence of 1 mmol of KOAc (formation of imine was
detected by GC-MS). d In the presence of 1 mmol of Cs2CO3 (formation of imine was detected by GC-MS). e Neat reaction (benzaldehyde, 0.5 mmol).
phthalides (Scheme 1). In general, fairly electron-rich and -
poor aldehydes were effective and functional groups such
as chloro, bromo, fluoro, ester, alkoxy, and trifluoromethyl
Scheme 1. Rh(III)-Amine Catalyzed Homocoupling of Aryl
Aldehydes to Phthalides
were well tolerated. Substitutions at para-, meta-, and
ortho- positions were suitable. Thus, the monosubstituted
aryl aldehydes 1aꢀ1k gave the corresponding C-3 aryl
substituted phthalide derivatives 2aꢀ2j in63ꢀ81% isolated
yields. In the case of the disubstituted benzaldehyde deri-
vative 3-fluoro-4-methoxybenzaldehyde, the correspond-
ing regioisomeric phthalides 2k and 2k0 were formed in a
ratio of 2:1 with an overall yield of 63%.
The scope of heterocoupling of aldehydes using this
protocol was then examined (Scheme 2). Initially, we per-
formed the reaction of two different aryl aldehydes, one
of them having substituted ortho positions. As such, the reac-
tion of benzaldehyde (1a) with 2,6-difluorobenzaldehyde
(1l) in a molar ratio of 1:3 resulted in the corresponding
heterocoupled phthalide product 3-(2,6-difluorophenyl)-
1,3-dihydro-2-benzofuran-1-one (3a) selectively in high
isolated yield (75%). Only a trace amount of 3-phenyl 1,3-
dihydro-2-benzofuran-1-one (2a) (the homocoupled pro-
duct of benzaldehyde) was observed under these conditions.
Under similar conditions, other aldehydes such as 4-methyl,
4-chloro, 4-bromo, 4-methoxy, and 4-carbomethoxy
benzaldehydes as well as 2-naphthaldehyde reacted with
2,6-diflourobenzaldehyde forming the corresponding
heterocoupled phthalide derivatives (3bꢀ3g) in moderate
to high yields (38ꢀ82%). Similarly, 4-methyl benzalde-
hyde (1f) reacted with 5-bromo-2H-1,3-benzodioxole-4-
carbaldehyde (1m) to form 3-(5-bromo-2H-1,3-benzo-
dioxol-4yl)-5-methyl-1-3-dihydro-2-benzofuran-1-one in
32% yield.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Rh(III)-Amine Catalyzed Heterocoupling of
Aldehydes to Phthalides
Scheme 3. Proposed Catalytic Cycle
Upon β-hydride elimination, the Rh(III) intermediate iv
forms the Rh(III) hydride v and the imine intermediate
6 which then hydrolyzes to form the phthalide product.
The RhIIIꢀH species upon reductive elimination of HBF4
results in vi which after oxidation by Ag2CO3 regenerates
the active catalyst back for further turnovers.
In conclusion, we have developed a novel coupling
reaction of aldehydes toward a single step method for
the synthesis of C3-susbtituted phthalides by Rh(III)-
amine dual catalysis. The reaction occurs under oxidative
conditions by the ortho CꢀH activation of the aryl alde-
hyde. This methodology was applied for the homo- and
heterocoupling of aldehydes forming various functiona-
lized aryl and alkyl phthalide derivatives in moderate
to high yields. We are currently studying the scope of this
co-operative dual catalytic strategy toward the enantio-
selective synthesis of C3-susbtituted phthalides and other
heterocyclic motifs by the ortho CꢀH activation of aryl
aldehydes.
Next, the heterocoupling of two different aryl aldehydes
having free ortho CꢀH bonds was studied. Remarkably,
the reaction between 4-methyl benzaldehyde with
2-chloro, 2,5-difluoro, 3,5-difluoro, and 4-trifluoromethyl
benzaldehydes in a molar ratio of 1:3 gave the correspond-
ing phthalide derivatives (3iꢀ3l) in high yields (67ꢀ82%).
However, moderate amounts of homocoupled products
of the excess aldehyde (R0CHO) were also found to form
in these cases (NMR yields of 5ꢀ26% with respect to the
excess aldehyde). More interestingly, aliphatic aldehydes,
e.g. trimethyl acetaldehyde and cyclohexaldehyde, also
reacted with 4-methyl benzaldehyde to form the corre-
sponding phthalide derivatives 3m and 3n respectively
though the yields were modest under these conditions.
The reaction is proposed to proceed through a Rh(III)ꢀ
Rh(I) catalytic cycle (Scheme 3) initiated by the cationic
Rh(III) complex i generated in situ from [RhCp*Cl2]2 and
AgBF4. The rhodium species i then activates the ortho
CꢀH bond of the in situ formed imine derivative 4 forming
the intermediate ii. Insertion of the second aldehyde
molecule in the RhꢀC bond in ii forms the rhodium
species iii followed by the nucleophilic attack of the alkoxy
oxygen on the electrophilic imine carbon leading to iv.
Acknowledgment. This work was funded by the “GSK-
Singapore Partnership for Green and Sustainable Manu-
facturing” and the Institute of Chemical and Engineering
Sciences (ICES), Agency for Science, Technology and
Research (A*STAR), Singapore. We thank Mr. Jeffery
Ng Kang Wai (ICES) for assistance on HRMS.
Supporting Information Available. Experimental pro-
1
cedures and compound characterization data; H, 13C,
and 19F NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX